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Treatment of toxic epidermal necrolysis and a review of six cases
Burns (1990) 16, (2), 97-104
R&d
97
in Greaf Britain
Treatment of toxic epidermal of six cases*
necrolysis and a review
D. J. Ward, E. C. Krzeminska and N. S. B. Tanner The McIndoe
Burns Unit, Queen Victoria Hospital, East Grinstead,
Six casesof drug-inducedtoxicepkkmal necrolysistreatedin a burns unit are presented. The mean skin kxs was 67.3 per cent of the total body surface area. Two patientsdevelopedrenal failure and two had ocular symptoms. The mortalityrate WEIS50 per cent, with two patients dying from septicaemia and onefrom resp?atoy and renalfailure. The diagnosis of toxic epidermal twcrolysisum be conjirmed by &in biopsy. We recommendthat this diseaszis ha&d in a bums unit so that both adequate wound care and essentialintensivesupportivefnxfment can be given. Antibioticsare indicatedonlyfor specificinfectionssuch as septiuzemiaor pneumonia. Steroidshave been shozunto increasegreatly the mortality from septiccomplicationsand are not recommena2. The mortalityranges from 10 per cent to 70 per cent and bad prognosticfactars include increasingage, greater than 50 per cent of body .su+ce skin loss and neutropenia.
Introduction Toxic epidermal necrolysis (TEN) is a rare skin disease in which a widespread erythematous rash leads to bullous necrosis of the epidermis and extensive skin loss. Associated with this is a severe inflammation of the mucous membranes and systemic toxicity. The disease has a very high mortality and poses major management problems which often require the medical and nursing skills of a burns unit. Between 1965 and 1988 six cases of TEN have been treated in the McIndoe Bums Unit at East Grinstead. All were caused by drugs and half of the patients died. The survivors were left with permanent scarring and one patient had severe permanent ocular damage. We present these cases and review the management of this condition and the literature.
Methods A retrospective review of the admissions to the McIndoe Burns Unit during the 23 years between 1965 and 1988 identified 16 patients who had been admitted with a dermatological disease rather than a thermal injury. Six had toxic epidermal necrolysis which had been treated initially by a dermatologist in a district general hospital with intravenous fluids and antibiotics. Four patients were given Part of this paper was presented Burns Association in April 1989.
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0 1990 Butterworth 0305-4179/90/020097--08
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to the Annual Meeting
Co (Publishers) Ltd
of the British
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systemic steroids. After transfer to the Burns Unit treatment with a standard regimen of vitamin supplements, antacids and histamine HZ-receptor antagonists was started. Intravenous resuscitation using colloid and crystalloid was necessary in five patients. In each patient there was a history of drug ingestion shortly before development of an erythematous rash.
Case reports Cl?91 A 55-year-old woman developed an upper respiratory tract infection whilst abroad which responded to a course of ampicillin with no apparent side-effects. Three weeks later she developed a fissure-in-an0 which was treated with Bactrim, a combination of trimethoprim and sulphamethoxazole. After 1 week she developed an erythematous rash on her arms, legs and face typical of TEN. She was treated with oral erythromycin but quickly became unwell with a temperature of 39°C. She was then transferred to the Burns Unit with 22 per cent full thickness and 3 per cent partial thickness skin loss but no mucosal or ocular involvement. Fresh frozen plasma and blood were given and the erythromycin was stopped. The areas of skin loss were dressed regularly with 0.5 per cent aqueous chlorhexidine-soaked gauze with antibiotic prophylaxis (cephalexin) for each dressing change. No steroids were used at any time. Meshed split skin grafts were applied to her buttocks, thighs and legs 7 days and 26 days after admission and the necrotic terminal phalanx of the second toe was amputated. She made a full recovery without other complications and was discharged home 60 days after the onset of the rash. Pressure garment therapy to the scars on her buttocks and lower limbs lasted 2 years. case2 A 21-year-old man took an antimalarial preparation (Fansidor) containing pyrimetharnine and sulphadoxine whilst working abroad. After 10 days he developed a fever and diarrhoea. An erythematous rash appeared on one shoulder 7 days later spreading to his back and legs. Bullae formed with a sore throat and mouth ulceration. He was treated with flucloxacillin and prednisolone but after deteriorating was transferred to the burns unit. He had 80 per cent superficial skin loss, sparing the anterior abdominal wall, buttocks and parts of the limbs. There were no
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mucosal or ocular symptoms. The areas of skin loss were dressed with aqueous chlorhexidine soaks with antibiotic prophylaxis on dressing changes. Twenty-seven days after the rash occurred he became septicaemic and Ps. aeruginosa, K pneumoniae and Acineto&u&r unifralus were found in blood cultures. Despite appropriate antibiotic therapy he developed meningism and died IS days later. ca.sfz3 A 53-year-old man developed an exfoliative dermatitis I week after taking chlorpromazine for depression; 64 per cent of the total body surface area (TBSA) was involved, mainly on the limbs, with mild conjunctivitis of the left eye. The wounds were treated initially with silver nitrate and then potassium permanganate but because of failure to heal he was transferred to the burns unit 3 weeks later. Wound swabs grew multiresistant Staph. umw, proteus species, E. wli and bacteroides species. Aqueous chlorhexidine dressings were applied regularly without antibiotic prophylaxis. The areas of skin loss healed rapidly and he was discharged home fully healed 27 days after the start of the TEN. No further treatment was required. case4 A 55-year-old woman developed erythema on her face and neck and abdominal pain 8 days after taking zimeldine, an antidepressant. Within 48 h the rash desquamated and bilateral conjunctivitis developed (Figtcre~a). She rapidly became comatose despite systemic erythromycin, increasing doses of steroids and intravenous plasma infusions. She was transferred to the burns unit 5 days after developing the rash, unconscious, oliguric and with 95 per cent superficial skin loss (F&4reI&). The steroids were withdrawn gradually. She required ventilation after a respiratory arrest and remained hypotensive and jaundiced. She became septicaemic from Strep. pyogenes, proteus species and Ps. aerugiwsa and died 7 days later despite peritoneal dialysis for anuria and broad-spectrum antibiotic therapy. case5 A 26-year-old woman took Augmentin, a combination of clavulanic acid and amoxycillin, for an upper respiratory tract infection. Two days later she developed an erythematous rash on her face and upper trunk and became photophobic with an associated conjunctivitis. The rash spread rapidly, desquamating 7 days later, 80 per cent of the total body surface area was involved (Figure~~,b),sparing parts of the trunk but with oral and vaginal ulceration. She was treated initially with systemic steroids which were later withdrawn. She then developed a paralytic ileus,
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followed by a septicaernia due to Staph. aurew which responded to ciprofloxacin. She became anuric and underwent haemodialysis for 3 weeks. As her renal function recovered she had two unexpected and almost fatal episodes of Gram-negative septicaemia. She also developed severe ocular problems due to the TEN, Her vision fell to perception of light only in the right eye and to 6160 in the left eye with a marked stromal haze on the right and abnormal epithelium on the left (Figure2c). The eyelid margins showed early keratinization and symblepharon formation. Her sight improved slowly over 18 months to 6/l&3 on the right and 6136 on the left. She has remained on lowdose steroid and antibiotic eyedrops as bulbar inflammation and infiltrates occurred each time these drugs were stopped. She has been left with recurrent ingrowing eyelashes and visible facial scarring accentuated by variable pigmentation in the affected areas. Case6 An 18-year-old woman took Septrin, a combination of trimethoprim and sulphamethoxazole, for cystitis. After 48 h she became unwell and developed a sore throat. Two days later the typical rash of TEN appeared. She was treated with systemic steroids and transferred to our Unit the next day with 60 per cent superficial skin loss over the trunk and upper limbs, bilateral symblepharon formation and conjunctival scarring. The ocular symptoms were treated with regular glass rodding and antibiotic and steroid eyedrops. Eleven days after the onset of the rash she developed a Staph. nureussepticaemia which did not respond to antibiotics and she died 2 days later.
