Adverse cutaneous drug reactions S ES E C T I O N 2

 

 

Introduction

 

A drug may be defined as a chemical substance, administered for the investigation, prevention or treatment of diseases or symptoms, real or imagined. An adverse drug reaction (ADR) may be defined as an undesirable clinical manifestation resulting from administration of a particular drug. The skin is often the first place where ADRs are noted when we call adverse cutaneous drug reactions (ACDRs).

 

Cutaneous reactions to drugs occur in up to 8% of hospitalized patients. Up to 5% of patients treated with antibiotics and aromatic anticonvulsants may develop a cutaneous eruption. Approximately 2% of all drug-induced skin reactions are considered “serious” according to the following World Health Organization (WHO) definition: “if it results in death, requires hospitalization or prolongation of existing hospital stay, results in persistent or significant disability/incapacity, or is life-threatening”. Toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS; also referred to as drug-induced hypersensitivity syndrome [DIHS]) are examples of such “serious reactions”. Roujeau and Stern estimated that 1 of every 1000 hospitalized patients has a serious cutaneous drug reaction. Prompt identification of severe cutaneous adverse reactions (SCARs) is an important goal, followed by discontinuation of the most likely offending drug(s) and thereby decreasing morbidity

 

 

Risk of adverse drug reactions among different patient groups

 

Certain patient groups are at increased risk of developing an ADR.

 

Age: The incidence of adverse reactions increases with patient age, the elderly have a significantly higher incidence of ADRs, related to decreased organ reserve capacity, altered pharmacokinetics and pharmacodynamics, and polypharmacy.

 

Sex: Women are more likely than men to develop ADRs.

 

Immunosuppressed:  patients are most frequently affected, such as those with connective tissue diseases, including systemic lupus erythematosus (SLE), AIDS patients and lymphoma.

 

 

Pathogenesis

Drug-induced skin reactions are mediated by either nonimmunologic or immunologic mechanisms. About 80% of drug reactions are nonimmunologic which are predictable, usually dose-dependent, related to the known pharmacological actions of the drug and occur in otherwise normal individuals. Side effects are unavoidable at the regular prescribed dose.  Immunologic reactions are unpredictable, dose-independent, are not related to the pharmacological action of the drug and may have a basis in genetic variation in drug bio activation and drug or metabolite detoxification or clearance. In immunologic reactions, drugs or their metabolites act as haptens, inducing a specific cell-mediated or humoral response.

 

MECHANISMS OF CUTANEOUS DRUG-INDUCED REACTIONS
Immunologic mechanism (unpredictable)	·       IgE-dependent drug reactions   ·       Cytotoxic drug-induced reactions   ·       Immune complex-dependent drug reactions   ·       Cell-mediated reactions
Non-immunologic mechanisms (sometimes predictable)	·       Overdose   ·       Pharmacologic side effects   ·       Cumulative toxicity   ·       Delayed toxicity   ·       Drug–drug interactions   ·       Alterations in metabolism   ·       Exacerbation of disease
Idiosyncratic with a possible immunologic mechanism (unpredictable)	·       DRESS   ·       SJS/TEN   ·       Drug reactions in the setting of HIV infection   ·       Drug-induced lupus(LE) .

Immunologically Mediated Drug reactions

 

·       IgE-dependent drug reactions (formerly type I, Gell–Coombs classification): urticaria, angioedema, and anaphylaxis.

 

·       Cytotoxic drug-induced reactions (antibody against a fixed antigen; formerly type II): petechiae secondary to drug-induced thrombocytopenia.

 

·       Immune complex-dependent drug reactions (formerly type III): vasculitis, serum sickness, and certain types of urticaria.

 

·       Delayed-type, cell-mediated drug reactions (activation of CD4⁺ and CD8⁺ T cells; formerly type IV): exanthematous, fixed, and lichenoid drug eruptions, as well as Stevens–Johnson syndrome (SJS) and TEN. This group has been further subdivided into the following:

 

1.   Th1 immune reaction (IVa): monocytes are preferentially recruited and activated by IFN-γ, leading to CD8⁺ T-cell activation and a proinflammatory response (TNF, IL-12)

 

2.   Th2 immune reaction (IVb): eosinophils are preferentially recruited and activated in part by IL-4, -5, -13 and eotaxin, as in DRESS

 

3.   Cytotoxic immune reaction (IVc): involves CD4⁺ and CD8⁺ T cells with release of perforin and granzyme B and/or Fas–FasL interactions, as in SJS/TEN  

 

4.   Neutrophil and T-cell-based immune reaction (IVd): mediated via chemokines (e.g. CXCL8) and cytokines (e.g. GM-CSF), as in acute generalized exanthematous pustulosis (AGEP)

Several immunologic mechanisms have been proposed to explain SCARs including:

 

(1) The hapten/pro-hapten concept – the drug or its metabolite covalently binds to an endogenous peptide and the resultant hapten is recognized by a highly restricted major histocompatibility complex (MHC);

 

(2) The pharmaco immune reaction (“p-i concept”) – drugs induce formation of HLA–drug complexes that can directly activate T-cell immune responses without the need for a specific peptide ligand; and

 

(3) Direct HLA–drug interactions – certain drugs such as carbamazepine, abacavir and sulfamethoxazole bind non-covalently within the peptide groove of a specific HLA and modify the antigen-binding cleft, thereby altering the endogenous peptide repertoire.

 

Genetic factors

 

Specific HLA alleles have emerged as important genetic risk factors for SCARs, especially SJS/TEN and DRESS. Given the strong associations between HLA-B*1502 and carbamazepine-triggered SJS/TEN in Asians and between HLA-B*5701 and abacavir-triggered DRESS, pretreatment genetic testing is now recommended.

 

Non-immunologic Mechanisms  

 

Overdose

 

The clinical manifestations of a drug overdose are predictable and represent an exaggeration of the medication’s pharmacologic actions. It may occur as a consequence of a prescribing error, deliberate excess by the patient, or altered absorption, metabolism or excretion. An example of the latter is methotrexate toxicity in elderly patients with reduced renal function.

 

 

Pharmacologic side effects

 

These reactions include undesirable or toxic effects that cannot be separated from the desired pharmacologic actions of the drug. An example would be alopecia and mucositis due to chemotherapeutic agents that target more rapidly dividing cells.

 

Cumulative toxicity

 

Prolonged exposure to a medication or its metabolites may lead to cumulative toxicity. For example, methotrexate can lead to hepatic fibrosis and accumulation of minocycline or amiodarone within the skin can lead to cutaneous discoloration.

 

Delayed toxicity

 

This corresponds to a toxic, dose-dependent effect that occurs months to years after the discontinuation of a medication. Examples include squamous cell carcinomas and palmoplantar keratoses following exposure to arsenic and acute leukemia due to alkylating agents.

Drug–drug interactions

 

Interactions between two or more drugs administered simultaneously may occur at several different steps: (1) intestinal drug interactions; (2) displacement from binding proteins or receptor sites; (3) enzyme stimulation or inhibition; and (4) altered drug excretion. Examples of each include the interactions between tetracycline and calcium, methotrexate and sulfonamides, cyclosporine and azoles, and methotrexate and probenecid.

 

Alterations in metabolism

 

Drugs may induce cutaneous changes by their effects on the nutritional or metabolic status of the patient. Bexarotene may induce severe hypertriglyceridemia and eruptive xanthomas, while isoniazid may be associated with pellagra-like changes.

 

Exacerbation of disease

 

A variety of drugs can exacerbate pre-existing dermatologic diseases, such as androgens in patients with acne vulgaris or lithium and interferon in patients with psoriasis.

 

 

Idiosyncratic with a Possible Immunologic Mechanism

 

The pathophysiology of drug-induced skin reactions such as exanthematous drug eruptions, DRESS, AGEP and TEN, as well as the increased susceptibility of HIV-infected patients, may be partially explained by an interplay between immune mechanisms and genetic predisposition (e.g. slow versus rapid acetylators).

