Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report

doi:10.1016/j.bjps.2004.12.007

British Journal of Plastic Surgery

Volume 58, Issue 4, June 2005, Pages 504-510

https://doi.org/10.1016/j.bjps.2004.12.007 Get rights and content

Summary

Toxic epidermal necrolysis (TEN) is an acute drug-induced life-threatening disorder characterised by extensive epidermal exfoliation and high rate of mortality. Between October 2000 and April 2003, five severe TEN patients were evaluated using a specific TEN severity-of-illness scale (SCORTEN) and treated for the first time, with a combined therapy using Intravenous Human Immunoglobulins (IVIG) and plasmapheresis.

The standardised mortality ratio (SMR) analysis ([Σ observed deaths/Σ expected deaths]×100) was applied to establish how IVIG and plasmapheresis treatment could reduce TEN patient mortality.

The observed mortality was one out of five patients corresponding to 20%. The expected mortality based on SCORTEN was 3.319 corresponding to 66%. The SMR analysis revealed a 70% reduction in mortality (SMR=0.30; 95% confidence interval, 0.0–0.96).

Our series show a low mortality rate (20%) related to the severity of the patients (66% expected mortality). The use of IVIG in association with plasmapheresis has a rational basis and may be effective in severe TEN patients.

Section snippets

Patients and methods

Between October 2000 and April 2003, five severe TEN patients were referred to the Intensive Care Burn Unit (ICBU) of Sassari, in the island of Sardinia, Italy, (about 1 600 000 inhabitants). Total body surface area (TBSA) involved was calculated using the Lund–Browder chart.²¹ The TBSA involved was defined by the Nicolsky's sign (detachment of epidermis by digital pressure), erythematous confluent maculae, blisters and areas of detached epidermis.

Every drug introduced in the preceding 3 weeks

Results

Patients were referred to ICBU after 4.6 days average delay (range 2–9). Mean percentage of TBSA involved was 78.6% (range 62–90%) and mean detached skin percentage was 39.6% (range 28–52%).

Patients' clinical status is reported in Table 3. Mucosal involvement was noticed in the mouths of all patients. Patient 3 suffered from Crohn's disease and corticosteroids administration was continued under specialist's control. In all patients, except patient 3, parenteral nutrition was required. Ocular

Discussion

TEN is a rare pathological condition with a high mortality rate that requires immediate systemic and topical treatment due to its high mortality rate. The mechanism causing reaction is unknown. Paul et al.¹⁶ have demonstrated destruction of keratinocytes in TEN as result of apoptosis process. This is related to activation of Keratinocytes' death receptor (CD95 or Fas) inducted by interaction with its ligand (Fas-L) that is found up-regulated in TEN, probably secreted by peripheral blood

Acknowledgements

The authors would like to thank Dr Amelia Lissia, Department of Pathology, University of Sassari, for her support on histological analysis and the Physicians of the Department of Hematology, A.S.L. n° 1, SS. Annunziata Hospital of Sassari, for having performed plasmapheresis on patients.

References (57)

W.J. Power et al.
Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens–Johnson syndrome/toxic epidermal necrolysis disease spectrum
Ophthalmology
(1995)
P. Wolkenstein et al.
Toxic epidermal necrolysis
Dermatol Clin
(2000)
R. Abe et al.
Toxic epidermal necrolysis and Stevens–Johnson syndrome are induced by soluble Fas ligand
Am J Pathol
(2003)
I. Viard-Leveugle et al.
Intracelleular localization of keratinocyte Fas ligand explains lack of cytolytic activity under physiological conditions
J Biol Chem
(2003)
C.A. Egan et al.
Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis
J Am Acad Dermatol
(1999)
P. Wolkenstein et al.
Randomized comparison of thalidomide versus placebo in toxic epidermal necrolysis
Lancet
(1998)
P. Paquet et al.
Treatment of drug-induced toxic epidermal necrolysis (Lyell's syndrome) with intravenous human immunoglobulins
Burns
(2001)
O. Correia et al.
Increased interleukin 10, tumor necrosis factor alpha, and interleukin 6 levels in blister fluid of toxic epidermal necrolysis
J Am Acad Dermatol
(2002)
A. Nassif et al.
Drug specific cytotoxic T-cells in the lesions of a patient with toxic epidermal necrolysis
J Invest Dermatol
(2002)
C. Mayorga et al.
Improvement of toxic epidermal necrolysis after the early administration of a single high dose of intravenous immunoglobulin
Ann Allergy Asthma Immunol
(2003)