Results Each of these six patients is thought to have developed TEN as a result of drug administration. This is based on the appearance of the typical erythematous rash within 3 weeks of ingestion of the suspect drug with no predisposing factors such as immunosuppression or concurrent disease. In five out of the six cases the rash developed within 8 days. Patient 2 became unwell 10 days after starting antimalarial prophylaxis and developed a rash a further 7 days later. The drugs involved are listed in TableI. Three contained a sulpha- component. Antibiotics had been prescribed in three cases for relatively minor illnesses (fissure-in-ano, upper respiratory tract infection and cystitis) and one of these patients (Case 6) died. Table II summarizes the course of the disease in each
Figure 1. Case 4. a, Conjunctivitis. b, On admission to the bums unit showing extensive exfoliation.
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Wiu.d et al.: Toxic epidermalnecrolysis
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Figure2. Case5. a, On admission with facial and eyelid epidermal loss and oral mucositis. b, Widespread exfoliation of the central trunk and coalescing vesicles on the lateral chest and abdominal walls and the suprapubic area. c, Stromal haze and vascularization of the cornea.
The mean onset of the rash after taking the drug was 7.5 days. The date of first admission to hospital varied from the day after the rash appeared (patient 6) to 17 days afterwards (patient 2). Transfer to the burns unit occurred between I and 7 days after admission to hospital (mean 4 days). For those who survived the mean inpatient stay was
patient.
50.7 days.
Table III gives a summary of the six patients in this series. Four were female and two were male, with a mean age of 38 years. The mean percentage total body surface area of skin loss was 67.3 per cent.
The mortality rate in this series of patients was SO per cent. The two youngest patients (18 and 21 years old) died, one following antimalarial prophylaxis and one following cystitis. The mean day of death was 25.7 days after the rash. Two patients died from septicaemia: Ps. aemginosa, K pneumoniae and Acinetobacter anitratus in Case2 and Staph.
aureus in Case 6. One patient (Case 4) died from respiratory and renal failure. Renal failure developed in two patients: Case.5 became anuric and required dialysis, although she ultimately survived, and Case4 was oliguric on arrival at our unit, developing renal failure 1 day before her death. The long-term affects of TEN were varied in the patients who recovered. Case I developed hypertrophic scars on the legs which required 2 years of pressure garment therapy to achieve a satisfactory cosmetic result. Case3 had mild permanent scarring of the affected areas on the limbs and the trunk but no permanent ocular damage. Case 5 had considerable scarring with patchy hypopigmentation and hyperpigmentation of the skin and still has severe ocular problems with permanently reduced visual acuity. She will probably remain on ophthalmic medication for life to prevent further deterioration in her eyesight.
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Table I. The drugs involved in the six cases of toxic epidermal necrolysis Case no.
: 3 4 5 6
Drug
Reason for treatment
Trimethoprim and sulphamethoxazole Pyrimethamine and sulphadoxine Chlorpromazine Zimelidine Amoxycillin and clavulanic acid Trimethoprim and sulphamethoxazole
Fissure-in-ano Antimalarial prophylaxis Depression Depression Upper respiratory tract infection Cystitis
Table II. Summary of the course of the disease Case no.
Time between ingestion of drug and onset of rash (days)
Time between onset of the rash and admission to hospital
7 17
13 17 14 2 3 1
: 3 4 5 6
: 2 4
(days)
Table III. Details of the six cases of toxic epidermal necrolysis Case no. 1 2 3 4 5 6
Sex
Age (yr)
%TBSA
Female Male Male Female Female Female
55 21 53 55 26 18
25 80 64 E
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Outcome
Survived Died Survived Died Survived Died
‘Necrolysis as percentage of total body surface area.
Discussion Toxic epidermal necrolysis is a severe inflammatory bullous disease of the skin often associated with conjunctivitis and mucositis but usually unrelated to staphylococcal infection. It has been recognized clinically for many years and was originally known as ‘erythema multiforme major’ or ‘erythema multiforme exuditavum’. In 1956 Lye11 redescribed necrolysis’, the disease, renaming it ‘toxic epidennal although it is often known as ‘Lyell’s disease’ (Lyell, 1956). He initially included cases caused by staphylococcal infection but later classified these separately as the ‘staphylococcal scalded skin syndrome’ (Lyell, 1979). The mechanisms responsible for the epidermal necrolysis are not well understood although it is likely that delayed hypersensitivity reactions involving cell-mediated mechanisms rather than humoral immunity are the cause of drug-induced TEN (Heng, 1985). TEN may be caused by the ingestion of drugs, may be idiopathic, or may very rarely be caused by staphylococcal infection. In idiopathic TEN recurrent attacks occur without any apparent cause in middle-aged or elderly females. Here the long-term prognosis is extremely poor as the attacks increase in severity. TEN due to staphylococcal infection is very rare and in an extensive review LyeU (1956) found only 13 cases. Most of these patients were male and nearly all either had underlying diseases such as renal failure, pneumonia or Hodgkin’s disease, or were immunosuppressed.
Time between admission and transfer to the burns unit (days) 1 7 ; 4 2
inpatient stay in the burns unit (days) 49 18 6 13 58 13
A similar cliical picture to TEN is seen in the StevensJohnson syndrome, a severe form of erythema multiforme (Figure3). First described in two children, the StevensJohnson syndrome is more common in children and young adults than in older patients (Stevens and Johnson, 1922). It is usually considered to be a separate disease from TEN, although Lyell(1979) believes that TEN is simply the most severe form of erythema multifonne. Both the StevensJohnson syndrome and TEN may be caused by similar drugs, but there are many more causes recorded of the Stevens-Johnson syndrome than of TEN (Champion, 1986). In both conditions there are lesions at the dermal-epidermal junction and mucosal involvement. However, in the Stevens-Johnson syndrome the bullae tend to be localized rather than involving the whole epidermis and the skin reaction may be mild compared to the extensive mucositis (Figrrre4). In the Stevens-Johnson syndrome there is a lymphohistiocytic infiltrate around the blood vessels in the upper dermis which are spared in TEN. The staphylococcal scalded skin syndrome occurs almost entirely in the newborn and young child and is due to an epidermolytic exotoxin produced by Staph. attrars, often of phage group 2. It is also known as Ritter’s disease after
Figure 3. A l&year-old girl with early Stevens-Johnson syndrome showing typical vesicle foormationon the abdomen and coalesced vesicles on the chest wall and nedc
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Ward et al.: Toxic epidermal necrolysis
Figure 4. Severe oral mucositis in Stevens-Johnson
syndrome.