 

 

Diagnostic Features

 

Drug eruptions, suspected and unsuspected, frequently lead to a dermatologic consultation, and it is often (although not always) possible to categorize a drug as having a high, medium or low probability of being the culprit. A logical approach begins with an accurate description of the skin lesions and their distribution, in addition to associated signs and symptoms. Data regarding all the drugs taken by the patient, including prescription, non-prescription/over-the-counter and complementary or alternative treatments, as well as the dates of administration and doses need to be collected. The chronology of drug administration is of paramount importance. The time between initiation of the drug and the onset of the skin eruption is a key element in identifying the offending drug, as most immunologically mediated reactions occur 8 to 21 days after initiation of a new medication.

 

LOGICAL APPROACH TO DETERMINE THE CAUSE OF A DRUG ERUPTION
Drug responsibility assessment
Clinical characteristics	·       Type of primary lesion (e.g. urticaria, erythematous papule, pustule, purpuric papule, vesicle, or bulla)   ·       Distribution and number of lesions   ·       Mucous membrane involvement, facial edema   ·       Associated signs and symptoms: fever, pruritus, lymph node enlargement, visceral involvement
Chronological factors	·       Document all drugs to which the patient has been exposed (including OTC and complementary) and the dates of administration   ·       Date of eruption   ·       Time interval between drug introduction (or reintroduction) and skin eruption   ·       Response to removal of the suspected agent   ·       Consider excipients (e.g. soybean oil)   ·       Response to rechallenge (often inadvertent)

 

Evolution after drug withdrawal may be helpful, as the cutaneous eruption usually clears when the suspected drug is discontinued. However, this assessment may prove difficult in the case of drugs with a long half-life or “persistent” drug reactions such as lichenoid and photo allergic eruptions or drug-induced pemphigus foliaceus and subacute cutaneous lupus erythematosus.

The suspect drug should be withdrawn as soon as possible. The usual practice is to discontinue all drugs that are non-essential. However, in some instances, it is necessary to weigh the risks versus the benefits of each drug and to determine if a similar-acting, but non-cross-reactive, drug is available as a substitute.

 

In the process of identifying the responsible drug, access to drug databases is very helpful. However, new or unusual drug reactions may not be identified. Moreover, the drug most frequently associated with adverse reactions may be innocent in a particular patient, and the physician dealing with a suspected drug reaction must remain open-minded.

 

Rechallenge carries the risk of inducing a more severe reaction, thus limiting its use for both ethical and medico-legal reasons. Furthermore, the recurrence rate is not 100% with rechallenge (e.g. there are refractory periods) and a negative result may give an erroneous sense of security. Even with these limitations, in patients with fixed drug eruptions, topical provocation or rechallenge may prove helpful.

 

 

Findings indicating possible life-threatening ACDR

 

• Skin pain.

• Confluent erythema.

• Facial edema or central facial involvement

• Palmar/plantar painful erythema.

• Epidermal detachment and blisters.

• Positive Nikolsky sign.

• Mucous membrane erosion.

• Urticaria.

• Swelling of the tongue.

• High fever (temperature > 40 degree C).

• Enlarged lymph nodes.

• Arthralgia.

• Shortness of breath, wheezing, and hypotension.

• Palpable purpura.

• Skin necrosis.

 

 

 

CLINICAL TYPES OF ADVERSE DRUG REACTIONS

 

 

Drug eruptions can mimic all the morphologic form in dermatology and must be suspected when an eruption appear suddenly.

 

Clinically cutaneous drug reactions commonly present as:

 

EXANTHEMATOUS, URTICARIA/ANGIOEDEMA, PUSTULAR or BLISTERING

Exanthematous reactions include maculopapular rashes and drug hypersensitivity syndrome. Urticarial reactions include urticaria, angioedema, and serum sickness-like reactions. Blistering reactions include fixed drug eruptions, Stevens-Johnson’s syndrome, and toxic epidermal necrolysis. Pustular eruptions include acneiform drug reactions and acute generalized exanthematous pustulosis. 

 

 

 

Drug‐induced exanthem

 

Introduction 

 

Exanthematic eruptions can be caused by a variety of drugs and resemble in appearance the classical rash of a viral infection, for which the paradigm is the morbilliform rash associated with measles. Typically, exanthematic drug reactions do not show the systemic involvement, such as fever, that would characterize a viral infection.

It is most common type of cutaneous drug reactions accounting for 90% of skin reactions.

 

 

Etiology

 

Any drugs can induce an exanthematous drug reaction in approx. 1% of patients, but few drugs can affect >3% of patients: aminopenicillins, sulphonamides, cephalosporin, aromatic anticonvulsants. non‐steroidal anti‐inflammatory drugs (NSAIDs) and allopurinol.

 

Certain viral infections are also known to increase the incidence of drug reactions. Depending upon the series, the frequency of aminopenicillin-induced exanthematous eruptions in patients with infectious mononucleosis ranges from 33% to 100%. One theory is that reactive drug metabolites disturb the balance between cytotoxic and regulatory immune responses, leading to a cytotoxic reaction that targets virally infected keratinocytes.

 

 

Pathophysiology

 

The primary underlying pathomechanisms are most likely immunologic, complex, and cell-mediated. Several mechanisms have been proposed (see above) in which the drug or drug-peptide hapten presented by dendritic cells to T lymphocytes can either bind covalently or non-covalently to MHC molecules. CD4⁺ and CD8⁺ T cells that strongly express perforin and granzyme are then recruited and their cytotoxic activity leads to death of keratinocytes.

 

 

Clinical features

 

The eruption, macules and/or papules classically begins 1-3 weeks after the start of a new medication, on the trunk and spreads peripherally in a bilateral and symmetric fashion to the extremities accompanied by pruritus, intertriginous areas may be a favored site but the face is typically spared.  In children, it may be limited to the face and extremities. In time, lesions become confluent forming large patches, polycyclic/gyrate erythema, reticular eruptions, or sheet-like erythema. It is typically confluent on the trunk, and discrete on the extremities. Palmar and plantar lesions may occur, and sometimes the eruption is generalized. In individuals with thrombocytopenia, exanthematous eruptions can mimic vasculitis because of intralesional hemorrhage. The eruption is typically more polymorphous than a viral exanthem. Sometimes, due to dependency, the lesions on the distal lower extremities become petechial or purpuric. Mucous membranes are usually spared but pruritus and a low-grade fever are often present. There may also be annular plaques or atypical “target” lesions, leading to a misdiagnosis of erythema multiforme. There may be relative sparing of pressure areas. It can even occur 1-2 days after the drug has been discontinued and within 2-3 days after re-administration of drug in previously sensitized patient.

 

 

Differential diagnosis

 

Viral infection is the most important differential diagnosis. It is useful in differentiating exanthematic drug eruptions from viral exanthems to remember that viral rashes tend to start on the face and acral sites with subsequent progression to involve the trunk, and are more often accompanied by fever, sore throat, gastrointestinal symptoms, conjunctivitis, cough and insomnia. Enanthems, which involve the mucous membranes, are more commonly associated with an infectious etiology. Peripheral blood eosinophilia and a polymorphous appearance point to a drug eruption, and in the absence of definitive evidence, drug eruptions are favored in adults whereas viral exanthems are favored in children.

 

 

Disease course and prognosis

 

The illness follows a benign course, and resolves without complications and/or sequelae following cessation of the offending drug. Once the drug is discontinued, the eruption disappears spontaneously after 1-2 weeks with a change in color from bright red to dark red, which may be followed by desquamation, sometimes with post‐inflammatory hyperpigmentation. However, for 1 to 3 days immediately following discontinuation of the responsible medication, an increase in extent and intensity may be observed. If the administration of the drug is continued, an exfoliative dermatitis may develop, although occasionally the eruption subsides despite continuation of the medication. Morbilliform drug eruptions usually, but not always, recur on rechallenge.

 

Of more concern, a morbilliform eruption may be the initial presentation of a more serious eruption, i.e., SJS, TEN, or drug hypersensitivity syndrome. Signs and symptoms that point to the possibility of a more severe drug-induced eruption include edema of the face, pustules, vesicles, dusky or painful lesions, skin fragility, mucous membrane involvement, and marked peripheral blood eosinophilia.

