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|CONTINUING MEDICAL EDUCATION
|Year : 2000 | Volume
| Issue : 1 | Page : 10-17
Toxic epidermal necrolysis: Current concepts in pathogenesis and treatment
|How to cite this article:|
Saha K. Toxic epidermal necrolysis: Current concepts in pathogenesis and treatment. Indian J Dermatol Venereol Leprol 2000;66:10-7
|How to cite this URL:|
Saha K. Toxic epidermal necrolysis: Current concepts in pathogenesis and treatment. Indian J Dermatol Venereol Leprol [serial online] 2000 [cited 2013 May 25];66:10-7. Available from: http://www.ijdvl.com/text.asp?2000/66/1/10/4853
Toxic epidermal necrolysis (TEN) also known as Lyell's syndrome is a rare but potentially lifethreatening condition with widespread epidermal detachment and mucosal erosions.To most physicians, TEN represents the most severe form in the broad spectrum of erythema multiforme (EM), the other forms being erythema multiforme minor and erythema multiforme major or Stevens Johnson syndrome (SJS). Some authorities believe that TEN may represent a distinct disease enitiy altogether.Recently, a consensus agreement was made on a 3grade classification within the SJS/TEN spectrum of diseases.SJS includes cases with mucosal erosions plus widespread purpuric macules and epidermal detachment up to 10%, transitional SJS-TEN represents epidermal detachment betwen 10 to 30%; and TEN represents skin detachment of more than 30% of the body surface areas (BSA). It is obvious that patients with TEN demand much more meticulous and aggressive therapy for better outcome.
| Epidemiology of TEN|| |
Population studies in the west have reported the incidence rate of TEN between 0.4 to 1.2 cases per million annually.  Specific epidemiological studies have not been published on the incidence of TEN in the developing countries like india. It is possible that frequency of TEN in countries such as India could be much higher considering the fact that the main etiologic agent of TEN, i.e. drugs such as antibiotics, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs) are easily available in these countries without any prescription. It is noteworthy that few cases of TEN has been reported in dogs, cats, and research monkeys after drug therapy.TEN is known to affect women more than men and the incidence of TEN increases sharply with age. Patients suffering from Human Immunodeficiency Virus (HIV) infection are also known to be at a much higher risk for developing TEN. ,It is possible that the greatly increased number of drugs taken by the HIV infected patients along with the associated immunodeficiency in this condition together are responsible for the incidence of TEN in these patients. With an estimated 8 million people already infected with HIV in India, one can only assume that in the coming years the incidence of TEN in India will go further up.
| Pathophysiology of TEN|| |
The exact pathogenesis of TEN still remains largely unknown. Role of humoral immunity (auto antibodies) which was believed to be the main culprit in the past has completely fallen into disfavour with numerous recent studies demonstrating the cytotoxic lymphocyte - mediated immune reaction (CTL) aimed at the destruction of the keratinocyte expressing foreign (drug- related?) antigens as the primary causes for development of TEN ,,,,,,Also, the recurrence of SJS and TEN within 48 hours of rechallenge(although the intial reaction takes about 14 days after drug therapy) strongly supports an immune - mediated mechanism.