Ritter’s first description of 297 cases in 1878 (Van Rittershain, 1878). The staphylococcal scalded skin syndrome occurs in adults only rarely and in these patients there is almost invariably a predisposing factor such as immunosuppression, renal failure, leukaemia, Hodgkin’s disease, other malignancy or alcoholism (Dowsett, 1984). The exotoxin is very specific for the granular layer of the epidermis where it causes an intraepidermal split with superficial bullae. TEN has a deeper plane of cleavage, thus enabling differentiation of TEN and the staphylococcal scalded skin syndrome to be made by a skin biopsy. Adverse drug reactions are the commonest cause of TEN. Sulphonamide-containing drugs are most frequently implicated in this syndrome (Guillaume et al., 1987). Other drugs involved include anticonvulsants, non-specific antiinflammatory drugs, barbiturates and penicillins (Heng, 1985). It is however difficult to prove conclusively that TEN has been caused by a drug. The occurrence of a rash within 3 weeks of taking a drug is highly suggestive of an adverse drug reaction, especially if the eruption occurs within 48 h of administration of a drug which caused a similar reaction on a previous occasion. Deliberate readministration of the drug to establish a repeat reaction is both dangerous and unethical but tests are now available which can help in establishing a causative relationship between the rash and the suspected drug. Lymphocyte transformation tests are sensitive and specific, giving information in both hurnoral as well as cellular hypersensitivity (Krebs, 1986). Positive results are only obtained however with certain groups of
drugs such as penicillins and sulphonamides, others giving only slight sensitization of lymphocytes which makes interpretation of the results difficult. The diagnosis of TEN is made on the history of the illness and the appearance of the rash. It can be confirmed by a biopsy of the involved skin. Fever, malaise and pharyngitis often precede the onset of erythema, but in severe cases this prodromal phase may be absent. Erythema usually appears first on the limbs and face, either as a diffuse redness of the skin or as discrete papules with dark centres and a red margin (target lesions). There is disagreement about the significance of these target lesions which are also characteristic of erythema m&for-me. Lyell (1976) believes that their presence in TEN indicates that TEN is therefore the most severe form of erythema multiforme. Goldstein et al. (1987) however define TEN as widespread blistering with erythema and no target lesions. Small blisters or large bullae form, usually within 2448 h. During this phase a mild shearing force applied to the skin causes separation of the epidermis from the dermis (the Nikolsky sign). Mucositis of the oropharynx, vagina, rectum, urethra and eye, ranging from mild oral ulceration to extensive erosion and crusting, occurs. The patient becomes toxic and pyrexial(38-40°C). If the patient survives, healing occurs by re-epithelialization from the hair follicles between 10 and 28 days after epidennal shedding, as in a superficial bum. TEN can be differentiated from the staphylococcal scalded skin syndrome by histological examination of a skin biopsy. In TEN there is vacuolization with eosinophilic bodies in the upper malpighian layers, progressing to widespread necrosis and neutrophil infiltration. There are only mild vascular changes and few dermal infiltrates (Rasmussen, 1980). The plane of cleavage is between the epidermis and the dermis, whereas in the staphylococcal scalded skin syndrome the disruption is in the superficial epidermis. Irnmunofluorescence studies of skin biopsies in TEN are unhelpful as there are few immunological deposits. Westly and Wechsler found no deposits in 63 per cent of their patients with TEN and only very faint deposits of IgG and IgM in the rest (Westly and Wechsler, 1984). In the TEN-like syndrome in acute graft-versus-host disease there is linear deposition of IgG, IgM, IgA and C3 at the dermo-epidermal junction (Spielvogel et al., 1976). It is widely recommended that patients with TEN should be managed in a bums unit where both the wound care needed to prevent further skin injury and the extensive supportive treatment required in these patients can be provided (Anon, 1984; Adzick et al., 1985; Heimbach et al., 1987; Pruitt, 1987). The principles of care of the TEN wound are the same as for a superficial burn: protection of the exposed surface from further damage and prevention of extension of the depth of the wound (Pruitt, 1987). The wound is cleaned with normal saline, removing all loose skin and blisters. Rubbing the skin will loosen any epithelium which is in the early stages of sloughing. If a crust of exudate has already formed on the areas of skin loss this is removed with a detergent and the area is then rinsed with saline. Treatment following cleansing varies: we use 0.5 per cent aqueous chlorhexidine soaks moistened and changed regularly. Halebian et al. (1986) recommend 0.5 per cent silver nitrate soaks but care must be taken because of absorption of the silver nitrate through a large raw area. Immediate cover with a biological dressing to prevent dessication and to provide a good environment for healing
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is widely advocated. Heimbach treated 19 patients with a mean skin loss of 75 per cent total body surface area with porcine cutaneous xenograft, replacing any dislodged or purulent xenograft with new xenograft (Heimbach et al., 1987). Others have also successfully used cadaver skin (Davidson and Hunt, 1981; Birchall et al., 1987), amniotic membrane (Artz et al., 1972) and synthetic dressings such as Biobrane (Halebian et al., 1983). As well as controlliig heat and fluid loss these biological dressings reduce the often severe pain but most are opaque, allowing local infection to arise undetected with the consequent risk of increasing the depth of the wound. Topical antibiotics such as neomycin are hazardous because of increased percutaneous absorption. Silver sulphadiazine cream should also be avoided as sulphonamides are one of the commonest causes of TEN. Silver sulphadiazine may also exacerbate the neutropenia seen in many of these patients (Marvin et al., 1984). Intravenous fluid requirements have been reported both as less than a thermal injury of the same area and as more than expected (Adzick et al., 1985). Low fluid needs are thought to be due to the slower onset of fluid loss in TEN than in a burn, allowing more oral replacement (Halebian et al., 1983). and also to the failure of release of acute-phase reactants in TEN which in burns cause massive oedema (Heimbach et al., 1987). High fluid requirements may be needed with prolonged desquamation which can take up to 3 weeks. Oral fluid intake is often poor because of the oropharyngeal mucositis. Fluid and heat loss are high in patients treated with impregnated soaks or on an air-fluidized bead bed. Other parameters which need careful monitoring are electrolyte levels, nitrogen balance for which enteral or even parenteral feeding will be required, and serum albumin levels which may fall dramatically. Renal dysfunction is seen in up to 50 per cent of patients and is usually due to acute tubular necrosis as a result of hypovolaemia. Occasionally a progressive membranous glomerulonephritis can develop up to 5 years after TEN (Krumlovsky et al., 1974). Control of infection is vital as most patients die from sepsis. The use of prophylactic broad-spectrum antibiotics in the treatment of TEN is controversial. Bjomberg advocated their use, reporting that all the patients in his series who were treated routinely with antibiotics and steroids survived, whereas some patients who did not receive antibiotics died from staphylococcal sepsis or bronchopneumonia (Bjomberg, 1973). The emergence of highly resistant strains of bacteria is a problem if antibiotics are used routinely as Halebian showed in his series: nine out of 11 patients who died from sepsis had organisms resistant to the broadspectrum antibiotics which they were receiving (Halebian et al., 1983). Most authors recommend that parenteral antibiotics should be prescribed only for specific infections such as septicaemia or pneumonia (Rasmussen, 1980; Heimbach et al., 1987). The use of prophylactic antibiotics where the risk of sepsis is particularly high, as in patients who are neutropenic, and where there is a particularly heavy single strain bacterial colonization of the skin has also been recommended (Revuz et al., 1987). The high incidence of pneumonia is thought to be related to the aspiration of sloughed mucosa, shallow breathing from chest wall pain and atelectasis (Heimbach et al., 1987). Septicaemia can occur rapidly and unexpectedly and is often late in the disease. Staph. aurats is the commonest cause of early sepsis (Halebian et al., 1986) and we routinely give
Burns (1990) Vol. 16/No. 2
appropriate prophylactic antibiotics (currently ciprofloxacin) before and after dressing changes. Gram-negative organisms such as Ps. aemgirwse, K pneumoniae and E. wli are the most common cause of late septicaemia and are especially common in patients treated with steroids (Halebian et al., 1986). Septicaemia is treated with intravenous antibiotics covering both Gram-positive and Gram-negative organisms, amending the choice of antibiotic, if necessary, when the results of blood cultures are available. Sulphonamide-containing drugs should be avoided in all cases and penicillins should be given only if they are not suspected to be the cause of the necrolysis. High-dose steroids mask the clinical signs of septicaemia and antibiotics should be given at the first indirect sign of sepsis such as hypothermia, fever, diminishing level of consciousness, falling urine output or any sudden deterioration in the patient’s condition (Revuz et al., 1987). The treatment of TEN contrasts with the management of the staphylococcal scalded skin syndrome where the immediate parenteral administration of a penicillinase-resistant antibiotic in high doses is essential (Dow&t, 1984). As the staphylococcal scalded skin syndrome is due to toxin production the antibiotics may only prevent further progression of the epidermal shedding. There has been much discussion about the use of steroids in the treatment of TEN and it is now generally agreed that steroids have only a very limited role. They are indicated in progressive membranous glomerulonephritis where they may limit progression of the disease (Pruitt, 1987). If steroid therapy has been started at another hospital it should be reduced rapidly and withdrawn (Heimbach et al., 1987). Halebian compared a group of 15 patients who had received steroid therapy with 15 patients in which no steroids were given (Halebian et al., 1986). In patients who developed sepsis there was a 91 per cent mortality if steroids were used compared to 56 per cent in those who were not given them. The overall mortality was 66 per cent with steroid use and 33 per cent without. The untreated group also had a reduced incidence of gastrointestinal epithelial ulceration, candida sepsis and an increased survival after septic complications. The incidence of septic complications was not significantly different but the causative organisms differed markedly between the two groups: of the steroid-treated group with sepsis, 73 per cent had Gram-negative organisms on blood culture, and only 18 per cent had Gram-positive organisms, with 18 per cent infected by candida species. In the patients in which steroids were not used, 44 per cent had Grampositive and only 56 per cent had Gram-negative sepsis, with no cases of candida sepsis. As steroids suppress the signs of sepsis the authors thought that the better survival in their patients who were not given steroids might be partly because of earlier detection of septic complications and hence earlier treatment. Kim et al. (1983) also showed a much higher mortality in patients treated with steroids (80 per cent) compared to those who did not receive them (20 per cent). TEN has been reported in patients already receiving high-dose steroids (Revuz et al., 1987) and bullae formation has also continued in patients on high-dose steroids (Rasmussen, 1980; Halebian et al., 1983). Halebian et al. (1983) found no evidence that steroid treatment halted the progression of bullae formation, epidennal shedding and mucosal erosions. In contrast, Bjomberg (1973) controlled the epidermal necrolysis in 15 patients with 200-800mg of hydrocortisone daily. Haematological abnormalities are common in TEN.