 

 

Pathology

 

Histology is generally non‐specific i.e. a mild superficial perivascular and interstitial lymphocytic infiltrate that may contain eosinophils (up to 70% of cases) in addition to interface changes.

 

 

Investigations

 

Blood tests to exclude organ dysfunction and hematological abnormalities associated with DRESS are important.

 

 

Treatment

 

Cessation of the culprit drug is essential. Generally, symptomatic treatment only is required; most cases benefit from emollients. Approximately 50% of exanthematous eruptions are pruritic and intermediate potency topical corticosteroids may be useful for these cases.

Resolution of drug‐induced exanthems is faster than for infectious exanthems.

 

 

 

Drug- induced acute urticaria, angioedema, and anaphylaxis

 

Salient features

 

• Drug-Induced urticaria and angioedema occur, caused by a variety of mechanisms and are characterized clinically by transient wheals and angioedema causing extensive tissue swelling with involvement of deep dermal and subcutaneous tissues. Angioedema is often pronounced on the face or mucous membranes (tongue).

• In some cases, cutaneous urticaria/angioedema is associated with systemic anaphylaxis, which is manifested by respiratory distress, vascular collapse, and/or shock.

 

Time from initial Drug Exposure to Appearance of Urticaria

 

• IgE-Mediated: Initial sensitization, usually 7 to 14 days. In previously sensitized individuals, usually within minutes or hours.

 

• Immune Complex-Mediated: Initial sensitization, usually 7 to 10 days, but as long as 28 days; in previously sensitized individuals, 12 to 36 h.

 

• Analgesics/Anti-Inflammatory Drugs: 20 to 30 min (up to 4 h).

 

Prior Drug Exposure

 

Radiographic Contrast Media: 25 to 35% probability of repeat reaction in individuals with history of prior reaction to contrast media.

 

Skin symptoms

 

Pruritus, burning of palms and soles, airway edema with breathing difficulties

 

Constitutional symptoms

 

IgE-mediated: Flushing, sudden fatigue, yawning, headache, weakness, and dizziness; numbness of tongue, sneezing, bronchospasm, substernal pressure, and palpitations; nausea, vomiting, crampy abdominal pain, diarrhea, and possibly arthralgia.

 

 

Introduction  

 

Urticaria and angioedema are physical signs characterized by short-lived swellings of the skin and mucosa due to plasma leakage. Anaphylaxis is a constellation of clinical findings which describes respiratory and cardiovascular compromise (bronchoconstriction and hypotension) in a life‐threatening manner.  

Drug‐induced urticaria can be seen in isolation or in association with anaphylaxis and angioedema. Aspirin and NSAIDs are the most frequently implicated drugs causing urticaria and β‐lactams antibiotics and NSAIDs are the most frequently implicated drugs causing anaphylaxis.

 

Urticaria develops in about 1% of patients receiving blood transfusions; it may also follow alcohol consumption, intraarticular methylprednisolone and even cetirizine.

 

 

Epidemiology

 

Urticaria is the second most common type of ACDR after exanthematous eruption.

 

 

Pathophysiology

 

In urticaria, there is vasodilation and transient edema within the superficial dermis whereas in angioedema, the edema is present in deep dermal, subcutaneous, and submucosal tissues.  The mechanisms underlying drug‐induced urticaria, angioedema (deeper in skin) and anaphylaxis (systemic circulation) are identical. Classically, these reactions are mediated by the presence of drug‐specific IgE. On exposure to the drug, cross‐linking of IgE on the surface of mast cells (and possibly basophils) is followed by inflammatory mediator release (including histamine), which induces vasodilation, neuronal activation and smooth muscle contraction. Clinically, “anaphylactoid” reactions may mimic IgE-induced histamine release, but are secondary to a non-immunologic liberation of histamine and/or other mediators of inflammation. Cyclo‐oxygenase inhibitors, such as aspirin and indometacin, may also cause urticaria or angioedema by pharmacological mechanisms. Other drugs, such as radiocontrast media, local anesthetics and dextrans (in plasma expanders) may release mast cell mediators directly. Angiotensin‐converting enzyme (ACE) inhibitors can cause angioedema which is bradykinin mediated rather than histamine dependent and will therefore not respond to antihistamines.

 

 

Clinical features

 

Urticaria, angioedema and anaphylaxis arise within 24–36 h of drug ingestion at the first occasion. On re‐challenge lesions may develop within minutes. Anaphylaxis usually develops on second exposure to a drug. Anaphylaxis and anaphylactoid reactions usually develop within minutes to hours (the vast majority within the first hour) of drug administration.

 

Urticaria 

 

Urticaria presents as transient, often pruritic, erythematous and edematous papules and plaques that may appear anywhere on the body, including the palms, soles, and scalp. Lesions can vary significantly in size and number and may assume a figurate configuration. The primary effector cell is the cutaneous mast cell which releases histamine and other inflammatory mediators.

 

Although drugs are thought to be responsible for <10% of all cases of urticaria, they are more often associated with acute rather than chronic urticaria. That said, patients with chronic urticaria should avoid acetylsalicylic acid (ASA; aspirin), as well as other NSAIDs, as they can lead to an exacerbation.

In IgE-mediated urticaria, lesions typically appear within minutes to less than an hour after drug administration, especially when there has been prior sensitization. Both immunologic assays, such as radio­allergosorbent tests (RAST) that detect specific IgE antibodies and skin tests (prick tests) can prove useful in confirming the diagnosis. However, the number of drugs for which there are commercially available assays is limited, consisting primarily of penicillin, aminopenicillin, cephalosporin, and insulin. Of course, prick tests should be performed under appropriate medical supervision due to the risk of an anaphylactic reaction. It should also be noted that in some series, only 10–20% of patients who reported a history of penicillin allergy were truly allergic when assessed by skin testing.

 

Drugs that most frequently produce immunologically-based urticaria are antibiotics, especially penicillins and cephalosporins, and less often, sulfonamides and minocycline. As the use of monoclonal antibodies for neoplastic and inflammatory diseases increases, so will cases of urticaria (and vasculitis; see below) due to these exogenous proteins.

 

In anaphylactoid reactions, vasodilation results from the liberation of large amounts of histamine, bradykinin, and/or leukotrienes. Acetylsalicylic acid is the classic example of a drug that induces an anaphylactoid reaction and it does so via cyclooxygenase inhibition and subsequent accumulation of leukotrienes. The majority of urticarial reactions to radiocontrast media are also non-immunologic, as are many, but not all, reactions to NSAIDs (e.g. ibuprofen, naproxen). Allergic reactions to latex in gloves or medical devices can induce local or generalized urticaria, especially in the case of direct contact with mucosal surfaces.

 

 

ADVERSE REACTIONS TO RADIOCONTRAST MEDIA

Iodinated

1.   Immediate (<1 hour) ·       Urticaria (usually non-immunologic), angioedema ·       Anaphylactoid reaction 2.     3.   Delayed (1 hour to 1 week) ·       Morbilliform eruption ·       Acute generalized exanthematous pustulosis (AGEP) ·       Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) ·       Iododerma (also >1 week)

Gadolinium

>Urticaria, erythema (rare) >Anaphylactoid reactions, anaphylaxis (rare) >Nephrogenic systemic fibrosis (in the setting of renal insufficiency)

 

 

Angioedema 

 

Angioedema is a reflection of transient edema of the deep dermal, subcutaneous and submucosal tissues. It is associated with urticaria in 50% of cases and may be complicated by life-threatening anaphylaxis. Angioedema occurs in 1 to 2 per 1000 new users of angiotensin-converting enzyme (ACE) inhibitors and is due to an accumulation of bradykinin. The most severe cases of angioedema may start within a few minutes after drug administration. However, in the case of ACE inhibitor-induced angioedema, lesions may appear from 1 day to several years after starting the drug; most appear within the first year. Women are at increased risk for developing ACE inhibitor-induced angioedema.

The most common clinical presentation is an acute, asymmetric, pale or pink, subcutaneous swelling involving the face. Involvement of the oropharynx, larynx, and epiglottis can lead to impaired swallowing and stridor. Occasionally, in drug-induced angioedema, there is edema of the intestinal wall with abdominal pain, nausea, vomiting, and diarrhea.