L. Leyva et al.

Anticonvulsant-induced toxic epidermal necrolysis: monitoring the immunologic response

J Allergy Clin Immunol

(2000)

A. Lyell

Toxic epidermal necrolysis: an eruption rembling scalding of the skin

Br J Dermatol

(1956)

J.T. Schulz et al.

A 10-year experience with toxic epidermal necrolysis

J Burn Care Rehabil

(2000)

M. Hollyoak et al.

Exfoliative and necrotizing conditions of the integument

S. Bastuji-Garin et al.

Toxic epidermal necrolysis (Lyell's syndrome) in 77 elderly patients

Age Ageing

(1993)

S. Honari et al.

Toxic epidermal necrolysis (TEN) in elderly patients

J Burn Care Rehabil

(2001)

I. Garcia-Doval et al.

Toxic epidermal necrolysis and Stevens–Johnson syndrome. Does early withdrawal of causative drugs decrease the risk of death?

Arch Dermatol

(2000)

D.N. Herndon

Toxic epidermal necrolysis: a systemic and dermatologic disorder best treated with standard treatment protocols in burn intensive care units without the prolonged use of corticosteroids

J Am Coll Surg

(1995)

J.C. Roujeau et al.

Lymphocyte transformation test in drug-induced toxic epidermal necrolysis

Int Arch Allergy Appl Immunol

(1985)

S. Bastuji-Garin et al.

Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome and erythema multiforme

Arch Dermatol

(1993)

S.L. Engelhardt et al.

Toxic epidermal necrolysis: an analysis of referral patterns and steroid usage

J Burn Care Rehabil

(1997)

D.R. Yarbrough

Experience with toxic epidermal necrolysis treated in a burn center

J Burn Care Rehabil

(1996)

T. McGee et al.

Toxic epidermal necrolysis syndrome: mortality rate reduced with early referral to regional burn center

Plast Reconstr Surg

(1998)

M.Z. Mofid et al.

Drug-induced linear immunoglobulin a bullous disease that clinically mimics toxic epidermal necrolysis

J Burn Care Rehabil

(2000)

C. Paul et al.

Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis

Br J Dermatol

(1996)

C. Prins et al.

Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins

Arch Dermatol

(2003)

I. Ducic et al.

Outcome of patients with toxic epidermal necrolysis revisited

Plast Reconstr Surg

(2002)

N. Bachot et al.

Intravenous Immunoglobulin treatment for Steven–Johnson syndrome and toxic epidrmal necrolysis

Arch Dermatol

(2003)