Several lines of evidence support the CTL mediated pathogensis of TEN. These include (1) link to some specific HLA haplotypes to increased susceptibility to TEN,  (2) characteristic lag between the exposure and disease onset (1 to 45 days, mean 14 days ),(3) increased inflammatory CD8+ T cells in the epidermis, and (4) increased apoptosis of the keratinocytes in TEN patients. Although a specific link between the drug metoblite and the immunologic hypothesis is still lacking, drug-reactive T cells have been shown in the skin and blood of patients with various types of adverse cutaneous drug reaction demonstrating that a CTL-mediated immune response against drugs occurs. Chemokines and cytokines such as interferon - g (IFN-g) has been shown to play major role in the pathogensis of other diseases like AIDS." Tumor necrosis factor -a (TNFa) and IL-6 have also been involved in the pathogensis of TEN as increased amount of these cytokines are found in the blister fluids in TEN patients. These inflammatory cytokines may play their damaging roles by recruiting the cytotoxic T cells to the epidermis. They may also cause damages directly as cytokines such as TNF -a are known to cause increased apoptosis. Probably the most significant finding in this regard was published recently by French and co-workers. These researchers have found that epidermal keratinocytes in TEN patients express large amount of lytically active Fas ligand (CD95L) and interactions between these CD95L and Fas (CD 95) on the effector cells are directly involved in the epidermal necrolysis. Indeed, the naturally occurring anti-Fas immunoglobulins in the plasma which is concentracted in human intravenous immunoglobulin (IVIG) were used very successfully by these scientists to quickly reverse the disease progression in TEN patients. Fas-mediated tissue destruction has been described in other diseases including graft- versushost disease (GVHD), Hashimoto's thyroiditis, and fulminant hepatitis.,, Many proinflammatory cytokines have been shown to upregulate Fas ligand expression and cause enhanced apoptosis. , It is tempting to speculate that increased production of inflammatory cytokines e.g. TNF-a in TEN patients may also indirectly cause necrolysis by upregulating expression of Fas ligand. In that scenario, resolution of TEN may also be achieved by treating patients with specific anti -cytokine antibodies. The difficulty towards understanding the molecular changes in the T cells or keratinocytes in TEN patients is also due to the lack of a suitable system to study human T cells at a clonal level in vitro. Using the recently described technique of immortalizing human T cell clones with a strain of Herpes virus saimiri (HVS),  we are currently invloved in the generation of immortalized CD4+and CD8+ T cell clones for TEN patients to understand their specific roles in the disease pathogenesis.
| Treatment of TEN|| |
TEN is an acute emergency and is potentially life threatening if not treated promptly. However, since the pathophysiology of the disease remained largely unclear (until the recent discovery that the Fas ligand plays a major role in the apoptotic cell death), there is no specific therapy for TEN patients. The primary objective for a favourable outcome depends on rapid and aggressive supportive care until the skin regenerates itself in this self- limiting acute skin condition.
The management of TEN and second-degree bruns have often been compared. ,, The primary cause of death in TEN is sepsis. Numerous recent reports have clearly demonstrated highly improved prognosis when TEN patients are treated through multidisciplinary management in a Burn Center. ,,, Treatment in a Burn Center must be strived for severe TEN patients. When Burn Centers are not available, management of patients should be undertaken in an intensive care unit (ICU) with reverse-isolation nursing techniques. ,,Meticulous monitoring of the patients in an ICU with daily laboratory examinations of blood and urinary electrolytes, creatine and urea, glycemia and glycosuria,CBC and phosphoremia and bacterial culture are mandatory. Sterile handling of the patients is a must and cannot be over emphasized to minimize nosocomial infection. 