 

The major drugs implicated in angioedema, besides penicillins and ACE inhibitors, are NSAIDs, radiographic contrast media and, more recently, monoclonal antibodies. Although angiotensin II receptor antagonists do not increase levels of bradykinin, they are also associated with angioedema, albeit less frequently. It is important to note that drug-induced angioedema may actually represent an unmasking of another cause for angioedema, e.g. acquired C1 inhibitor deficiency due to autoimmune or lymphoproliferative disorders.

 

Anaphylaxis

 

Anaphylaxis consists of an acute life-threatening reaction that occurs within minutes of drug administration, usually parenteral. It occurs in about 1 per 5000 exposures to penicillin. Intravenous administration is associated with more severe reactions and rapid progression.

 

Etiopathogenesis

Anaphylaxis is caused by activation of cells of the immune system, primarily mast cells in the skin and mucous membranes and basophil granulocytes in the blood. This activation can take place either via immunoglobulin E antibodies or by direct release of mediators (non-immunological anaphylaxis, pseudo-allergy). Risk factors for severe anaphylaxis include underlying diseases such as mastocytosis, the use of β-blockers or angiotensin-converting enzyme inhibitors. In certain patients, anaphylactic symptoms occur only after the combined action of various stimuli, such as physical exertion, mental or emotional stress, acute infection or simultaneous exposure to irritants (e.g., alcohol) or additional allergens. For this phenomenon, it is often used the term summation or augmentation anaphylaxis and consider it much more common than generally suspected.

The most frequent triggers of anaphylactic reactions are the following:

·        Drugs (all forms of application)

·        Food products

·        Insect venoms

·        (in Childhood foods are the most frequent elicitors)

Other triggers are:

·        Aeroallergens

·        Contact urticariogens

·        Seminal fluid

·        Occupational substances (e.g., latex)

·        Cold, heat, UV radiation

·        Echinococcal cysts

·        Additives

·        Summation factors, including exercise, infection, stress, concomitant exposure to other allergens, medication: β blockers, NSAIDs

·        Idiopathic

·        Underlying diseases: C1 inhibitor deficiency, systemic mastocytosis

 

The most frequently incriminated drugs are antibiotics, in particular the penicillins/aminopenicillins but also cephalosporins and quinolones; additional causes are muscle relaxants (e.g. suxamethonium), acetaminophen, and gadolinium-based contrast media. Anaphylaxis can also be seen following exposure to latex while anaphylactoid reactions are usually seen with NSAIDs and radiocontrast media. Rarely, anaphylaxis occurs following cutaneous injections (e.g. local anesthetics) or topical applications of medications (e.g. bacitracin, chlorhexidine).

 

Clinical Features

Clinically, anaphylaxis manifests as a syndrome, with various organ manifestations that can occur one after the other, simultaneously or individually. The skin is particularly often affected, with flushing, itching, hives or angioedema.

The gastrointestinal tract can be involved in the form of nausea, abdominal pain, vomiting, and diarrhea. Rhinitis, hoarseness, laryngeal swelling, shortness of breath with bronchoconstriction, asthma, and even respiratory arrest occur in the respiratory tract.

In the cardiovascular system, tachycardia and fluctuations in blood pressure (often a drop, but sometimes an acute rise in blood pressure), as well as cardiac arrhythmia, are frequently observed, which can lead to circulatory shock and circulatory arrest.

Subjective symptoms (formerly called “prodromes”) include paresthesia of the palms or soles, itch in the anogenital area, metallic or fishy taste, anxiety, sweating, and  disorientation.

According to the intensity of the symptoms, classification into degrees of severity of I-IV has proven successful. Not all symptoms have to be present.

 

Degree	Skin and subjective general symptoms	Abdomen	Respiratory tract	Cardiovascular system
I	Itching Flush Urticaria Angioedema	–
II	(Not obligatory)	Nausea Cramps	Rhinorrhea Hoarseness Dyspnea	Tachycardia Hypotension Arrhythmia
III	”	Vomiting Defecation	Laryngeal edema Bronchospasm Cyanosis	Shock, unconsciousness
IV	”	”	Apnea	Circulatory arrest

 

 

 

Disease course and prognosis

 

On withdrawal of the offending culprit, clinical improvement in drug‐induced urticaria and angioedema occurs within 24–48 h. It is important to recognize that after an initial improvement from anaphylaxis, late‐phase reactions may arise 5–6 h afterwards. Deaths from drug‐induced anaphylaxis are uncommon (<2%); the major predisposing risk factor for poor outcome is coexistent severe asthma.

 

 

Treatment

 

For evolving urticaria with or without angioedema or anaphylaxis, the key principal management step is to stop the offending drug and disease resolution occurs quickly.

Acute measures for the therapy of anaphylactic reactions follow guidelines and depend on the severity of the symptoms. If the reaction only extends to the skin and the breathing and circulation are stable, initial therapy can be done with antihistamines. In all patients, intravenous access has to be established. If circulation or breathing is affected, adrenaline therapy is required. Adrenaline autoinjectors for intramuscular self-medication (e.g. EpiPen) is commercially available, which differ from one another slightly in handling. Initially, 300–500 μg is administered intramuscularly to adults. In severe therapy-resistant reactions, 1:10 diluted adrenaline should be applied slowly intravenously or by infusion of 1:100 dilutions under continuous pulse and blood pressure control. In the case of predominant respiratory symptoms, β₂-adrenergic receptor agonists or adrenaline are given by inhalation. In hypotension, volume therapy (up to 1–3 l for adults initially) is of crucial importance. Of note, patients taking β-blockers may have a limited response to epinephrine. In cases of insect sting‐related and food‐induced anaphylaxis, the syndrome evolves more slowly.

The use of glucocorticoids in anaphylactic shock is controversially discussed, as glucocorticoids require up to 60 min to take its effect. However, their action may be needed for suppressing the late phase reaction after 6–12 h. In the event of respiratory and/or circulatory arrest, the acute measure of cardiopulmonary resuscitation (CPR) must be applied.

As most anaphylactic reactions are accompanied by skin symptoms and skin symptoms are often the first visible symptoms of incipient anaphylaxis, the dermatologist is at the forefront of managing this most severe and life-threatening form of immediate allergic reaction.

 

Patients should avoid all NSAIDs if possible. Paracetamol, ibuprofen, and tramadol have a low risk of urticaria and can be substituted for the other NSAIDs.

 

 

 

Drug‐induced serum sickness‐like reaction

 

Introduction 

 

Drug‐induced serum sickness‐like reactions (SSLR) are characterized by a clinical triad of fever, rash and arthralgia/arthritis.

 

SSLR is a drug reaction pattern, so named because of its similarity in clinical presentation to serum sickness. Classical serum sickness is a type III hypersensitivity reaction to foreign proteins (e.g. antithymocyte globulin, tositumomab, infliximab) resulting in the deposition of immune complexes in small blood vessels of various organs such as the skin, joints and other systems. In distinction, SSLR is typically due to medications and despite the clinical similarity, there is no circulating immune complexes, no vasculitis, no renal lesions with normal complement level.

 

Incidence and prevalence

 

Cefaclor is the most common reported trigger, occurring at 1 per 3000 cefaclor prescriptions compared to 1 per 120 000 in the case of amoxicillin. Other drugs associated with serum sickness-like reactions are penicillins, NSAIDs, bupropion, phenytoin, sulfonamides, minocycline, and propranolol.

 

Age

 

SSLR is more commonly reported in children and this may reflect the relatively frequent use of high‐risk medications such as cefaclor in the young.

 

Pathophysiology

 

The pathophysiology of SSLR is not well studied. Biotransformation of the parent drug to reactive metabolites is essential and inherited defects in the metabolism of these reactive intermediates may be a predisposing factor.

 

 

Clinical features

 

History

 

The typical median latency from drug initiation to onset of rash ranges is 7 days with a range from 1 to 13 days.

 

Presentation

 

The primary lesions of SSLR are urticarial weals. Some lesions may have purpuric or dusky centers and may be mistaken for erythema multiforme. Facial and periorbital edema may coexist. No mucosal membranes are involved.

