Severe cutaneous adverse reactions to drugs - relevant aspects to diagnosis and treatment - Part I: Anaphylaxis and anaphylactoid reactions, erythroderma and the clinical spectrum of Stevens-Johnson syndrome & toxic epidermal necrolysis (Lyell´s disease)

Abstracts

As reações cutâneas graves adversas a droga (RCGAD) são as que geralmente necessitam de internação hospitalar, por vezes em unidade de terapia intensiva ou de queimados, com observação minuciosa dos sinais vitais e da função de órgãos internos. O objetivo é descrever essas reações, facilitando seu reconhecimento e tratamento. Fazem parte desse grupo a anafilaxia, a síndrome de Stevens-Johnson (SSJ), a necrólise epidérmica tóxica (NET) e, dependendo do envolvimento sistêmico, as eritrodermias. Neste artigo, são abordados as características clínicas e o tratamento de algumas reações adversas a droga: anafilaxia, as eritrodermias, a síndrome de Stevens-Johnson (SSJ) e a necrólise epidérmica tóxica (NET).

anafilaxia; eritema multiforme; hipersensibilidade a drogas; necrólise epidérmica tóxica; preparações farmacêuticas; síndrome de Stevens-Johnson

REVIEW ARTICLE

Severe cutaneous adverse reactions to drugs - relevant aspects to diagnosis and treatment - Part I: Anaphylaxis and anaphylactoid reactions, erythroderma and the clinical spectrum of Stevens-Johnson syndrome & toxic epidermal necrolysis (Lyell´s disease)^*

Paulo Ricardo Criado^I; Roberta Fachini Jardim Criado^II; Cidia Vasconcellos^III; Rodrigo de Oliveira Ramos^IV; Andréia Christina Gonçalves^V

^IDermatologist, Master's Degree in Clinical Medicine, Assistant M.D. and lecturer, Dermatology Service of the Sao Paulo Hospital do Servidor Público Estadual and Padre Bento de Guarulhos Hospital Complex

^IIAllergologist, Master's Degree in Clinical Medicine, Assistant M.D. and lecturer, Dermatology Service of the Sao Paulo Hospital do Servidor Público Estadual, Voluntary Allergologist of the ABC Faculty of Medicine

^IIIDermatologist, Ph.D. in Medicine, Assistant M.D. Dermatology Service of the Sao Paulo Hospital do Servidor Público Estadual and LIM-56 of the Hospital das Clinicas, University of Sao Paulo Faculty of Medicine

^IVDermatologist in residence, Dermatology Service, Sao Paulo Hospital do Servidor Público Estadual

^VPh.D. candidate (sixth-year), Estácio de Sá University (RJ), doing an elective internship

^{Correspondence}

SUMMARY

Severe Cutaneous Adverse Reactions to drugs (SCARD) generally require hospitalization, and at times in the intensive therapy or burn care unit for observation of the vital signs and the viscera function. The aim of this study is to describe these reactions in order to facilitate recognition and treatment. This group of drug reactions includes anaphylaxis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and, depending on the systemic involvement, erythroderma. In this article we approach the characteristics and treatment of some adverse reactions to drugs: anaphylaxis, erythroderma, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Key-words: anaphylaxis; eryithema multiforme; drug hypersensitivity; epidermal necrolysis, toxic; pharmaceutical preparations/adverse effects; Stevens-Johnson syndrome.

INTRODUCTION

Adverse reactions to drugs are complications that are of relevance to medicinal therapy.¹ It is estimated that 5-15% of patients treated with some medication develop adverse reactions.¹

The incidence of adverse reactions to drugs in hospitalized patients is roughly 30%, 2-3% constituting cutaneous reactions.^1,2 Such reactions are seldom severe, but they might lead to high mortality rates.³

The prevalence of Severe Cutaneous Adverse Reactions to drugs (SCARD) is estimated at 1/1000 hospitalized patients. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are particularly severe.⁴ In general, fatal cutaneous drug-induced reactions occur in 0.1% of clinical patients and 0.01% of surgery patients.¹