| Use of corticosteroids|| |
Historically, corticosteroids had been used routinely for the treatment of TEN patients until the early 1980s. Many early case reports have acclaimed the benefits of steroid thearpy in accordance with the hypothesis of an allergic reaction and that such interventions were meant to stop the progression of TEN. However, more recent studies have described prolonged wound healing and higher rate of mortality and morbidity,,,associated with the use of corticosteroids. Morever, many TEN cases have occurred in patients who were already on high doses of corticosteroids for other conditions suggesting that corticosteroids may have no role in preventing TEN. Indeed, in the widely reported SCAR study, corticosteroids appear to be an important risk factor for TEN: the crude relative risk being 12 (4.4 multivariate) suggesting that at least from epidemiological point of view, corticosteroids behave just as do other responsible drugs. On the basis of these reports, most authorities no longer routinely recommend corticosteroid therapy for patients with TEN. , Indeed, in the first international symposium on erythema multiforme and Lyell's syndrome (TEN) in Creteil, France in 1985 where most of the world's authorities on this disease were present including Lyell himself, it was the unanimous conclusion of the group (including Lyell) that corticosteroids are of no particular value in the management of TEN and they condemned it's use once the disease has progressed to large (more than 20% of BSA) areas. ,,
The issue of whether to use steroids or not in the treatment of TEN still invariably evokes heated discussion in any gathering of physicians. In spite of several recent studies demonstrating no benefit for steroids, many authorities all over the world still use corticosteroids for the management of SJS/TEN in the earlycourseofthe disease.,,, However, when steroids are used, it should be given only very early (within the first 24 to 48 hours) in the disease process in a relatively high dose (equivalent to 1-2 mg per kg body weight of oral Prednisolone or intravenous methylprednisolone e.g. solumedrol) for only a brief period of time of not more than 3 to 5 days. Ideally, the reaction should be controlled within 25 hours or at the most 48 hours. The steroid therapy should be stopped or tapered very quickly after that to avoid the principal adverse effect of corticosteroids, i.e. development of sepsis, by far the most common cause of death in TEN patients. In a widely quoted study by Patterson and co-workers at the Northwestern University in Chicago in support of steroid therapy as being "lifesaving", high doses of corticosteroids were used in 13 patients with SJS with complete recovery in all patients.  Interestingly, in this study not a single patient had TEN. Indeed, these researchers have advised against the use of corticosteroids for treatment of TEN and routinely refer their TEN patients to the Burn Center, (personal communication with Dr. R.Patterson, Northwestern University Medical School, Chicago,IL). It is almost universally agreed by the "pro-steroid" experts that once the epidermal detachment exceeds 25% of the BSA, no steroids should be used in TEN patients since any benefit of corticosteroids is then far outweighed by its potential risk, , (personal communication with Dr.J.D.Fine, University of North Carolina, Chapel Hill, NC). All of these recent studies on the detrimental effects of prolonged steroid use in TEN patients, however, did not exclude a potential benefit from these agents if used shortly and very early in the course of the disease (personal communication with Dr.J.C. Roujeau, University of Paris, Creteil, France).
| Fluid/Nutrition balance|| |
The large areas of denuded skin in TEN patients allows continous loss of massive amount of body fluids through oozing and evaporation very much like second-degree burn patients. However, unlike burn patients, mucous membrane involvement usually antedates skin necrolysis in TEN patients, hampering eating and drinking for several days before admission and worsening fluid/nutrition deficit.Therefore, fluids must be replaced intravenously, preferably through a peripheral line,especially during the first few days.,,Predicted volume of fluid replacement is proportional to the area of skin lesions (sum of detached and detachable areas). However, the fluid requirements of TEN patients are about 2/3 to3/4 of those patients with comparable second- degree burns., The exact volume of fluid required needs to be calculated daily from the % BSA affected using the "rule of nine" or modified "Lund-Browder chart" From exudation and evaporation only, daily water losses through skin average 2 to 3 liters in adualts with epidermal detachment on 50% of their BSA. On an average, between 4 to 6 liters of fluids per day including 1 to 2 liters of macromoleculer solutions are needed in the first several days in a TEN patient with more than 35-40% BSA affected., Strict urinary output should be maintained, if necessary through a catheter. The electrolyte balance is maintained by daily check up of serum electrolytes. A positive nitrogen balance must be maintainted. Massive nutritional support by nasogastric feeding with a thinbored silicone tube must be initiated as soon as possible to minimize protein losses and to promote healing. On an average 1.3 Kcal% BSA/kg/day is required as nutrtional calorie requirement and should be evualuated daily based on the total BSA affected. sub Between 3000 to 4000 calories per day with a high protein diet through a nasogastric tube is recommended in most cases. Environmental temperature should be raised to 30 to 32° C to reduce caloric loss through the exposed skin and the resultant shivering and stress. Heat loss can also be limited by raising the temperature of the antiseptic baths and using heat shield, infra red lamps and airfluidized bed.