Joints of the hands and feet are also often affected; associated symptoms include arthralgia, swelling, warmth and decreased range of movement. Systemic involvement of the kidneys and liver is rare, in contrast to true serum sickness.

 

 

Disease course and prognosis

 

Cutaneous and musculoskeletal manifestations resolve on drug withdrawal.

 

 

Treatment

 

Withdrawal of the culprit drug is essential; the rash and joint symptoms usually resolve within 1 week of withdrawal. Symptomatic treatment such as antihistamines, antipyretics and systemic corticosteroids are required.

 

 

 

Drug eruption, fixed

 

Introduction

 

Fixed drug eruption (FDE) is a cutaneous adverse drug reaction characterized by recurrent well‐defined lesions occurring in the same sites each time the offending drug is taken. It has short latency and is benign in nature. The drugs most frequently associated with FDE include antibiotics (Co‐trimoxazole, tetracyclines > β-lactams, fluoroquinolones, macrolides), NSAIDs, paracetamol (acetaminophen), aspirin, barbiturates, dapsone, proton pump inhibitors, and azole antifungal drugs.  

 

 

Age

 

FDE has been reported in all ages. However, it is more common in adults, particularly in the range of 40–80 year olds.

 

 

Pathophysiology

 

FDE is a form of classical delayed‐type hypersensitivity reaction and skin resident T cells are believed to be the key mediators in eliciting FDE. Long after clinical resolution, ‘resting’ FDE lesions contain CD8+ T cells with an effector/memory phenotype. These cells are located at the dermal–epidermal junction and remain quiescent until drug re‐challenge. On re‐exposure to the drug, there is activation and expansion of these CD8+ lymphocytes with the release of interferon (IFN) ‐γ and cytotoxic granules resulting in keratinocyte apoptosis.

 

Pathology

 

Early biopsy specimens show an interface dermatitis reaction pattern with vacuolar degeneration of basal keratinocytes, papillary dermal edema and a perivascular lymphocytic infiltrate of the upper dermis. There may be scattered necrotic keratinocytes in the epidermis or extensive epidermal necrosis. Resolved or healing lesions are characterized by pigment‐laden macrophages in the upper dermis.

 

 

Clinical features

 

History

 

Lesions develop from a few days to two weeks after the initial exposure. With subsequent exposures, they appear within 24 hours (30 min to 8 h).

 

Presentation

 

Typically, FDE presents as a sharply‐defined, round or oval erythematous and edematous plaque which evolves to become dusky, violaceous and occasionally may become bullous and then eroded due to epidermal detachment. Eroded lesions, especially on genitals or oral mucosa, are quite painful. Lesions are usually solitary or few in number although multiple lesions may be present or may develop as a consequence of repeated challenges.

Although FDEs can occur anywhere on the skin surface as well as the mucous membranes, they are commonly found on the perioral and periorbital areas, hands and feet, glans penis, and oral mucosa. The initial acute phase lasts for days to weeks and then heals leaving dark brown with violet hue post inflammatory hyper pigmentation; pigmentation may be all that is visible between attacks. Upon re-administration of the causative drug, lesions recur in exactly the same sites. With each subsequent recurrence, additional sites of involvement may appear or the number of lesions may remain constant. Typically, the time interval between exposure and development of the lesions shortens on repeated exposures.

 

Drug‐specific clinical patterns have been reported. These include: NSAID‐induced FDE affecting the genitals and lips; tetracycline‐ and trimethoprim/sulfamethoxazole‐induced FDE affecting the genitals.

The presence of numerous lesions is referred to as generalized bullous FDE. Generalized bullous FDE (GBFDE) is a form of extensive FDE which may be misdiagnosed as toxic epidermal necrolysis (TEN). Differentiating features from TEN include: (i) prior history of similar episodes; (ii) mucosal surfaces are relatively uninvolved; (iii) the presence of large blisters with intact intervening skin; and (iv) the absence of multiple purpuric or atypical target macules. In generalized disease, prognosis correlates with the extent of skin detachment.

 

 

Different morphological variants of FDE:

 

·       Pigmented FDEs

·       Nonpigmented FDEs

·       Bullous FDEs

·       Multifocal FDEs

·       Erythema multiforme like FDEs

·       Linear FDEs

·       Generalized bullous/TEN like FDEs

·       Wandering FDEs

 

 

Complications and co‐morbidities

 

Patients with GBFDE generally lack visceral complications and are thought to have a benign clinical course. In contrast with SJS/TEN, GBFDE generally has modest or no mucosal involvement and is not associated with respiratory tract or intestinal involvement. However, the mortality in GBFDE was not significantly lower that of SJS/TEN.

 

 

Disease course and prognosis

 

The majority of FDE is self‐limiting with an excellent prognosis. Post‐inflammatory hyperpigmentation can be prominent and persist for several months after the acute episode. In GBFDE, the mortality is approximately 20%. Patients with GBFDE require the same level of treatment and care as for SJS and TEN.

 

In some patients, the responsible drug can be re-administered without inducing an exacerbation, and there may be a refractory period after the occurrence of a fixed eruption. Provocation via patch testing in a previously involved site may be useful in determining the responsible drug (as long as not performed during the refractory period).

 

 

Treatment

 

Treatment involves stopping the offending drug. For noneroded lesions: Potent topical glucocorticoid ointment and for eroded lesions: Antimicrobial ointment. For widespread, generalized, and highly painful mucosal lesions, oral prednisone 1 mg/kg body weight tapered over a course of 2 weeks. GBFDE should be treated in an intensive care center with expertise in skin loss syndromes, or in a burns unit.

 

 

 

Drug reaction with eosinophilia and systemic symptoms (DRESS)

 

Introduction

 

DRESS is an idiosyncratic, unusual, potentially life-threatening, multi-organ adverse drug reaction that begins acutely in the first 2 months after initiation of the drug. It is characterized by cutaneous features, namely a rash, and systemic involvement. The latter includes hematological disturbance, with eosinophilia being the most consistent finding. Leucocytosis, lymphopenia, lymphocytosis, thrombocytosis and thrombocytopenia are also described. Atypical lymphocytes are a common finding on blood film in DRESS patients, the presence of which is used as a component of the diagnostic criteria. Lymphadenopathy is found in more than 75% of patients, with involvement of two nodal basins required to meet diagnostic criteria.

 

Internal manifestations include lymphadenopathy and hepatic involvement (~80% of patients); rarely, the latter may become life-threatening. Patients may develop interstitial nephritis, myocarditis, interstitial pneumonitis, myositis, thyroiditis, and even infiltration of the brain by eosinophils. The cutaneous and visceral involvement may persist for several weeks or months after drug withdrawal, and additional sites of involvement (e.g. cardiac, thyroid) may develop weeks or months later, including following a taper of corticosteroids.

 

Management in the acute phase is centered on the identification and withdrawal of the culprit drug, and corticosteroid therapy, administered by topical, oral or intravenous route; the choice being guided by the severity of the disease. In most patients, the disease is of less than 4 weeks’ duration, with few or no sequelae. However, a minority of patients enter a chronic phase of disease characterized by persistence either of the cutaneous features or of the systemic involvement.

 

 

Epidemiology

 

Incidence and prevalence

 

It occurs in approximately 1 in 3000 exposures to aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbital; cross-sensitivity among the three drugs is common) and sulphonamide (antimicrobial agents, dapsone, or sulfasalazine).  

 

Drugs associated with drug reaction with eosinophilia and systemic symptoms syndrome (DRESS).

Most commonly associated drugs are in bold.

 

DRUGS ASSOCIATED WITH DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS SYNDROME (DRESS)
Drug category	Specific drugs
Anticonvulsants	Carbamazepine, lamotrigine*, phenobarbital, phenytoin, oxcarbazepine, zonisamide > valproic acid
Antimicrobials	Ampicillin, cefotaxime, dapsone, ethambutol, isoniazid, linezolid, metronidazole, minocycline, pyrazinamide, quinine, rifampin, sulfasalazine (salazosulfapyridine), streptomycin, trimethoprim–sulfamethoxazole, teicoplanin, vancomycin
Antiretrovirals	Abacavir, nevirapine, zalcitabine
Antidepressants	Bupropion, fluoxetine
Antihypertensives	Amlodipine, captopril
NSAIDs	Celecoxib, ibuprofen
Miscellaneous	Allopurinol**, azathioprine, imatinib, mexiletine, ranitidine, ziprasidone

 

* Especially when co-administered with valproic acid.