SCARD may be defined as usually requiring hospital internment, at times in intensive therapy or burn care units for close observation of vital signs and viscera function. This group of drug reactions includes anaphylaxis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug hypersensitivity, and depending on the systemic involvement, erythroderma, acute generalized exanthematous pustulosis (AGEP), cutaneous necrosis induced by anticoagulants, drug-induced vasculitis and reactions like serum disease.⁴

Quick differentiation between SCARD and a less severe eruption may be difficult, although essential. Withdrawal of the suspected drug is the surest way of intervening to reduce mortality.⁴

Most cutaneous reactions to drugs are usually observed as a morbilliform or maculopapulous exanthema.^2,5,6 IUnfortunately, erythema morbilliform (Figure 1) most often characterizes the appearance at onset in the severest of cases, including TEN, serum disease and drug hypersensitivity syndrome.⁴

Djien et al.,³ studying 133 patients with reactions to drugs clinically presenting with erythematous cutaneous eruptions (morbilliform and scarlatiniform exanthema, maculopapulous, and small isolated papules), reached the conclusion that three types of severe clinical markers exist with respect to this kind of reaction: fever, lymphadenopathy and extensive cutaneous affection. The authors excluded specific forms from the study, such as SJS, TEN, fixed drug eruption, AGEP, phototoxicity and vasculitis. This suggests that in cases of drug-induced reactions with extensive cutaneous affection, with or without lymphadenopathy, a laboratory investigation is required with a complete hemogram and hepatic function test.

In 1994, Roujeau and Stern⁴ put forth clinical and laboratory criteria leading to the suspicion that a reaction to drugs could develop into more severe behavior (Chart 1).

This article discusses the following reactions: anaphylaxis and anaphylactoid reactions, erythroderma and the clinical spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell´s disease).

DISCUSSION

1. Anaphylaxis and Anaphylactoid Reactions

Anaphylaxis is a quick systemic reaction usually presenting a risk to life and resulting in immediate hypersensibility mediated by IgE. Anaphylactoid reactions mimic anaphylaxis, though they are not related to immulogical mechanisms.^4,7 These reactions lead to a powerful activation of mastocytes, with a massive release of mediators.^7,8

Drugs are not the more important cause of anaphylaxis as they are responsible for merely 13-20% of cases.⁸ Some of the drugs causing anaphylactic reactions are the following: beta-lactamic antibiotics (responsible for 75% of fatal anaphylactic reactions in the United States of America), cephalosporin, sulphonamides, hemoderivatives, enzymes (trypsin, chemopapaine and streptokinase), insulin (very rare nowadays, due to use of recombinant human insulin), vaccines (due to conservatives, proteic components, gelatin, and there are reports of patients showing sensitivity to eggs and having allergic reactions to vaccines), allergenic extracts, protamine and progesterone.^7,8

The anaphylactoid reactions may occur with acetylsalicylic acid, non hormonal anti-inflammatories, iodide contrasts, ACE inhibitors and fluoresceine.⁷

During general anesthesia, anaphylactic and anaphylactoid reactions may occur. They are difficult to differentiate due to the large amount of medications used, like anesthetics, muscular relaxant, analgesics, non-hormonal anti-inflammatories and antibiotics.⁷

Their clinical emergence tends to occur suddenly within 30-minute to one-hour intervals after contact with the precipitating factor, though delayed reactions are rarer. They show an appearance of pruritus, urticaria, (Figure 2) rhinoconjuntival symptoms, angioedema symptoms, especially laryngitis, hypotension and lung sounds.⁷ The following ailments may be observed: abdominal pains, diarrhea, vomiting, uterine contraction and cardiac arrhythmia. After a few hours, there is a possibility of a late phase with symptoms reappearing, though this is by no means automatic.^4,7

Identifying patients with anaphylaxis must be done as fast as possible, and treatment begun immediately.⁸ This reduces the risk of fatal reactions.⁸ SThe following are signs of anaphylaxis that pose a risk to life: presence of stridor, edema of the glottis, intense dyspnea, lung sounds, hypotension, cardiac arrhythmia, shock, convulsions and loss of consciousness.^7,8 With patients using betablockers, anaphylaxis is often severe and may be resistant to conventional treatment.⁸