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Kvasnicka used a wide range of coagulation studies ~IIeight patients with TEN and showed the presence of disseminated intravascular coagulation (DIC) in all the patients (Kvasnicka et al., 1979). DIC developed in 27 per cent of the patients who died in the series reported by Halebian et al. (1983). Neutropenia due to a granubcytopenia commonly occurs 2-5 days after development of the rash. Persistent granulocytopenia is a very poor prognostic sign according to Westly and Wechsler (1984). All their patients in whom granulocytopenia persisted for longer than 7 days died. Neutropenia, lymphocytopenia and granulocytopenia were also found by Revuz et al. (1987) to be a bad prognostic factor. Nearly all their patients with a neutrophil count of less than 1.0 x 10” per litre died. Reverse isolation nursing techniques are necessary as sepsis is extremely common in these patients. Halebian et al. (1986) found Gram-negative sepsis present in 92 per cent of patients with leucopenia. A normocytic anaemia characterized by a progressive drop in haemoglobin level and a lymphopenia also occurs very often (Goens et al., 1986). The lymphopenia appears early, sometimes before the skin signs, and is profound. It recovers very slowly. It has been suggested that the lymphopenia and anaemia are related to a disorder of the cell-mediated immunity system which may be the cause of TEN (Goens et al., 1986). Ocular problems can be severe in TEN and require urgent treatment (Rasmussen, 1980). TEN produces a conjunctivitis which destroys the goblet cells, similar to that found in the Stevens-Johnson syndrome. Tarsorrhaphy may be necessary to arrest cornea1 opacification due to invasion of the cornea by deep vessels. The severity of the ophthalmic complications is related to the severity of the disease in its acute phase rather than the local treatment used on the eyes (Arstikaitis, 1973). Synechiae are prevented by the regular separation of the eyelids from the conjunctiva using a glass rod lubricated with a non-medicated ophthalmic ointment or chloramphenicol ointment. Further application of chloramphenicol ointment minimizes the risk of infection and also forms a layer between the lid and the globe. Other external complications include lid keratinization, ingrowing eyelashes and tear duct atrophy. Neovascularization and thinning of the cornea with infection, infiltration, ulceration and perforation may occur. Local application of prednisolone and antibiotic drops such as gentamicin help, but complications may still arise. Howard (1963) found that poor long-term visual function occurred in 9 per cent of patients with the Stevens-Johnson syndrome. Other aspects of treatment include meticulous oral hygiene to prevent parotitis, a common complication. Careful insertion of urethral catheters and cleansing of an indwelling catheter are important as the urethral mucosa is often involved, leading to acute or chronic stricture. Intravenous lines should be avoided if possible because of the high risk of infection. Halebian et al. (1986) found that 56 per cent of catheter tips were infected on culturing. The mortality of TEN remains high. Revuz et al. (1987) reviewed the 350 patients in the 10 largest reported series and found an overall mortality rate of 28.6 per cent (range 10.3-70 per cent). In their own series of 87 patients several prognostic factors were significant. The mortality rose with increasing age, extension of the area of necrolysis, elevation of the blood urea, creatinine and glucose levels, neutropenia, lymphopenia and thrombocytopenia. Halebian et al. (1986) found a significant improvement in mortality if steroids were not used, but skin loss of greater than SO per cent,
increasing age and the presence of associated diseases increased the death rate. TEN is a disease carrying a high mortality, usually due to sepsis. A burns unit has wide experience in the management of extensive areas of skin loss and can provide both the specialist wound care necessary to encourage healing and to minimize infection and also can treat the serious complications of the disease. We strongly recommend the early referral of patients with TEN to the nearest bums unit before complications occur.
Acknowledgements We would like to thank the following for referring their patients to us and for their help in the management of this disease: Drs D. France, K. Liddell, P. Sharpstone, D. Whitfield, I. Wilson and the Renal Unit at Guy’s Hospital. We would also like to thank the Department of Medical Illustration at the Queen Victoria Hospital for the illustrations.
References Adzick N. S., Kim S. H., Bondoc C. C. et al. (1985) Management of toxic epidennal necrolysis in a pediatric bum center. Am. 1. Dis. Child. 139,499. Anon. (1984) Management of toxic epidermal necrolysis. Lancefii,
1250. Arstikaitis M. J. (1973) Ocular aftermath of Stevens
Johnson
syndrome. Arch. Ophfhalmol. 90, 376. Artz C. P., Rittenbury M. S. and Yarbrough
D. R. (1972) An appraisal of allografts and xenografts as biological dressings for wounds and bums. Ann. Surg. 175,934.
Birchall N., Langdon R., Cuono C. et al. (1987) Toxic epidermal necrolysis: an approach to management using cryopreserved allograft skin. 1. Am. Ad. Dermfol. 16, 368.
Bjomberg A. (1973) 15 cases of toxic epidermal necrolysis (Lyell). Acfa Dtnnafol. Vinereol.53, 149.
Champion R. H. (1986) Disorders
affecting small blood vessels: erythema and telangiectasia. In: Rook A. (ed), 7kfbook of Dermatology,vol. 2. Oxford: Blackwell Scientific, p. 1085. Davidson B. L. and Hunt J. L. (1981) Human cadaver homograft in toxic epidermal necrolysis. J. Bum Care R&&if. Z, 94. Dowsett E. G. (1984) The staphylococcal scalded skin syndrome. J. Hosp. Infect.5, 347. Goens J., Song M., Fondu P. et al. (1986) Haematological disturbances and immune mechanisms in toxic epidermal necrolysis. Br. 1. Dermatol. 114, 255. Goldstein S. M., Wintroub B. W. and Elias P. M. (1987) Toxic epidermal necrolysis: unmuddying the waters. Arch. Dermafol. 123,1153. Guillaume J-C., Rougeau J-C., Revuz J. et al. (1987) The culprit drugs in 87 cases of toxic epidermal necrolysis (Lyell’s syndrome). Arch. Dermatol. 123, 1166. Halebian P., Corder V., Hemdon D. et al. (1983) A burn center experience with toxic epidermal necrolysis. J. Bum Care Rehbil. 4,176. Halebian P. H., Madden M. R., Finklestein J. L. et al. (1986) Improved bum center survival of patients with toxic epidennal necrolysis managed without corticosteroids. Ann. Surg. 204, 503. Heimbach D. M., Engrav L. H., Marvin J. A. et al. (1987) Toxic epidermal necrolysis: a step forward in treatment. J.A.M.A. 257,217l.