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Impact of multiple medical interventions on mortality, length of hospital stay and reepithelialization time in Toxic Epidermal Necrolysis, Steven-Johnsons Syndrome, and TEN/SJS Overlap – Metanalysis and metaregression of observational studies
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Citation Excerpt :
Interventions like IVIG alone, Varia (heterogenous group of patients treated with concomitant combinations of steroids, IVIG, cyclophosphamide and supportive care) TPE, and TPE with IVIG proved to be linked to higher mortality than overall event rate and higher than supportive care alone. Although, these groups were reported with higher SCORTEN than average, these observations can prove that those interventions in these patients were detrimental regarding mortality [4,40–45]. Our results are different in comparison to a meta-analysis published by Zimmerman et al.
Stevens-Johnson’s Syndrome (SJS) and Toxic Epidermal Necrolysis are rare, life-threatening dermatologic conditions with acute onset and not clearly established treatment protocol. A plethora of observational studies are present with lack of up-to-date consensus based on evaluation of objective endpoints, among others mortality. Thorough analysis of available databases (Pubmed, EMBASE, Cinahl, Web of Science, Clinical Trials) was conducted according to PRISMA guidelines. Authors initially identified 700 papers, with 82 of them potentially eligible according to adopted criteria. A total of 42 studies were included into pooled synthesis. For continuous outcomes we analyzed the pooled means for endpoint scores using observed cases data. Categorical outcomes were analyzed by calculating the pooled event rates. We conducted subgroup and exploratory maximum likelihood random effects meta-regression analyses regarding SCORTEN of all outcomes. Using random-effects model, the overall pooled Mortality Rate was 0.191 (95%CI, 0.132–0.269). The lowest mortality rate was found to be linked with Etanercept and highest in Total Plasma Exchange (TPE) and Intravenous Immunoglobulin (IVIG). Overall reepithelization was 13.278 days (95%CI, 8.773–17.784),The highest was found in cyclosporine treatment; 14.739 whilst the lowest for steroids. Length of hospital stay in overall analysis was 19.99 days (95%CI, 16.53–23.44),the highest was linked with TPE/TPE+IvIg treatment, the lowest with steroids. Risk of bias of assessed studies was estimated to be high (for observational studies mean STROBE score 12.44). High quality TEN and SJS studies are lacking. Almost all papers report observational data without randomization and double-blind control. Therefore, the pooled analysis cannot be presented with initial bias. In our meta-analysis the most successful regimen was Etanercept treatment. It was linked with the lowest mortality. The most negative treatment outcome was observed in studies reporting TPE and IVIG. Randomized trials of high quality are needed in SJS and TEN.
A review of toxic epidermal necrolysis management in Japan
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Citation Excerpt :
The timing could have contributed to the beneficial effect.30 Plasmapheresis has been reported to be effective, through case reports and a literature review especially in Japan.31,39–44 Whether simple plasma exchange or double filtration plasmapheresis is more beneficial, remains to be known.
Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction characterized by necrosis of the epidermis. Its incidence is approximately 1 per million a year and average mortality rate is high at 25–50%. TEN has a flu-like prodrome, followed by atypical, targetoid erythematous or purpuric macules on the skin. These macules coalesce to form flaccid blisters that slough off as areas of epidermal necrosis. Drugs such as allopurinol, sulfonamides, and carbamazepine are the most common causes. The human leukocyte antigen (HLA)-B*15:02 in Asians being administered carbamazepine and the HLA-B*58:01 antigen in patients of all ethnicities being administered allopurinol are known to be high-risk factors. Rapid diagnosis, discontinuation of the causative drug, and supportive treatment are essential for better prognosis and improvement of sequelae. Till now, systemic corticosteroids and intravenous immunoglobulins have been used as the most common active interventions; however, no gold standard has been established. In Japan, physicians follow a unique diagnostic criteria and treatment guideline to improve the diagnosis rate and streamline treatments. This may be a contributing factor for the lower mortality rate (14.3%). The efficacy of systemic corticosteroids, immunoglobulins, and plasmapheresis may have been beneficial as well. In Japan, TEN is defined as an epidermal detachment of over 10% of the body surface area (BSA), while the globally accepted definition established by Bastuji-Garin describes it as an epidermal detachment of over 30% of the BSA. In Japanese individuals, HLA-A*02:06, HLA-A*02:07, HLA-A*31:01 and HLA-B*51:01 may be linked to higher risks of TEN.
Immunoglobulin Replacement
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The concept of transfer of protection dates back to 1890, when Emil Behring and Shibasaburo Kitasato discovered that guinea pigs injected with killed diphtheria or tetanus bacilli developed a soluble substance that could be transferred to a second guinea pig to provide protection for an infectious challenge. This concept was extended to humans in the 1930s, but side effects were common. Immunoglobulin purification began when Cohn developed an ethanol fractionation method to separate plasma proteins into stable fractions in 1946. In 1952, Bruton described the first case of agammaglobulinemia and showed that subcutaneous injections with Cohn fraction II was an effective treatment. This landmark case began the modern era of immunoglobulin replacement. Many of the early cases of immunoglobulin replacement utilized intramuscular injections, because the products contained prekallikrein and other biologically active components and intravenous administration led to fever and cardiovascular symptoms. The Swiss Red Cross laboratories developed methods to adapt the Cohn fraction II for use intravenously by using exchange chromatography, and in 1981 the first commercial intravenous immunoglobulin (IVIG) became available in the United States. Today, patients have a wide variety of subcutaneous or intravenous immunoglobulin products and patients receive immunoglobulin replacement in their own homes, thus facilitating a higher quality of life. In this chapter, the uses of immunoglobulin and adverse events are reviewed.
Toxic epidermal necrolysis: An update
2013, Asian Pacific Journal of Tropical Disease
Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a rare, life-threatening dermatological condition that is usually induced by reaction to medications. It is characterized by the detachment of the top layer of skin (the epidermis) from the lower layers of the skin (the dermis) all over the body. There is broad agreement in medical literature that TEN can be considered a more severe form of Stevens Johnson syndrome, and debate whether it falls on a spectrum of disease that includes erythema multiforme. Some authors consider that there is an overlap between the two syndromes (usually between 10% and 30% of skin detachment). This article deals with history, epidemiology, diagnosis, pathophysiology treatment and management of TEN.
Effectiveness of early treatment with plasma exchange in patients with Stevens–Johnson syndrome and toxic epidermal necrolysis
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: ^☆Presented in part at the 14° National Congress of the Italian Burns Society, SIUst, Milano, 31 May–1 June 2001 and at the Summer Meeting of the British Association of Plastic Surgeons, Newport, South Wales, 2–4 July, 2003.