Various conditions must be considered in the differential diagnosis when suspecting anaphylaxis:⁸ cardiac arrhythmia, acute myocardic infarction, food aspiration, convulsive disease, reaction to insulin, pulmonary embolism, syndromes causing (like, for example, the presence of carcinoid tumors or reaction to alcohol and chlorpropamide), hysterical behavior, vasovagal reactions and fictitious allergic reactions. Vasovagal reactions are most often confused with anaphylaxis.⁸ In general, they are consequences of procedures like injections, which present as a clinical condition consisting of facial paleness, nausea, profuse sweating and syncope, with symptoms improving without treatment 20-to-30 minutes later.⁸ Absence of pruritus in the presence of a slow pulse and normal blood pressure distinguish vasovagal reactions from anaphylaxis.⁸

The treatment of anaphylaxis consists of short and long-term measures.⁸ The immediate goal is to maintain the permeability of the air pipes and blood pressure, in addition to administering oxygen in more severe cases.⁸ Epinephrine must be administered as soon as possible, with a standard dose of 0.01 mg/kg of a 1:1000 solution, up to a maximum of 0.3-0.5 ml, subcutaneously every 10-to-20 minutes until the patient's stabilization. An algorithm for treating anaphylaxis may be observed in chart 2.⁷

2. Erythrodermas

This is a condition characterized by a state of generalized erythema and scaling (exfoliative dermatitis) of the skin. It has the morphological appearance of various cutaneous diseases, like psoriasis, atopic dermatitis, T-cell cutaneous lymphoma and reactions to drugs.⁹

The dissemination of a maculopapular condition caused by medication may lead to the emergence of an erythrodermic syndrome. Various types of drug-induced cutaneous reactions (including contact dermatitis, photosensitivity and maculopapulous reactions) would be responsible for roughly 7.3% of erythroderma cases.¹⁰ The secondary drug-induced erythroderma conditions, as opposed to erythrodermas due to other etiologies, most often set in quickly and tend to regress quickly also after withdrawing the medication being used.¹⁰

One to four weeks after starting drug use, pruritus arises in association with diffuse erythema covering roughly 90% of the body surface, then lymphadenopathy and scaling. When acute, large amounts of epidermis are exfoliated; when chronic, it produces small elements⁹ (Figure 3). Pruritus and a sensation of diffuse burning occur.⁹

Exfoliative dermatitis leads to systemic complications, such as hydroelectrolytic and thermoregulatory disturbances, high cardiac insufficiency, tachycardia, capillary leak syndrome and infection.^11,12,13 The effect of exfoliative dermatitis on the organism depends on the intensity and duration of the process.¹³ Complications from erythroderma may be seen in chart 3.

Common laboratory findings in the erythrodermic state include light anemia, leukocytosis with eosinophil, high IgE, an increase of the hemosedimentation process, a drop in seric albumin and rise in uric acid.^9,13 OIncreased IgE and eosinophil is a non-specific finding, and is found only in secondary drug-induced erythrodermas. But it might also be due to atopic dermatitis.^9,13

Multiple cutaneous biopsies performed simultaneously on distinct points of the skin might increase the accuracy of the diagnosis of the base disease.⁹ In drug-reactions, vacuolar alterations may be observed on the epidermis, as well as necrotic keratinocytes.⁹

The initial treatment of the erythrodermic patient for drug reaction is identical to treating erythrodermas from other causes.^9,13 Suspending the drug is the quickest way to improving the patient's condition. One ought to consider the nutritional state and hydroelectrolytic replacement, as well as administering local measures such as antiseptic baths, humid compresses on the crusts, applying soft emollients and low-strength corticosteroids.⁹ Classic oral anti-histamines may be prescribed to alleviate the pruritus and anxiety. They provide the patient with a warm and humid environment so as to prevent hypothermia and improve cutaneous hydration.^9,13 Symptoms and signs of cardiac and respiratory insufficiency may require emergency assistance and hospitalization.⁹ The most aggressive and debilitating erythrodermic states may require similar care to that offered to SJS or NET patients.