** Full doses in the setting of renal dysfunction a risk factor.

 

Age

 

A mean age of onset is 48 years.

 

 

Pathophysiology

 

The two main theories are that of a drug‐specific T‐cell reaction, and that of viral reactivation.

 

Some patients have a genetically determined inability to detoxify the toxic metabolic products of particular drugs due to a defect in normal enzymatic methods of detoxifying the medications. As a result, this toxic metabolite may act as a hapten and initiate an immune response. Drug specific activated T lymphocytes release IL-5 that contributes to eosinophilia, a key feature of this syndrome.

For example, genetic polymorphisms that affect detoxification of anticonvulsants and sulfonamides have been identified in patients recovering from DRESS. For aromatic anticonvulsants, the inability to detoxify toxic arene oxide metabolites is probably a key factor and would provide an explanation for the cross-reactivity between phenytoin, carbamazepine, and phenobarbital which has been well documented, both in vivo and in vitro. Slow N-acetylation of sulfonamide and increased susceptibility of leukocytes to toxic hydroxylamine metabolites are associated with a higher risk of hypersensitivity syndrome.

 

Immune mechanisms have also been implicated based upon several observations including the requirement for sensitization, positive skin tests for the culprit drug in some patients, and a shorter time-to-onset upon rechallenge. Notably, distinct HLA alleles have been associated with a significantly increased risk of developing drug-specific DRESS. In addition, IL-5 plays a role in the generation of eosinophilia and drug-specific T cells, activated in the skin and internal organs, serve to mediate the disorder.

 

Herpes virus reactivation occurs in DRESS. The implicated viruses have included HHV‐6, CMV, Epstein–Barr Virus (EBV) and HHV‐7. Virus reactivation appears to occur in a sequential fashion, with HHV‐6 and EBV being detected earlier in the course of the disease, followed by HHV‐7 and CMV. It has been postulated that a drug‐induced immunosuppressed state, characterized by hypo gammaglobulinaemia, facilitates the initial reactivation of latent herpes virus. The sequential nature of viral reactivation suggests a correlation with the clinical phases of DRESS. Rash and fever are often the first presenting features, followed by lymphadenopathy and internal organ dysfunction. Some authors have hypothesized that it is the fluctuation of viral loads that gives rise to these ‘waves’ of disease in DRESS. It has also been asserted that the persistence of viral reactivation explains the so‐called ‘chronic’ phase of DRESS experienced by some patients.

 

 

Pathology

 

Histopathologically, various inflammatory patterns can be seen, including eczematous, interface dermatitis, AGEP-like, and erythema multiforme-like.  Walsh et al. found a correlation between the presence of EM‐like changes histopathologically and more severe liver dysfunction, and suggested that such features may be predictive of a higher mortality.

 

 

Clinical features

 

History

 

Between 2 and 6 weeks, may have elapsed between ingestion of the culprit drug and the onset of symptoms i.e. later than most other immunologically mediated skin reactions. With re-exposure, there can be a shorter time to onset.

 

Since a familial tendency has been reported, family members of affected patients should be warned. Familial cases of DRESS to carbamazepine, linked to HLA‐A3101, have been described.

 

Presentation

 

DRESS is, by definition, characterized by a rash suspected to be drug induced, accompanied by a fever, lymphadenopathy and systemic involvement, the latter referring to derangement of the function of at least one organ system, and hematological abnormalities.

 

A clinical classification system for the cutaneous findings in DRESS has been proposed. The most common variant appears to be the urticated papular exanthem. This consists of widespread ­papules and plaques, often accompanied by cutaneous edema. A morbilliform eruption has been noted in a smaller proportion of patients, consisting of a pinkish macular rash resembling measles. Erythroderma may occasionally be the presenting cutaneous feature, characterized by a widespread exfoliative erythema. A number of patients with DRESS may present with erythema ­multiforme‐like features in the skin, developing dusky or purpuric atypical ­targets not necessarily confined to acral sites and may be associated with a more severe systemic phenotype.

 

Less common manifestations include vesicles, follicular or non-follicular pustules (~20% of patients), and purpuric lesions on legs.

 

An important clinical finding in the majority of patients with DRESS is head and neck edema. This is often most noticeable by looking at the ears. The face may be uniformly swollen, or have a more leonine appearance.

 

The lesions are distributed symmetrically and almost always occur on the trunk and extremities. Lesions may become confluent and generalized.

 

Although frank mucous membrane involvement is a rarity (and indeed its presence should call the diagnosis of DRESS into question), cheilitis is a common finding.

 

Clinical examination reveals lymphadenopathy in at least two sites in the majority of patients. One set of clinical criteria require the nodes to be at least 2 cm in diameter to be considered clinically significant.

 

Regarding hematological abnormalities, the most common seen is that of eosinophilia. Pancytopenia is seen in some cases, and is a negative predictive factor in terms of outcome. A ­pronounced lymphocytosis may be seen, with levels rising to >20 × 109 leukocytes/L. It is imperative in all cases for a blood film to be examined for the presence of atypical lymphocytes, which are frequently present in DRESS. Leukopenia, lymphopenia (possibly virally induced) and thrombocytopenia have been noted.

 

The liver is the most common viscera to be involved.  Although any drug has the potential to cause liver dysfunction in the context of DRESS, phenytoin, minocycline and dapsone is the most common offender. Severity of involvement varies widely, from mild and transient hepatitis, to fulminant hepatic failure requiring liver transplantation. Early identification of patients at highest risk has proved difficult, but there are indications that certain clinical markers (such as the presence of atypical targets and purpura at presentation) and specific high‐notoriety drugs (such as minocycline) may confer a higher risk of more severe hepatic involvement. Liver dysfunction is the primary cause of mortality from DRESS.

 

Up to 10% patients manifest renal involvement in the course of their illness. Again, certain drugs confer a higher risk of kidney injury, notably allopurinol. Histologically, interstitial nephritis is seen. Cardiac involvement, both pericarditis and myocarditis, is reported in DRESS.

 

Pulmonary involvement in DRESS reveals pleural effusion, pleuritis or acute interstitial pneumonitis.

 

Central nervous system involvement in DRESS includes inflammation of the meninges and encephalitis.

 

Gastrointestinal involvement in DRESS includes ulcerative colitis and esophagitis.

 

Endocrine system is usually involved in the latter phase of DRESS than the acute phase, with the thyroid gland being most frequently involved. Both hyper‐ and hypothyroidism are recognized in the convalescent phase, both of which may have a chronic course, and therefore regular monitoring of thyroid function for a year after the acute event is advocated.

 

Other autoimmune phenomena such as alopecia areata and SLE have also been described in the aftermath of DRESS.

 

 

Clinical variants

 

The preferred Diagnostic criterion is that proposed by the RegiSCAR group.

 

 

RegiSCAR SCORING SYSTEM FOR DRESS
Criteria	No	Yes	Unknown/unclassifiable
Fever (≥38.5°C)	-1	0	−1
Lymphadenopathy (≥2 sites; >1 cm)	0	1	0
Circulating atypical lymphocytes	0	1	0
Peripheral hypereosinophilia	0		0
0.7–1.499 × 109/L - or - 10–19.9%*		1
≥1.5 × 109/L - or - ≥20%*		2
Skin involvement
Extent of cutaneous eruption > 50% BSA	0	1	0
Cutaneous eruption suggestive of DRESS**	­-1	1	0
Biopsy suggests DRESS	-1	0	0
Internal organs involved†	0		0
One		1
Two or more		2
Resolution in ≥15 days	-1	0	−1
Laboratory results negative for at least three of the following (and none positive): (1) ANA; (2) blood cultures (performed ≤3 days after hospitalization); (3) HAV/HBV/HCV serology; and (4) Chlamydia and Mycoplasma serology	0	1	0
Final score: < 2, no case; 2–3, possible case; 4–5, probable case; >5, definite case

 

 

* If leukocytes <4.0 × 10⁹/L

** At least two of the following: edema, infiltration, purpura, scaling.

† Liver, kidney, lung, muscle/heart, pancreas, or other organ and after exclusion of other explanations.