| Infection control|| |
As mentioned above, sepsis is the most common cause of death in TEN patients. Therefore, sterile handling and maintenance of asepsis can never be over- emphasized in the treatment of TEN patients. It is now standard treatment to admit a TEN patients to a Burn Unit whenever possible.43, 46, 47 If Burn Units are not accessible, then patients should be treated in individual ICU room with reverse isolation nursing techniques through nurses experienced in treating burn patients. , Extreme care should be taken to prevent nosocomial infection and spread of infection from the raw skin surface. Routinely patients are bathed and painted with topical antiseptic solutions (0.5% silver nirate,0.05% chlorhexidine) and the efficiency of asepsis needs to be monitored daily by semi-quantitative bacterial sampling on multiple sites of the wounds. Silver sulfadiazine, popular in burn units, is normaly avoided as sulfonamides are frequently implicated in the etiology of TEN. ,, In the recent years, use of cryo preserved xenografts, homografts, or biosynthetic grafts have greatly improved the mortality and morbidity of TEN patients., Care of wounds also includes meticulous therapy for the eyes since there is a high risk of early and late ocular complications. Daily examinations by an opthalmologist and antiseptic and/or antibiotic eye drops are instilled every hour or two and developing synechiae are disrupted by a blunt instrument. If lesions are not managed through diligent nursing and medical interventions, ocular scar tissue can form, resulting in permanent ocular damage. Similarly, mouth and crusted lips should be gently rinsed atleast every two hours with physiologic saline and sparyed with antiseptics several times each day., Finally, pulmonary complications may occur at any time due to sloughing anywhere in the tracheobronchial tree and need to be specially cared for. Clinical manifestations range from a sore throat to respiratory failure. Pulmonary care includes aerosols, bronchial aspiration, and physical therapy. Sedatives (preferred narcotic is morphine) are used liberally to relieve pain and discomfort. Regarding the use of antibiotics, there are two schools of thought. A broad spectrum antibiotic is used routinely by some as soon as TEN is diagnosed. However, prophylactic systemic antibiotics are no longer advised for routine management of TEN patients by most authorities in the field because there is concern about possible cross- reactivity with the drug that initiated the TEN and more importantly, because of the risk of infection with resistant organisms. It is imperative to have daily test of blood, urine, swabs of the wounds at different sites including eyes and mouth done to monitn development of any sepsis. Antibiotics should be given for culture proven sepsis or when there is neutropenia or an increase in bacterial counts of a single strain on the swabs. Antibiotics need to be given in a higher dose than usual because of large amount of protein loss in TEN patients.
| Other measures|| |
Many other therapies have been attempted in the recent times to treat TEN patients. Several immunosuppressants including cyclosporine , and cyclophosphamide,, have been tried to prevent progression of the disease. Although some success have been claimed in the small number of patients treated with cyclosporine, in most cases disease recurred as a rebound after a suppresive effect of cyclosporin. Cyclospohphamide was also considered to have some beneficial effect towards halting disease progression. However, in most cases cyclophosphamide was begun several days after hospitalization following an ineffective treatment with corticosteroids for 1 to 5 days. Therefore,it remains doubtful that the progression of the lesions was actually shorter than the expected one. These drugs are supposed to stop necrolysis but the practical value of such therapy is very limited because necrolysis of most patients has stopped to evolve at the time of hospitalization and in most untreated patients, the average duration of progression is less than four days. , Importantly, most of these treatments are potentialy harmful because they promote infection, the main cause of death in TEN.  Infusions of anti-tumor necrolysis factor -a (TNF-a) and/or anti-IL-2 monoclonal antibodies have been used in patients with GV-HD-related TEN,  their efficacy needs to be tested in larger cohorts before universal use. Thalidomide, another potent TNF-a suppressor, has been successfully used in some immune disorders such as GVH disease. However, the first randomized placebocontrolled double-blind study to test the efficacy of thalidomide in TEN patients has proven to be a castastrophe. This recently published study had to be stopped prematurely due to excessive mortality in the "thalidomide group" compared to the "placebo group": Obviously, unproven therapy such as that with thalidomide has no role in the management of TEN and should never be used experimentally in such patients. Other treatments attempting to boost the failing immune systems of the TEN patients and regeneration of the epidermis have used recombinant granulocyte colny- stimulating factor (rG-CSF) and g ran u locyte-macrophage colony-stimulating factor (GM-CSf) that not only helped to recover from neutropenia but also enhanced epidermal regrowth. ,These reagents may have a supportive role in the management of critical TEN patients. Similarly, hyperbaric oxygen has also been given in small number of patients with TEN that enhanced re-epithelialization of the skin and hinder sepsis.  Plasmapheresis has also been used successfully in several studies. , Plasmapheresis is done to remove the offending drug and/or metabolites by separation of plasma from blood cells with removal (apheresis) of the plasma. At the University of Utah, six patients with severe TEN were treated with Plasmapheresis when the picture looked very bleak and all of these patients recovered (personal communication with Dr.Jhon Zone, University of Utah Health Science Center, Salt Lake City, UT; manuscript submitted). Where available, the sophisticated technology may be used for care of severe TEN patients.