The differential diagnosis must be performed with other types of secondary erythrodermas to cutaneous diseases, such as psoriasis, contact dermatitis, seborrheic dermatitis, lichen planus, bullous pemphigoid, pemphigus foliaceus, as well as systemic diseases, like leukemias, T-cell cutaneous lymphoma, Hodgkin's lymphoma, in addition to secondary erythrodermic states to internal cancer.^9,13

3. The Clinical Spectrum of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (Lyell´s Syndrome)

What currently exists is a combination of concepts according to which the spectrum of erythema multiforme (EM), including EM minor (EMm) as well as major (EMM), is separated from another spectrum of reactions, which include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (Lyell´s syndrome) (TEN), here referred to as the SJS/TEN spectrum.^14-17

However, according to Assier et al.¹⁸ it seems possible to separate EMM patients from real SJS patients based on clinical symptoms and disease origin. These authors define the EMM pattern as consisting of characteristic mucous erosions and cutaneous lesions (typical targets, with or without blisters), symmetrically distributed and commonly acral. SJS would be represented by mucous erosions and disseminated cutaneous purpuric macules that are frequently confluent, with a positive Nikolsky sign and epidermal scaling limited to less than 10% of the body surface.^14,18 EM would include recurrent, post-infectious cases (especially related to herpes simplex and mycoplasma), or eventually related to exposure to medication, with a low mortality rate and without lethality. On the other hand, SJS would comprise a severe adverse drug reaction with high mortality rates and a reserved prognosis for many cases.^4,14,19

In 1993, Bastuji-Garin et al.¹⁹ put forward a clinical classification of the spectrum which included ME bullosa up to TEN. To better understand this classification,¹⁹ let us note the characteristics of the dermatological lesions of which the group consists, which are defined as follows:

- Epidermal detachment: refers to epidermal loss, which at times occurs in flaps (Figure 4).

- Typical targets: consists of lesions less than 3 cm in diameter, in disc shape, with well-defined borders, and exhibiting at least three distinct zones, namely two concentric halos around a central disk (Figure 5).

- Atypical flat targets: lesions that are not raised, but are round or disk shaped, with two zones and/or borders that are not well defined.

- Atypical raised targets: round lesions or in disk shape, palpable or raised, however without the two zones and/or well-defined borders (Figure 6).

- Macules/spots: erythematous or purpuric stains, irregularly shaped or confluent, with or without blisters (Figure 7).

Insofar as the area of epidermal necrolysis makes up one of the two main factors of prognosis, a consensus was reached on classifying the spectrum as follows:^14,19 19 SJS in cases with mucous erosions and disseminated purpuric macules and scaling of the epidermis below 10%; SJS-TEN superposition or transition in cases with epidermal scaling between 10% and 30% of the body surface, and TEN in cases with disseminated purpuric macules and epidermal scaling above 30% or in rare cases with disseminated necrolysis (over 10% scaling) without any of the lesions described above.

3.1. Stevens-Johnson Syndrome (SJS)

This is an entity characterized by the presence of lesions similar to those of erythema multiforme, however with purpuric macula and widely distributed blisters or even lesions in atypical targets disposed over the dorsal aspect of the hands, palms, plants of the feet, extensor region of the extremities, neck, face, ears and perineum, with the face (Figure 7) and trunk (Figure 8) being prominently involved.⁴ Incidence of SJS is estimated at roughly one in three cases per million residents yearly.^20,21,22

It may be preceded by a discreet maculopapulous eruption similar to exanthema morbilliform.¹⁹ Blister formations are possible, though usually not determined by an epidermal detachment of over 10% of the body surface.^4,14,19 Mucous involvement occurs in roughly 90% of cases, in general, on two distinct mucous surfaces; this may precede or follow cutaneous involvement.^4,14,19 Onset begins with enanthema and edema, which give rise to erosions and pseudomembranous formations on the eyes, mouth, genitals, pharynx and upper air ways.¹⁹ Some 10 to 30% of cases occur with fever and lesions in the gastrointestinal and respiratory tracts.⁴ Its prognosis appears to not be affected by the type and dose of the drug responsible, nor by HIV infection.⁴