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Heng M. C. Y. (1985) Drug-induced toxic epidennal necrolysis. Br. 1. Dermato1.113,597. Howard G. (1963) The Stevens-Johnson syndrome, ocular prognosis and treatment. Am. J Ophthulmol.55,893. Kim P. S., Goldfarb I. W., Gaisford J. C. et al. (1983) StevensJohnson syndrome and toxic epidermal necrolysis: a pathophysiological review with recommendations for a treatment protocol.]. Bum Care Rehabil.4, 91. Krebs A. (1986) Drug eruptions: pathogenesis, diagnosis and clinical manifestations. In: Champion R. H. (ed.), RecentAdvances in Dermatology.Edinburgh: Churchill Livingstone, p. 155. Krumlovsky F. A., Del Greco F., Herson P. B. et al. (1974) Renal disease associated with toxic epidermal necrolysis (LyelJ’s disease). Am. 1. Med. 57, 817. Kvasnkka J., Rezac J., Svejda J. et al (1979) Disseminated intravascular coagulation associated with toxic epidermal necrolysis (Lyell’s syndrome). Br. J Dermutol. 120,721. Lyell A. (1956) Toxic epidennaJ necrolysis: an eruption resembling scakiing of the skin. Br. J Dermafol. 68,355. LyelJ A. (1979) Toxic epidermal necrolysis (the scalded skin syndrome): reappraisal. Br. J Dnmatol. 100, 69. Marvin J. A., Heirnbach D. M., Engrav L. H. et al. (1984) Improved treatment of the Stevens-Johnson syndrome. Arch. Surg. 119, 601.
Pruitt B. A. (1987) Bum treatment for the unburned. 1.A.M.A. 25 7, 2207. Rasmussen J. (1980) Toxic epidermal necrolysis. Med. Clin. North Am. 64, 901. Revw J., Penso D.. Roujean J-C. et al. (1987)Toxic epidermal necrolysis: clinical findings and prognosis factors in 87 patients. Arch. Dermufol. 123,1160. Spielvogel R. L., Ullman S. and Goltz R. W. (1976) Skin changes in graft-versus-host disease. South. Med. 1. 69, 1277. Stevens A. M. and Johnson F. C. (1922) A new eruptive fever associated with stomatitis and opthalmia. Am. J. Dis. Child. 24, 526. Von Rittershain G. R. (1878) Die exfoliative dermatitis jungere saulinge. Cent. Z. Kinderhtd. 2, 3. Westly E. D. and Wechsler H. L. (1984) Toxic epidermal necrolysis. Granulocytic leucopenia as a prognostic indicator. Arch. Dermdol. 120,721.
Paper accepted 19 September
1989.
Currespondenreshould be aci.fd to: Mr D. J. Ward, The M&doe Burns Unit, Queen Victoria Hospital, Holtye Road, East Grinstead, West Sussex, RH19 3DZ, UK.
R&d
97
in Greaf Britain
Treatment of toxic epidermal of six cases*
necrolysis and a review
D. J. Ward, E. C. Krzeminska and N. S. B. Tanner The McIndoe
Burns Unit, Queen Victoria Hospital, East Grinstead,
Six casesof drug-inducedtoxicepkkmal necrolysistreatedin a burns unit are presented. The mean skin kxs was 67.3 per cent of the total body surface area. Two patientsdevelopedrenal failure and two had ocular symptoms. The mortalityrate WEIS50 per cent, with two patients dying from septicaemia and onefrom resp?atoy and renalfailure. The diagnosis of toxic epidermal twcrolysisum be conjirmed by &in biopsy. We recommendthat this diseaszis ha&d in a bums unit so that both adequate wound care and essentialintensivesupportivefnxfment can be given. Antibioticsare indicatedonlyfor specificinfectionssuch as septiuzemiaor pneumonia. Steroidshave been shozunto increasegreatly the mortality from septiccomplicationsand are not recommena2. The mortalityranges from 10 per cent to 70 per cent and bad prognosticfactars include increasingage, greater than 50 per cent of body .su+ce skin loss and neutropenia.
Introduction Toxic epidermal necrolysis (TEN) is a rare skin disease in which a widespread erythematous rash leads to bullous necrosis of the epidermis and extensive skin loss. Associated with this is a severe inflammation of the mucous membranes and systemic toxicity. The disease has a very high mortality and poses major management problems which often require the medical and nursing skills of a burns unit. Between 1965 and 1988 six cases of TEN have been treated in the McIndoe Bums Unit at East Grinstead. All were caused by drugs and half of the patients died. The survivors were left with permanent scarring and one patient had severe permanent ocular damage. We present these cases and review the management of this condition and the literature.
Methods A retrospective review of the admissions to the McIndoe Burns Unit during the 23 years between 1965 and 1988 identified 16 patients who had been admitted with a dermatological disease rather than a thermal injury. Six had toxic epidermal necrolysis which had been treated initially by a dermatologist in a district general hospital with intravenous fluids and antibiotics. Four patients were given Part of this paper was presented Burns Association in April 1989.
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0 1990 Butterworth 0305-4179/90/020097--08
&
to the Annual Meeting
Co (Publishers) Ltd
of the British
UK
systemic steroids. After transfer to the Burns Unit treatment with a standard regimen of vitamin supplements, antacids and histamine HZ-receptor antagonists was started. Intravenous resuscitation using colloid and crystalloid was necessary in five patients. In each patient there was a history of drug ingestion shortly before development of an erythematous rash.
Case reports Cl?91 A 55-year-old woman developed an upper respiratory tract infection whilst abroad which responded to a course of ampicillin with no apparent side-effects. Three weeks later she developed a fissure-in-an0 which was treated with Bactrim, a combination of trimethoprim and sulphamethoxazole. After 1 week she developed an erythematous rash on her arms, legs and face typical of TEN. She was treated with oral erythromycin but quickly became unwell with a temperature of 39°C. She was then transferred to the Burns Unit with 22 per cent full thickness and 3 per cent partial thickness skin loss but no mucosal or ocular involvement. Fresh frozen plasma and blood were given and the erythromycin was stopped. The areas of skin loss were dressed regularly with 0.5 per cent aqueous chlorhexidine-soaked gauze with antibiotic prophylaxis (cephalexin) for each dressing change. No steroids were used at any time. Meshed split skin grafts were applied to her buttocks, thighs and legs 7 days and 26 days after admission and the necrotic terminal phalanx of the second toe was amputated. She made a full recovery without other complications and was discharged home 60 days after the onset of the rash. Pressure garment therapy to the scars on her buttocks and lower limbs lasted 2 years. case2 A 21-year-old man took an antimalarial preparation (Fansidor) containing pyrimetharnine and sulphadoxine whilst working abroad. After 10 days he developed a fever and diarrhoea. An erythematous rash appeared on one shoulder 7 days later spreading to his back and legs. Bullae formed with a sore throat and mouth ulceration. He was treated with flucloxacillin and prednisolone but after deteriorating was transferred to the burns unit. He had 80 per cent superficial skin loss, sparing the anterior abdominal wall, buttocks and parts of the limbs. There were no
98
mucosal or ocular symptoms. The areas of skin loss were dressed with aqueous chlorhexidine soaks with antibiotic prophylaxis on dressing changes. Twenty-seven days after the rash occurred he became septicaemic and Ps. aeruginosa, K pneumoniae and Acineto&u&r unifralus were found in blood cultures. Despite appropriate antibiotic therapy he developed meningism and died IS days later. ca.sfz3 A 53-year-old man developed an exfoliative dermatitis I week after taking chlorpromazine for depression; 64 per cent of the total body surface area (TBSA) was involved, mainly on the limbs, with mild conjunctivitis of the left eye. The wounds were treated initially with silver nitrate and then potassium permanganate but because of failure to heal he was transferred to the burns unit 3 weeks later. Wound swabs grew multiresistant Staph. umw, proteus species, E. wli and bacteroides species. Aqueous chlorhexidine dressings were applied regularly without antibiotic prophylaxis. The areas of skin loss healed rapidly and he was discharged home fully healed 27 days after the start of the TEN. No further treatment was required. case4 A 55-year-old woman developed erythema on her face and neck and abdominal pain 8 days after taking zimeldine, an antidepressant. Within 48 h the rash desquamated and bilateral conjunctivitis developed (Figtcre~a). She rapidly became comatose despite systemic erythromycin, increasing doses of steroids and intravenous plasma infusions. She was transferred to the burns unit 5 days after developing the rash, unconscious, oliguric and with 95 per cent superficial skin loss (F&4reI&). The steroids were withdrawn gradually. She required ventilation after a respiratory arrest and remained hypotensive and jaundiced. She became septicaemic from Strep. pyogenes, proteus species and Ps. aerugiwsa and died 7 days later despite peritoneal dialysis for anuria and broad-spectrum antibiotic therapy. case5 A 26-year-old woman took Augmentin, a combination of clavulanic acid and amoxycillin, for an upper respiratory tract infection. Two days later she developed an erythematous rash on her face and upper trunk and became photophobic with an associated conjunctivitis. The rash spread rapidly, desquamating 7 days later, 80 per cent of the total body surface area was involved (Figure~~,b),sparing parts of the trunk but with oral and vaginal ulceration. She was treated initially with systemic steroids which were later withdrawn. She then developed a paralytic ileus,