 

Liver: transaminases >2 × upper limit of normal (ULN) on two successive dates or bilirubin × 2 ULN on 2 successive days or aspartate aminotransferase (AST), γ‐glutamyltransferase (GGT) and alkaline phosphatase >2 × ULN on one occasion. Renal: creatinine 1.5 × patient's baseline. Cardiac: echocardiographic evidence of pericarditis.

Japanese Research Committee on Severe Cutaneous Adverse [Drug] Reactions (J-SCAR) diagnostic criteria for DIHS (drug-induced hypersensitivity syndrome)/DRESS (drug reaction with eosinophilia and systemic symptoms).

Typical DIHS is defined as the presence of all 7 criteria, while atypical DIHS is defined as the presence of only the first 5 criteria.

 

J-SCAR DIAGNOSTIC CRITERIA FOR DIHS/DRESS

1.   Maculopapular rash developing >3 weeks after starting therapy with a limited number of drugs   2.   Prolonged clinical symptoms after discontinuation of the causative drug   3.   Fever (>38°C)   4.   Liver abnormalities (ALT >100 U/L)*   5.   Leukocyte abnormalities (at least one present): (a) leukocytosis (>11 × 109/L); (b) atypical lymphocytes (>5%); and (c) eosinophilia (>1.5 × 109/L)   6.   Lymphadenopathy   7.   HHV-6 reactivation

 

* This can be replaced by other organ involvement, such as renal involvement.

 

 

Differential diagnosis

 

The other SCAR syndromes should be considered in the differential diagnosis of DRESS. Certain clinical features are common to different SCAR syndromes, such as pustules, which when present should provoke consideration of AGEP as a differential diagnosis. However, the pustules in AGEP tend to be predominantly flexural, whereas in DRESS they are unlikely to be localized to these sites. Epidermal loss, purpura and target lesions of the skin may be present in DRESS, all of which may occur in EM, SJS or TEN. One of the most helpful features in distinguishing DRESS from the other SCAR syndromes is latency of onset of the eruption; this is classically shorter in AGEP (<5 days) and SJS/TEN (7–10 days) than in DRESS, where the latency may be 2–6 weeks after drug ingestion.

 

 

Classification of severity

 

Walsh et al. classified the eruption seen in DRESS morphologically into four categories: urticated papular exanthem, morbilliform erythema, exfoliative erythroderma and an EM‐like reaction. The EM‐like group demonstrated more pronounced liver dysfunction with high mortality.

 

A number of hematological markers such as eosinophilia, pancytopenia and thrombocytopenia are poor prognostic indicators.

 

 

Complications and co‐morbidities

 

The most severe and life‐threatening complication of DRESS is fulminant liver failure, necessitating transplant. Mortality has been estimated at 5–10%, with hepatic failure being the predominant cause of death. A delayed‐onset interstitial nephritis is described, following cases of DRESS where kidney involvement has been prominent, and, analogous to this, a persistent interstitial pneumonitis is also described where pulmonary involvement has been present. Thyroid dysfunction may supervene in the convalescent phase of DRESS. Myocarditis, with associated cardiac insufficiency has also been described.

 

Autoimmune phenomena may arise following DRESS, including lupus erythematosus and autoimmune thyroid disease. One author has described detection of autoantibodies in the convalescent phase in 44% patients with DRESS syndrome. The autoantibodies detected were antinuclear antibody (ANA), antithyroglobulin antibody (ATGA) and antithyroperoxidase antibody (ATPOA). There is preponderance of autoantibody positivity in the non‐corticosteroid treated group as compared to the group who received corticosteroid, suggesting a possible protective role for this treatment.

 

A small number of patients may develop chronic exfoliative dermatitis.

 

 

Disease course and prognosis

 

The majority of patients with DRESS will recover fully, following withdrawal of the culprit drug and management of the acute episode. A number of organ‐specific chronic sequelae may arise following involvement of these organs in the acute phase. In addition, a number of autoimmune phenomena such as alopecia areata and autoimmune thyroid disease are described.

 

 

Investigations

 

Assessment and longitudinal evaluation of patients with DRESS (drug reaction with eosinophilia and systemic symptoms).
BM, bone marrow; BUN, blood urea nitrogen; CBC, complete blood count; CK, creatine kinase; CRP, C-reactive protein; LDH, lactic dehydrogenase; LFTs, liver function tests; PFT, pulmonary function test; PT, prothrombin time; PTT, partial thromboplastin time; TSH, thyroid stimulating hormone.

 

ASSESSMENT AND LONGITUDINAL EVALUATION OF PATIENTS WITH DRESS (DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS)

Basic laboratory screening during the acute phase with recommended repetitive tests in italics^

·       CBC with differential, platelet count, peripheral smear for atypical lymphocytes   ·       BUN, creatinine, urinalysis, spot urine for protein : creatinine ratio*   ·       LFTs, creatine kinase (CK), lipase, CRP   ·       TSH, free T4 (repeat at 3 months, 1 year, and 2 years)   ·       Fasting glucose (in anticipation of systemic corticosteroids)

Additional testing

·       ECG, troponin T, baseline echocardiogram   ·       Quantitative PCR for HHV-6, HHV-7, EBV, CMV   ·       Wright stain of urine for eosinophilia (prior to instituting corticosteroids)   ·       ANA, blood cultures (exclusion criteria in RegiSCAR scoring system)   ·       If hemophagocytic lymphohistiocytosis suspected**, ferritin, triglycerides, LDH, BM examination

Further testing based upon laboratory abnormalities or signs and symptoms**

·       Liver – PT, PTT, albumin   ·       Renal – albumin, renal ultrasound (if laboratory abnormalities)   ·       Cardiac – ECG, troponin T, echocardiogram   ·       Neurologic – brain MRI   ·       Pulmonary – CXR, PFTs   ·       Gastrointestinal – endoscopy

 

^ Testing is more frequent during the acute phase (e.g. twice weekly) with frequency also a reflection of disease severity. Longitudinal evaluation is recommended for at least one year.

 

* Allows for immediate assessment for proteinuria.

 

** Including during longitudinal evaluation.

 

 

Treatment

 

The most important initial task is to identify and stop the culprit drug, but this may not result in a rapid complete recovery.

 

The mainstay of active treatment is corticosteroid therapy, administered topically, orally or intravenously. In refractory cases, or where the disease enters a chronic phase, a steroid‐sparing agent such as cyclosporine may be required.

First line

In cases of limited severity with minimal cutaneous involvement, or where administration of systemic corticosteroid is contraindicated, the application of highly potent topical steroids may suffice as treatment. However, the majority of patients will require systemic corticosteroid therapy, either via the oral route or the intravenous route, as guided by clinical state. A dose oral prednisolone of 1 mg/kg/day is recommended as initial treatment. Because relapse can occur when the dosage is reduced, a slow taper of corticosteroids over a period of several weeks to months (on an average 1 to 3 months) is often required. Where intravenous therapy is required, or where institution of oral therapy has failed to produce a satisfactory clinical improvement, methylprednisolone is indicated using a dose of 1 g/day for 3 days.

Second line

Cases of DRESS refractory to steroid treatment may require cyclosporine, and is useful in patients where a protracted course of illness (e.g. with persistent liver dysfunction or a chronic exfoliative dermatitis) supervenes.

 

 

Prevention

 

The individual must be aware of his or her specific drug hypersensitivity and that other drugs of the same class can cross-react. These drugs must never be readministered. Patient should wear a medical alert bracelet.