The therapeutic options for SJS are limited and controversial.^4,23,24 Corticosteroids are frequently used,²⁵ however some cases have not shown satisfactory response.²⁴ In agreement with most authors, the use of systemic corticosteroids on the initial SJS and TEN forms do not currently demonstrate any proven benefits. The advanced forms of this spectrum of relations have clearly deleterious effects on the patient.²⁶ The treatment and prognosis of SJS will be tackled in combination with that of TEN.

3.2 Toxic Epidermal Necrolysis (TEN) or Lyell´s Syndrome

This is an entity characterized by extensive scaling of the epidermis in the wake of necrosis (epidermal necrosis).^4,14,15 The term "toxic epidermal necrosis" was introduced by Lyell in 1956.¹⁴ Fortunately, it consists of a very rare adverse reaction to drugs. In Europe, its incidence is estimated to be at 1-1.⁴ cases per million residents yearly.²⁶ With AIDS patients, however, the risk of this reaction does rise, estimated at one case per every 1,000 patients yearly.¹⁴ In general, there is a slight predominance among women (1.5-to-2 cases in females for every male case). Indeed, the disease's occurrence in Aids patients ends up balancing out the incidence rate between the sexes.¹⁴

The initial characteristics of TEN are non-specific influenza-like symptoms, such as fever, sore throat, coughing and burning eyes. These are considered prodromic manifestations preceding a cutaneous and mucous affection by one to three days.⁴ An erythematous eruption emerges symmetrically on the face (Figure 9) and in the upper part of the trunk, extending to the craniocaudal region to provoke symptoms of burning or painful skin.^4,14 The individual cutaneous lesions are, for the most part, characterized by erythematous macules with poorly defined contours and a purple center. They progressively spread over the anterior thorax and back (Figure 10).^4,14 In some cases, less commonly, the initial eruption may consist of an extended scarlatiniform exanthema. In roughly two to five days or, at times, within a few hours, or more seldom, in about a week, the complete extension of the cutaneous condition occurs.¹⁴ At first, some cases may see lesions persisting in sun-exposed areas of the skin.¹⁴ The apex of the process consists of characteristic denuding of the necrotic epidermis, standing out as veritable red strips or flaps on the areas affected by the base erythema (Figure 11).^4,14

The epidermis is raised by the serum content of flaccid blisters, which are progressively confluent and provoke rupture of the blisters and detaching of the skin. This causes an aspect of severe burns on the patient's skin, with the skin denuded, bleeding and with an erythematous-purple color, and with continued elimination of serosity, which contributes to hydroelectrolytic unbalance and accentuated protein loss.^4,14 The Nikolsky sign is positive over widespread areas of the skin.^4,14 The areas of the skin subjected to pressure, like the lower shoulders, back and buttocks, are the first to release epidermal flaps.^4,14 The cutaneous extensor affection might determine a state of acute cutaneous failure (Chart 4).^15,27 The cutaneous surface can virtually be affected 100%, though scalp affection is exceptional.¹⁴ Some 85-95% of patients experience affection of the mucous membranes. It is common for the latter to precede skin involvement by a day or two.¹⁴ In the order of frequency, the disease afflicts the oropharynx, eyes, genitalia and anus.¹⁴ Extensive and painful erosions lead to labial crusts, salivation, feeding obstruction, photophobia, painful urination and evacuation.¹⁴

Severe eye sequelae, with the formation of synechias between the eyelids and conjunctiva by pseudomembranous conjunctival erosions, and blindness may occur.^4,14 Ceratitis and corneal erosions have been reported, as well as a secondary siccalike syndrome.¹⁴