Burns (1990) Vol. 16/No. z
followed by a septicaernia due to Staph. aurew which responded to ciprofloxacin. She became anuric and underwent haemodialysis for 3 weeks. As her renal function recovered she had two unexpected and almost fatal episodes of Gram-negative septicaemia. She also developed severe ocular problems due to the TEN, Her vision fell to perception of light only in the right eye and to 6160 in the left eye with a marked stromal haze on the right and abnormal epithelium on the left (Figure2c). The eyelid margins showed early keratinization and symblepharon formation. Her sight improved slowly over 18 months to 6/l&3 on the right and 6136 on the left. She has remained on lowdose steroid and antibiotic eyedrops as bulbar inflammation and infiltrates occurred each time these drugs were stopped. She has been left with recurrent ingrowing eyelashes and visible facial scarring accentuated by variable pigmentation in the affected areas. Case6 An 18-year-old woman took Septrin, a combination of trimethoprim and sulphamethoxazole, for cystitis. After 48 h she became unwell and developed a sore throat. Two days later the typical rash of TEN appeared. She was treated with systemic steroids and transferred to our Unit the next day with 60 per cent superficial skin loss over the trunk and upper limbs, bilateral symblepharon formation and conjunctival scarring. The ocular symptoms were treated with regular glass rodding and antibiotic and steroid eyedrops. Eleven days after the onset of the rash she developed a Staph. nureussepticaemia which did not respond to antibiotics and she died 2 days later.
Results Each of these six patients is thought to have developed TEN as a result of drug administration. This is based on the appearance of the typical erythematous rash within 3 weeks of ingestion of the suspect drug with no predisposing factors such as immunosuppression or concurrent disease. In five out of the six cases the rash developed within 8 days. Patient 2 became unwell 10 days after starting antimalarial prophylaxis and developed a rash a further 7 days later. The drugs involved are listed in TableI. Three contained a sulpha- component. Antibiotics had been prescribed in three cases for relatively minor illnesses (fissure-in-ano, upper respiratory tract infection and cystitis) and one of these patients (Case 6) died. Table II summarizes the course of the disease in each
Figure 1. Case 4. a, Conjunctivitis. b, On admission to the bums unit showing extensive exfoliation.
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Wiu.d et al.: Toxic epidermalnecrolysis
-
Figure2. Case5. a, On admission with facial and eyelid epidermal loss and oral mucositis. b, Widespread exfoliation of the central trunk and coalescing vesicles on the lateral chest and abdominal walls and the suprapubic area. c, Stromal haze and vascularization of the cornea.
The mean onset of the rash after taking the drug was 7.5 days. The date of first admission to hospital varied from the day after the rash appeared (patient 6) to 17 days afterwards (patient 2). Transfer to the burns unit occurred between I and 7 days after admission to hospital (mean 4 days). For those who survived the mean inpatient stay was
patient.
50.7 days.
Table III gives a summary of the six patients in this series. Four were female and two were male, with a mean age of 38 years. The mean percentage total body surface area of skin loss was 67.3 per cent.
The mortality rate in this series of patients was SO per cent. The two youngest patients (18 and 21 years old) died, one following antimalarial prophylaxis and one following cystitis. The mean day of death was 25.7 days after the rash. Two patients died from septicaemia: Ps. aemginosa, K pneumoniae and Acinetobacter anitratus in Case2 and Staph.
aureus in Case 6. One patient (Case 4) died from respiratory and renal failure. Renal failure developed in two patients: Case.5 became anuric and required dialysis, although she ultimately survived, and Case4 was oliguric on arrival at our unit, developing renal failure 1 day before her death. The long-term affects of TEN were varied in the patients who recovered. Case I developed hypertrophic scars on the legs which required 2 years of pressure garment therapy to achieve a satisfactory cosmetic result. Case3 had mild permanent scarring of the affected areas on the limbs and the trunk but no permanent ocular damage. Case 5 had considerable scarring with patchy hypopigmentation and hyperpigmentation of the skin and still has severe ocular problems with permanently reduced visual acuity. She will probably remain on ophthalmic medication for life to prevent further deterioration in her eyesight.
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Table I. The drugs involved in the six cases of toxic epidermal necrolysis Case no.
: 3 4 5 6
Drug
Reason for treatment
Trimethoprim and sulphamethoxazole Pyrimethamine and sulphadoxine Chlorpromazine Zimelidine Amoxycillin and clavulanic acid Trimethoprim and sulphamethoxazole
Fissure-in-ano Antimalarial prophylaxis Depression Depression Upper respiratory tract infection Cystitis
Table II. Summary of the course of the disease Case no.
Time between ingestion of drug and onset of rash (days)
Time between onset of the rash and admission to hospital
7 17
13 17 14 2 3 1
: 3 4 5 6
: 2 4
(days)
Table III. Details of the six cases of toxic epidermal necrolysis Case no. 1 2 3 4 5 6
Sex
Age (yr)
%TBSA
Female Male Male Female Female Female
55 21 53 55 26 18
25 80 64 E
??
60
Outcome
Survived Died Survived Died Survived Died
‘Necrolysis as percentage of total body surface area.
Discussion Toxic epidermal necrolysis is a severe inflammatory bullous disease of the skin often associated with conjunctivitis and mucositis but usually unrelated to staphylococcal infection. It has been recognized clinically for many years and was originally known as ‘erythema multiforme major’ or ‘erythema multiforme exuditavum’. In 1956 Lye11 redescribed necrolysis’, the disease, renaming it ‘toxic epidennal although it is often known as ‘Lyell’s disease’ (Lyell, 1956). He initially included cases caused by staphylococcal infection but later classified these separately as the ‘staphylococcal scalded skin syndrome’ (Lyell, 1979). The mechanisms responsible for the epidermal necrolysis are not well understood although it is likely that delayed hypersensitivity reactions involving cell-mediated mechanisms rather than humoral immunity are the cause of drug-induced TEN (Heng, 1985). TEN may be caused by the ingestion of drugs, may be idiopathic, or may very rarely be caused by staphylococcal infection. In idiopathic TEN recurrent attacks occur without any apparent cause in middle-aged or elderly females. Here the long-term prognosis is extremely poor as the attacks increase in severity. TEN due to staphylococcal infection is very rare and in an extensive review LyeU (1956) found only 13 cases. Most of these patients were male and nearly all either had underlying diseases such as renal failure, pneumonia or Hodgkin’s disease, or were immunosuppressed.