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Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report

Summary

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Ophthalmology

Dermatol Clin

Am J Pathol

J Biol Chem

J Am Acad Dermatol

Lancet

Burns

J Am Acad Dermatol

J Invest Dermatol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Toxic epidermal necrolysis: an eruption rembling scalding of the skin

Br J Dermatol

A 10-year experience with toxic epidermal necrolysis

J Burn Care Rehabil

Exfoliative and necrotizing conditions of the integument

Toxic epidermal necrolysis (Lyell's syndrome) in 77 elderly patients

Age Ageing

Toxic epidermal necrolysis (TEN) in elderly patients

J Burn Care Rehabil

Toxic epidermal necrolysis and Stevens–Johnson syndrome. Does early withdrawal of causative drugs decrease the risk of death?

Arch Dermatol

Toxic epidermal necrolysis: a systemic and dermatologic disorder best treated with standard treatment protocols in burn intensive care units without the prolonged use of corticosteroids

J Am Coll Surg

Lymphocyte transformation test in drug-induced toxic epidermal necrolysis

Int Arch Allergy Appl Immunol

Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome and erythema multiforme

Arch Dermatol

Toxic epidermal necrolysis: an analysis of referral patterns and steroid usage

J Burn Care Rehabil

Experience with toxic epidermal necrolysis treated in a burn center

J Burn Care Rehabil

Toxic epidermal necrolysis syndrome: mortality rate reduced with early referral to regional burn center

Plast Reconstr Surg

Drug-induced linear immunoglobulin a bullous disease that clinically mimics toxic epidermal necrolysis

J Burn Care Rehabil

Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis

Br J Dermatol

Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins

Arch Dermatol

Outcome of patients with toxic epidermal necrolysis revisited

Plast Reconstr Surg

Intravenous Immunoglobulin treatment for Steven–Johnson syndrome and toxic epidrmal necrolysis

Arch Dermatol