High fever or hypothermia may occur due to a thermoregulatory imbalance until complete healing, even in the absence of concomitant infections.¹⁴ AThe abrupt drop in temperature is more indicative of sepsis than of fever itself.¹⁴ Psychomotor agitation and mental confusion are not uncommon, and are usually indicative of hemodynamic complications and sepsis.¹⁴ Many internal organs are affected by the same pathological process that involves the skin and determines a spectrum of systemic manifestations.^4,14

Systemic involvement occurs causing erosion in the esophagus, in the gastrointestinal tract, which may progress into esophagal constrictions, transaminasis increases in 50% of cases (hepatitis in 10%), pseudomembranous colitis and pancreatitis.²³ In the respiratory tract tracheobronchial erosions and secondary pulmonary interstitial edema or not, with the correction of hypovolemia, can be found.¹⁵ Anemia can be constantly observed, as well as lymphopenia in up to 90% of patients.¹⁵ Thrombocytopenia is found in 15% of patients; neutropenia occurs in 30% of cases, and when present it indicates a worse prognosis.^15,23

The medications most commonly causing TEN are sulfas, phenobarbital, carbamazepine, dipyrone, piroxicam, phenylbutazone, aminopeniciline and allopurinol. However, it is necessary to consider that new drugs are continually being reported as triggering TEN.^4,14,15,23

Considerations on the Physiopathology of SJS and TEN

The exact mechanism by which SJS and TEN develop is not to well defined.

Some authors have suggested the participation of the altered metabolism of drugs with the predominance of a slow acetylator genotype in SJS and TEN patients, and a deficiency in the mechanisms involved in detoxification of reactive intermediary metabolites.^28,29,30

In addition to the metabolic mechanisms, there is evidence to suggest that, especially in TEN, the epidermal necrosis is mediated immunologically.^4,14,30 It is known today that SJS and TEN are disturbances mediated by T-cells, similarly to acute graft-vs-host disease (GVHD), with cytotoxic T-cells being responsible for the epidermal necrosis through an apoptosis in eratinocytes.^14,30

Posadas et al.³¹ have shown the association of high TNF-alpha levels (tumor necrosis factor alpha) with the severity of the reaction. This cytokine has been related to an induction in the adhesion and activation of T-cells and monocytes. It also participates in the apoptosis, irrespective of the action of perforins.³¹ It has been demonstrated also that apart from TNF-alpha, the perforins, GRB (Granzyme B) and a Fas ligand (FasL) are found to be high in the initial stages of a drug-reaction, particularly in SJS and TEN. This reinforces the hypothesis of the participation of cytotoxic mechanisms.³¹

Correia et al.³² have observed a similar seric cytokine profile between TEN and acute GVHD. These authors showed a significantly high seric level of IL-6 (interleukin 6) and IL-10 (interleukin 10) in TEN and acute GVHD patients as opposed to normal blood donors.³² IL-6 Is a multifunctional pro-inflammatory cytokine produced by various cells, including the keratinocytes. It consists of a main circulating endogenous pyrogen.³² This explains the presence of fever that is unrelated to the infection in the first days of TEN and GVHD.³² In turn, IL-10 is an endogenous anti-pyrogen agent. It is produced by keratinocytes with the purpose of blocking inflammatory cytokines like IL-1, IL-6 and TNF-alpha, in addition to being a powerful suppressant of macrophage, T-cell and NK-cell functions.³² By contrast, as IL-10 recruits CD8+ lymphocytes from the peripheral blood, its increase in blister fluid explains the high number of these cells in patients' epidermis.³²The elevation of IL-10 makes up a natural mechanism against excessive tissue inflammatory reaction.³²

Chosidow et al.³³ have suggested that the cellular cytotoxic targets are viral antigens with a potential to alter immune responses resulting from exposure to medications.