Time between admission and transfer to the burns unit (days) 1 7 ; 4 2
inpatient stay in the burns unit (days) 49 18 6 13 58 13
A similar cliical picture to TEN is seen in the StevensJohnson syndrome, a severe form of erythema multiforme (Figure3). First described in two children, the StevensJohnson syndrome is more common in children and young adults than in older patients (Stevens and Johnson, 1922). It is usually considered to be a separate disease from TEN, although Lyell(1979) believes that TEN is simply the most severe form of erythema multifonne. Both the StevensJohnson syndrome and TEN may be caused by similar drugs, but there are many more causes recorded of the Stevens-Johnson syndrome than of TEN (Champion, 1986). In both conditions there are lesions at the dermal-epidermal junction and mucosal involvement. However, in the Stevens-Johnson syndrome the bullae tend to be localized rather than involving the whole epidermis and the skin reaction may be mild compared to the extensive mucositis (Figrrre4). In the Stevens-Johnson syndrome there is a lymphohistiocytic infiltrate around the blood vessels in the upper dermis which are spared in TEN. The staphylococcal scalded skin syndrome occurs almost entirely in the newborn and young child and is due to an epidermolytic exotoxin produced by Staph. attrars, often of phage group 2. It is also known as Ritter’s disease after
Figure 3. A l&year-old girl with early Stevens-Johnson syndrome showing typical vesicle foormationon the abdomen and coalesced vesicles on the chest wall and nedc
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Ward et al.: Toxic epidermal necrolysis
Figure 4. Severe oral mucositis in Stevens-Johnson
syndrome.
Ritter’s first description of 297 cases in 1878 (Van Rittershain, 1878). The staphylococcal scalded skin syndrome occurs in adults only rarely and in these patients there is almost invariably a predisposing factor such as immunosuppression, renal failure, leukaemia, Hodgkin’s disease, other malignancy or alcoholism (Dowsett, 1984). The exotoxin is very specific for the granular layer of the epidermis where it causes an intraepidermal split with superficial bullae. TEN has a deeper plane of cleavage, thus enabling differentiation of TEN and the staphylococcal scalded skin syndrome to be made by a skin biopsy. Adverse drug reactions are the commonest cause of TEN. Sulphonamide-containing drugs are most frequently implicated in this syndrome (Guillaume et al., 1987). Other drugs involved include anticonvulsants, non-specific antiinflammatory drugs, barbiturates and penicillins (Heng, 1985). It is however difficult to prove conclusively that TEN has been caused by a drug. The occurrence of a rash within 3 weeks of taking a drug is highly suggestive of an adverse drug reaction, especially if the eruption occurs within 48 h of administration of a drug which caused a similar reaction on a previous occasion. Deliberate readministration of the drug to establish a repeat reaction is both dangerous and unethical but tests are now available which can help in establishing a causative relationship between the rash and the suspected drug. Lymphocyte transformation tests are sensitive and specific, giving information in both hurnoral as well as cellular hypersensitivity (Krebs, 1986). Positive results are only obtained however with certain groups of
drugs such as penicillins and sulphonamides, others giving only slight sensitization of lymphocytes which makes interpretation of the results difficult. The diagnosis of TEN is made on the history of the illness and the appearance of the rash. It can be confirmed by a biopsy of the involved skin. Fever, malaise and pharyngitis often precede the onset of erythema, but in severe cases this prodromal phase may be absent. Erythema usually appears first on the limbs and face, either as a diffuse redness of the skin or as discrete papules with dark centres and a red margin (target lesions). There is disagreement about the significance of these target lesions which are also characteristic of erythema m&for-me. Lyell (1976) believes that their presence in TEN indicates that TEN is therefore the most severe form of erythema multiforme. Goldstein et al. (1987) however define TEN as widespread blistering with erythema and no target lesions. Small blisters or large bullae form, usually within 2448 h. During this phase a mild shearing force applied to the skin causes separation of the epidermis from the dermis (the Nikolsky sign). Mucositis of the oropharynx, vagina, rectum, urethra and eye, ranging from mild oral ulceration to extensive erosion and crusting, occurs. The patient becomes toxic and pyrexial(38-40°C). If the patient survives, healing occurs by re-epithelialization from the hair follicles between 10 and 28 days after epidennal shedding, as in a superficial bum. TEN can be differentiated from the staphylococcal scalded skin syndrome by histological examination of a skin biopsy. In TEN there is vacuolization with eosinophilic bodies in the upper malpighian layers, progressing to widespread necrosis and neutrophil infiltration. There are only mild vascular changes and few dermal infiltrates (Rasmussen, 1980). The plane of cleavage is between the epidermis and the dermis, whereas in the staphylococcal scalded skin syndrome the disruption is in the superficial epidermis. Irnmunofluorescence studies of skin biopsies in TEN are unhelpful as there are few immunological deposits. Westly and Wechsler found no deposits in 63 per cent of their patients with TEN and only very faint deposits of IgG and IgM in the rest (Westly and Wechsler, 1984). In the TEN-like syndrome in acute graft-versus-host disease there is linear deposition of IgG, IgM, IgA and C3 at the dermo-epidermal junction (Spielvogel et al., 1976). It is widely recommended that patients with TEN should be managed in a bums unit where both the wound care needed to prevent further skin injury and the extensive supportive treatment required in these patients can be provided (Anon, 1984; Adzick et al., 1985; Heimbach et al., 1987; Pruitt, 1987). The principles of care of the TEN wound are the same as for a superficial burn: protection of the exposed surface from further damage and prevention of extension of the depth of the wound (Pruitt, 1987). The wound is cleaned with normal saline, removing all loose skin and blisters. Rubbing the skin will loosen any epithelium which is in the early stages of sloughing. If a crust of exudate has already formed on the areas of skin loss this is removed with a detergent and the area is then rinsed with saline. Treatment following cleansing varies: we use 0.5 per cent aqueous chlorhexidine soaks moistened and changed regularly. Halebian et al. (1986) recommend 0.5 per cent silver nitrate soaks but care must be taken because of absorption of the silver nitrate through a large raw area. Immediate cover with a biological dressing to prevent dessication and to provide a good environment for healing
102
is widely advocated. Heimbach treated 19 patients with a mean skin loss of 75 per cent total body surface area with porcine cutaneous xenograft, replacing any dislodged or purulent xenograft with new xenograft (Heimbach et al., 1987). Others have also successfully used cadaver skin (Davidson and Hunt, 1981; Birchall et al., 1987), amniotic membrane (Artz et al., 1972) and synthetic dressings such as Biobrane (Halebian et al., 1983). As well as controlliig heat and fluid loss these biological dressings reduce the often severe pain but most are opaque, allowing local infection to arise undetected with the consequent risk of increasing the depth of the wound. Topical antibiotics such as neomycin are hazardous because of increased percutaneous absorption. Silver sulphadiazine cream should also be avoided as sulphonamides are one of the commonest causes of TEN. Silver sulphadiazine may also exacerbate the neutropenia seen in many of these patients (Marvin et al., 1984). Intravenous fluid requirements have been reported both as less than a thermal injury of the same area and as more than expected (Adzick et al., 1985). Low fluid needs are thought to be due to the slower onset of fluid loss in TEN than in a burn, allowing more oral replacement (Halebian et al., 1983). and also to the failure of release of acute-phase reactants in TEN which in burns cause massive oedema (Heimbach et al., 1987). High fluid requirements may be needed with prolonged desquamation which can take up to 3 weeks. Oral fluid intake is often poor because of the oropharyngeal mucositis. Fluid and heat loss are high in patients treated with impregnated soaks or on an air-fluidized bead bed. Other parameters which need careful monitoring are electrolyte levels, nitrogen balance for which enteral or even parenteral feeding will be required, and serum albumin levels which may fall dramatically. Renal dysfunction is seen in up to 50 per cent of patients and is usually due to acute tubular necrosis as a result of hypovolaemia. Occasionally a progressive membranous glomerulonephritis can develop up to 5 years after TEN (Krumlovsky et al., 1974). Control of infection is vital as most patients die from sepsis. The use of prophylactic broad-spectrum antibiotics in the treatment of TEN is controversial. Bjomberg advocated their use, reporting that all the patients in his series who were treated routinely with antibiotics and steroids survived, whereas some patients who did not receive antibiotics died from staphylococcal sepsis or bronchopneumonia (Bjomberg, 1973). The emergence of highly resistant strains of bacteria is a problem if antibiotics are used routinely as Halebian showed in his series: nine out of 11 patients who died from sepsis had organisms resistant to the broadspectrum antibiotics which they were receiving (Halebian et al., 1983). Most authors recommend that parenteral antibiotics should be prescribed only for specific infections such as septicaemia or pneumonia (Rasmussen, 1980; Heimbach et al., 1987). The use of prophylactic antibiotics where the risk of sepsis is particularly high, as in patients who are neutropenic, and where there is a particularly heavy single strain bacterial colonization of the skin has also been recommended (Revuz et al., 1987). The high incidence of pneumonia is thought to be related to the aspiration of sloughed mucosa, shallow breathing from chest wall pain and atelectasis (Heimbach et al., 1987). Septicaemia can occur rapidly and unexpectedly and is often late in the disease. Staph. aurats is the commonest cause of early sepsis (Halebian et al., 1986) and we routinely give