Finally, as mentioned above, the major recent discovery that. Fas-FasL interactions are directly responsible for apoptotic death of the keratinocytes in TEN patients has opened up a specific mode of treatment for the first time for these patients. It is obvious that naturally occuring immunoglobulin in IVIG which is pooled from plasma of healthy donors may have little or no adverse effect compared to systemic corticosteroids or other immunosuppressants. Along with the standard supportive therapy, high concentration of naturally occuring antiFas immunoglobulin (Ig) in IVIG (0.2- 0.75 gm/kg/ day) are being used as a specific therapy to treat TEN patients in various centers in this condition and has been recommended in the recently held (March, 1999) annual meeting of the American Academy of Dermatology in New Orleans, LA (personal communications with Dr.John Zone, University of Utah and Dr.Jerome Parsons, Chesapeake, Virginia). This therapy should have. a tremendous potential to improve the outcome of TEN patients in the future.
In conclusion, major strides have been made in the recent years and patst statistics of high mortality and morbidity in patients with TEN patients have been changed significantly. The current treatment plan for TEN patients as recommended by most authorities in the field, ,,,,, is summarized in the [Table - 1]. (personal communication with Dr.John Zone, University of Utah and D.J.Parsons, Virginia). Early referral to a burn center (or suitable ICU) with avoidence of corticosteroids especially after the first few days (or when more than 25% of BSA affected) and focussing the therapeutic goal towards promotion of wound healing, aggressive correction of fluid, electorlyte, and portein balance, provision of good pulmonary and eye care and above all, prevention of sepsis have made the mortality rate to almost 0% in large cohorts of TEN patients.30, 32, 62 The few patients who died in these studies after aggressive treatment in a Burn Center were already immunocompromised either through extremes of age or through other pre-existing medical conditions. In the near future, the use of IVIG as specific therapy in TEN should improve even further the prognosis of this previously dreadful acute skin condition.
| Acknowledgment|| |
We thank Drs.J.C. Roujuau (University of paris, France), Jo-David Fine (University of North Carolina), Jerome M.Parsons (Virginia), John J: Zone (University of Utah), Roy Patterson (Northwestern University), Peter Fritsch (University of Innsbruck, Austria), Warren Piette (University of Lowa), David Heimbach (University of Washington), J.S. Pasricha (New Delhi), Binod Khaitan (All India Institute of Medical Sciences, New Delhi), Philip D. Walson (Ohio State University ),Basil A Pruitt (University of Taxes) James E Rasmussen (University of Michigan), Timothy Bradley (Illinois) and Ewa Matczhak (Ohio State University) for their comments and kind cooperation. We would also like to thank Amy Ott for preparation of this manuscript. Finally, we would like to acknowledge the continued support from the Children's Hospital at Columbus, Ohio and the National Institute of Health, Bethesda.
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[Table - 1]