Considerations on treating SJS and TEN

Treatment for SJS and TEN patients is similar to that for patients who have suffered extensive burns, with a number of rare exceptions.²³ All patients have to submit to cutaneous biopsy to confirm the diagnosis.²³ The patient must be observed in an ITU, in an isolated and heated environment so as to avoid any cutaneous trauma.^4,14,23 The treatment must proceed by suspending any drug that is not essential to the patient's life and begin replacement of intravenous fluid, mainly when an oral mucous lesion obstructs liquids from being ingested.^4,14,23 Isolation and feeding through the nasogastric probe must be done, because the patient shows calorie and protein loss.^4,14,23

Corticosteroids should only be administered within 48 hours of the condition's onset. It has not proved to be beneficial after this period due to its delaying epithelization and increasing proteic catabolism, in addition to increasing the risk of infection.^23,26

Antibioticotherapy has to be performed on cases in which a sudden drop in temperature occurs and with a drop in the general state or increase of cultivated bacteria on the skin with a predominance of a single strain.^23,26 It must be emphasized that during the first days, the most common infections are by Staphylococcus aureus and later by gram-negatives (Pseudomonas aeruginosa) or Candida albicans.²³

The general therapeutic measures for more severe cases of SJS and TEN can be viewed in chart 5.²⁷

Cases do exist of non-controlled reports and studies on treating TEN, as using intravenous immunoglobulin, cyclosporine, cyclophosphamide, plasmapheresis, anticytokine monoclonal antibodies, among others, in an attempt to curb the process of epidermal necrosis. The value of these studies has been questioned though, particularly owing to the fact that in most patients who are hospitalized the phenomenon of necrosis virtually comes to a halt.¹⁵

Recently Prins et al.³⁴ published the multicentric and retrospective study on intravenous immunoglobulin use in treating TEN patients, which obtained excellent results. A 48-patient cohort, average age 43 years (+24) and consisting of 24 women and 24 men, with a 10-95% variation of epidermal detachment of the total body surface area. Mucous was affected in 91.7% of these patients. The patients received intravenous infusion of gammaglobulins begun on average seven days after onset of TEN (with a variation of two to 30 days). It was administered over a period of one to five days, in doses varying from 0.65-to-5.8 g/kg (mean total dose of 2.7 g/kg). An objective positive response to treatment occurred with a break in the progression of TEN, observed in 43 (90%) of the 48 patients. In all, there were six deaths. The authors concluded that early use of intravenous gammaglobulin is safe, with a recommended dose of 1 g/kg daily for three days in a row. In contrast to the studies of Prins et al.,³⁴ the French group (Bachot, Revuz and Roujeau) led a non-comparative, prospective study of 34 patients diagnosed with SJS (nine patients), SJS-TEN overlapping (five patients) and TEN (20 patients). They concluded that intravenous gammaglobulin in a 2g/kg daily dose, administered for two days in a row, did not reduce patient mortality.³⁵

Until such discrepancies in the results have been cleared up, intravenous gammaglobulin use in treating TEN will remain controversial.³⁶ However, as the volume of data encourages its application and effective alternate therapies keep lacking, it seems difficult to not suggest a high dose of intravenous gammaglobulin, especially as a way of intervening early on quickly progressing TEN cases.

Considerations on the prognosis

Whereas mortality rate is low for EMM (< 1%) and SJS (roughly 5%), it is above 40% for TEN patients with macules.³⁷ The mortality rate rises with age range and increased surface area of the epidermal scaling.³⁷

CONCLUSIONS

In the paper, the authors sought to synthesize the main topics related to diagnosing the lesion spectrum of SJS and TEN. They emphasized the classification methodology adopted by multicenter studies, prospectively named SCARD (Severe Cutaneous Adverse Reactions). The results of the latter were recently published based on the analysis of 552 patients and 1.720 controls.³⁸ This classification system may be viewed in chart 6.

Despite the large range and amount of drugs that may pose a great risk of contracting SJS and TEN, an annual risk rate of five cases per year among medication users has not been exceeded.³⁹

REFERENCES

Received on April 29, 2003.

Approved by the Consultive Council and accepted for publication on December 17, 2003.

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*

Work done at São Paulo Hospital do Servidor Público Estadual and the Complexo Hospitalar Padre Bento de Guarulhos, Sao Paulo state.

Publication Dates

• Publication in this collection
  21 Sept 2004
• Date of issue
  Aug 2004

History

• Accepted
  17 Dec 2003
• Received
  29 Apr 2003