Burns (1990) Vol. 16/No. 2
appropriate prophylactic antibiotics (currently ciprofloxacin) before and after dressing changes. Gram-negative organisms such as Ps. aemgirwse, K pneumoniae and E. wli are the most common cause of late septicaemia and are especially common in patients treated with steroids (Halebian et al., 1986). Septicaemia is treated with intravenous antibiotics covering both Gram-positive and Gram-negative organisms, amending the choice of antibiotic, if necessary, when the results of blood cultures are available. Sulphonamide-containing drugs should be avoided in all cases and penicillins should be given only if they are not suspected to be the cause of the necrolysis. High-dose steroids mask the clinical signs of septicaemia and antibiotics should be given at the first indirect sign of sepsis such as hypothermia, fever, diminishing level of consciousness, falling urine output or any sudden deterioration in the patient’s condition (Revuz et al., 1987). The treatment of TEN contrasts with the management of the staphylococcal scalded skin syndrome where the immediate parenteral administration of a penicillinase-resistant antibiotic in high doses is essential (Dow&t, 1984). As the staphylococcal scalded skin syndrome is due to toxin production the antibiotics may only prevent further progression of the epidermal shedding. There has been much discussion about the use of steroids in the treatment of TEN and it is now generally agreed that steroids have only a very limited role. They are indicated in progressive membranous glomerulonephritis where they may limit progression of the disease (Pruitt, 1987). If steroid therapy has been started at another hospital it should be reduced rapidly and withdrawn (Heimbach et al., 1987). Halebian compared a group of 15 patients who had received steroid therapy with 15 patients in which no steroids were given (Halebian et al., 1986). In patients who developed sepsis there was a 91 per cent mortality if steroids were used compared to 56 per cent in those who were not given them. The overall mortality was 66 per cent with steroid use and 33 per cent without. The untreated group also had a reduced incidence of gastrointestinal epithelial ulceration, candida sepsis and an increased survival after septic complications. The incidence of septic complications was not significantly different but the causative organisms differed markedly between the two groups: of the steroid-treated group with sepsis, 73 per cent had Gram-negative organisms on blood culture, and only 18 per cent had Gram-positive organisms, with 18 per cent infected by candida species. In the patients in which steroids were not used, 44 per cent had Grampositive and only 56 per cent had Gram-negative sepsis, with no cases of candida sepsis. As steroids suppress the signs of sepsis the authors thought that the better survival in their patients who were not given steroids might be partly because of earlier detection of septic complications and hence earlier treatment. Kim et al. (1983) also showed a much higher mortality in patients treated with steroids (80 per cent) compared to those who did not receive them (20 per cent). TEN has been reported in patients already receiving high-dose steroids (Revuz et al., 1987) and bullae formation has also continued in patients on high-dose steroids (Rasmussen, 1980; Halebian et al., 1983). Halebian et al. (1983) found no evidence that steroid treatment halted the progression of bullae formation, epidennal shedding and mucosal erosions. In contrast, Bjomberg (1973) controlled the epidermal necrolysis in 15 patients with 200-800mg of hydrocortisone daily. Haematological abnormalities are common in TEN.
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Ward et al.: Toxic epidermal necrolysis
Kvasnicka used a wide range of coagulation studies ~IIeight patients with TEN and showed the presence of disseminated intravascular coagulation (DIC) in all the patients (Kvasnicka et al., 1979). DIC developed in 27 per cent of the patients who died in the series reported by Halebian et al. (1983). Neutropenia due to a granubcytopenia commonly occurs 2-5 days after development of the rash. Persistent granulocytopenia is a very poor prognostic sign according to Westly and Wechsler (1984). All their patients in whom granulocytopenia persisted for longer than 7 days died. Neutropenia, lymphocytopenia and granulocytopenia were also found by Revuz et al. (1987) to be a bad prognostic factor. Nearly all their patients with a neutrophil count of less than 1.0 x 10” per litre died. Reverse isolation nursing techniques are necessary as sepsis is extremely common in these patients. Halebian et al. (1986) found Gram-negative sepsis present in 92 per cent of patients with leucopenia. A normocytic anaemia characterized by a progressive drop in haemoglobin level and a lymphopenia also occurs very often (Goens et al., 1986). The lymphopenia appears early, sometimes before the skin signs, and is profound. It recovers very slowly. It has been suggested that the lymphopenia and anaemia are related to a disorder of the cell-mediated immunity system which may be the cause of TEN (Goens et al., 1986). Ocular problems can be severe in TEN and require urgent treatment (Rasmussen, 1980). TEN produces a conjunctivitis which destroys the goblet cells, similar to that found in the Stevens-Johnson syndrome. Tarsorrhaphy may be necessary to arrest cornea1 opacification due to invasion of the cornea by deep vessels. The severity of the ophthalmic complications is related to the severity of the disease in its acute phase rather than the local treatment used on the eyes (Arstikaitis, 1973). Synechiae are prevented by the regular separation of the eyelids from the conjunctiva using a glass rod lubricated with a non-medicated ophthalmic ointment or chloramphenicol ointment. Further application of chloramphenicol ointment minimizes the risk of infection and also forms a layer between the lid and the globe. Other external complications include lid keratinization, ingrowing eyelashes and tear duct atrophy. Neovascularization and thinning of the cornea with infection, infiltration, ulceration and perforation may occur. Local application of prednisolone and antibiotic drops such as gentamicin help, but complications may still arise. Howard (1963) found that poor long-term visual function occurred in 9 per cent of patients with the Stevens-Johnson syndrome. Other aspects of treatment include meticulous oral hygiene to prevent parotitis, a common complication. Careful insertion of urethral catheters and cleansing of an indwelling catheter are important as the urethral mucosa is often involved, leading to acute or chronic stricture. Intravenous lines should be avoided if possible because of the high risk of infection. Halebian et al. (1986) found that 56 per cent of catheter tips were infected on culturing. The mortality of TEN remains high. Revuz et al. (1987) reviewed the 350 patients in the 10 largest reported series and found an overall mortality rate of 28.6 per cent (range 10.3-70 per cent). In their own series of 87 patients several prognostic factors were significant. The mortality rose with increasing age, extension of the area of necrolysis, elevation of the blood urea, creatinine and glucose levels, neutropenia, lymphopenia and thrombocytopenia. Halebian et al. (1986) found a significant improvement in mortality if steroids were not used, but skin loss of greater than SO per cent,
increasing age and the presence of associated diseases increased the death rate. TEN is a disease carrying a high mortality, usually due to sepsis. A burns unit has wide experience in the management of extensive areas of skin loss and can provide both the specialist wound care necessary to encourage healing and to minimize infection and also can treat the serious complications of the disease. We strongly recommend the early referral of patients with TEN to the nearest bums unit before complications occur.
Acknowledgements We would like to thank the following for referring their patients to us and for their help in the management of this disease: Drs D. France, K. Liddell, P. Sharpstone, D. Whitfield, I. Wilson and the Renal Unit at Guy’s Hospital. We would also like to thank the Department of Medical Illustration at the Queen Victoria Hospital for the illustrations.
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Paper accepted 19 September
1989.
Currespondenreshould be aci.fd to: Mr D. J. Ward, The M&doe Burns Unit, Queen Victoria Hospital, Holtye Road, East Grinstead, West Sussex, RH19 3DZ, UK.