 

 

Acute generalized exanthematous pustulosis (AGEP)

 

Definition 

 

Acute generalized exanthematous pustulosis (AGEP) is one of the severe cutaneous adverse reaction (SCAR) syndromes. It is an acute febrile drug eruption characterized by numerous small primarily non-follicular, sterile pustules, arising within large areas of edematous erythema, usually localized to the major flexures. It is a self‐limiting phenomenon, which usually resolves without sequelae. It has short latency, rapid onset and resolution, and full recovery without recurrence. More than 90% of cases of AGEP are drug-induced. Occasionally, it may be due to other causes, e.g. an enteroviral infection or exposure to mercury.

 

Epidemiology

 

The incidence of AGEP is estimated to be 1–5 per million per year.

 

Age

 

AGEP occurs more frequently in the adult population with a mean age of onset is 56 years.

 

Sex

 

A slight female preponderance is noted.

 

 

Pathogenesis

 

HLA-B5, -DR11 and -DQ3 are found more frequently in patients with AGEP, and mutations in IL36RN may be a risk factor as well. A prior sensitization (including a contact sensitization) would explain the short interval (<4 days) between drug administration and the onset of the eruption, as this suggests an immunologic recall phenomenon. The percentage of positive patch tests to an incriminated drug is relatively high (50–60%). Blood neutrophilia and the accumulation of neutrophils within the lesions suggest the release of neutrophil-activating cytokines by drug-specific T lymphocytes (e.g. IL-3, IL-8, IL-17, G-CSF), but the precise underlying mechanisms of AGEP are still unknown.

 

Antibiotics are the primary drugs implicated in AGEP. 

Commonest drugs causing AGEP:

 

AGEP – MOST COMMONLY ASSOCIATED MEDICATIONS
Acetaminophen   Antibiotics ·       Penicillins, aminopenicillins ·       Cephalosporins ·       Clindamycin ·       Pristinamycin ·       Sulfonamides ·       Metronidazole ·       Carbapenems ·       Quinolones ·       Macrolides	·       Calcium channel blockers, especially diltiazem   ·       Carbamazepine   ·       Cetirizine   ·       Herbal medicines   ·       Antimalarials, especially hydroxychloroquine   ·       NSAIDs, including oxicam derivatives and COX-2 inhibitors   ·       Proton pump inhibitors   ·       Terbinafine

Common culprits are in italics.

 

 

Clinical features

 

AGEP is characterized by a high fever and pustular rash. After drug administration, it may take 1 to 3 weeks before skin lesions appear. However; in previously sensitized patients, the skin symptoms may occur within 2 to 3 days. This short latency is typical of AGEP. A prodrome of burning or itching in the skin may be described, and the patient may be asthenic.

 

Small (<5 mm), primarily non-follicular, yellow sterile pustules appearing suddenly on a diffuse, edematous erythematous skin, usually starts either on the face or in the major flexural creases such as the neck, axillae and inframammary and inguinal folds, and then rapidly disseminated over a few hours to involve the trunk and upper limbs. Typically, there are > 100 pustules which may be irregularly dispersed or grouped. The palms and soles are spared.  Edema of the face and hands, purpura, vesicles, bullae, erythema multiforme-like lesions, and/or mucous membrane involvement is observed in ~50% of patients. Pustules resolve spontaneously in < 15 days and generalized post pustular superficial desquamation occurs approximately 2 weeks later.  

 

A set of diagnostic criteria was proposed by Roujeau et al. in 1991 as follows:

1.   Appearance of hundreds of sterile non‐follicular pustules at flexural sites.

2.   Histopathological changes of spongiosis and epidermal pustule formation.

3.   Fever >38°C.

4.   Blood neutrophil count >7 × 10⁹/L.

5.   Acute evolution.

 

Pathology

Histologically, both spongiform sub corneal and/or intra epidermal pustules, a marked edema of the papillary dermis and a perivascular mixed infiltrate with neutrophils and some eosinophils are usually present. CSVV and focal necrotic keratinocytes are unusual findings.

 

Differential diagnosis

AGEP must be differentiated from acute pustular psoriasis of the von Zumbusch type. The pustules are clinically indistinguishable, but additional skin lesions such as petechiae, purpura, atypical target-like lesions and vesicles are more frequently observed in AGEP. Histologically, massive edema in the superficial dermis, exocytosis of eosinophils, vasculitis, and necrosis of keratinocytes are all suggestive of AGEP, whereas acanthosis is more characteristic of pustular psoriasis. The two major differences are the acuteness (rapid appearance) of the disease and the history of recent drug exposure in AGEP. However, AGEP may occur more frequently in patients with a history of psoriasis, thus making the distinction even more difficult.

A relevant drug history, the lack of a personal or family history of psoriasis and the absence of other stigmata of psoriasis on clinical examination may be helpful in directing the clinician to diagnosis of AGEP rather than psoriasis.

 

Features which distinguish AGEP from pustular psoriasis

 

	AGEP	Psoriasis
History of psoriasis	Possible	Common
Distribution pattern	Predominance in the folds	More generalized
Duration of pustules	Shorter	Longer
Duration of fever	Shorter	Longer
History of drug reaction	Usual	Uncommon
Recent drug administration	Very frequent	Less frequent
Arthritis	Rare	∼30%
Histology	Spongiform subcorneal and/or intraepidermal pustules, edema of papillary dermis, vasculitis, exocytosis of eosinophils, single‐cell necrosis of keratinocytes	Subcorneal and/or intraepidermal pustules, papillomatosis, acanthosis

 

Subcorneal pustular dermatosis (Sneddon–Wilkinson disease) may be distinguished by its less acute course, and the presence of flaccid pustules which demonstrate a hypopyon.

 

Common exanthematous drug eruptions may have a few pustules, but they are usually follicular. In severe forms of AGEP, the confluence of the pustules and subsequent superficial epidermal detachment may lead to confusion with TEN. However, the presence of subcorneal pustules in biopsy specimens allows one to distinguish between the two entities.

In addition to facial edema, pustules may also be observed in DRESS, however pustules will generally be less numerous in DRESS than in AGEP, and the prolonged evolution, atypical lymphocytosis, marked hype eosinophilia, and common visceral involvement usually permit differentiation.

 

Investigations

 

In most cases, a careful drug history is adequate to elucidate the culprit drug, which must be excluded as a matter of priority in the care of these patients. A skin biopsy should be taken early in the disease presentation as it will assist in the distinction from pustular psoriasis. Baseline hematological investigations reveal a marked leukocytosis with an elevated neutrophil count and mild to moderate eosinophilia. Biochemical investigations should be performed to rule out renal and liver dysfunction, as well as hypocalcemia. Measurement of acute phase reactants such as C‐reactive protein (CRP) may help to distinguish infection from the systemic involvement in AGEP. A septic screen may be instituted if suspicion of infection is high.

 

 

Management

 

Management of AGEP generally involves corticosteroid therapy, the route of administration being determined by the severity of the presentation. In cases where the patient appears systemically well, with limited areas of involvement, potent topical corticosteroid may suffice. In cases of more extensive involvement, or where systemic features such as fever, hemodynamic compromise or systemic upset are seen, oral corticosteroids may be required. Emollient therapy should be prescribed, and continued throughout the phase of post pustular desquamation, until full skin integrity is restored.

In cases where systemic involvement such as renal impairment or liver function disturbance is noted, appropriate supportive care such as intravenous fluids and careful hemodynamic monitoring should be employed. If the patient is febrile, care should be taken to exclude an infective source, and if suspicion of this remains, then empiric antibiotic therapy should be considered.

 

 

 

STEVENS -JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS

 

Salient features

 

·       Prodrome of upper respiratory tract symptoms, fever, and painful skin

 

·       Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two rare, potentially fatal, adverse cutaneous drug reactions of differing severity, characterized by mucocutaneous tenderness and erythema as well as extensive exfoliation

 

·       SJS is characterized by <10% body surface area of epidermal detachment, SJS/TEN overlap by 10–30%, and TEN by >30%

 

·       The medications most frequently incriminated are allopurinol, nonsteroidal anti-inflammatory drugs, antibiotics, and aromatic anticonvulsants; TEN and SJS usually occur 7–21 days after initiation of the responsible drug

 

·       The average mortality rate is 1–5% for SJS and 25–35% for TEN; the mortality rates are often higher in the elderly and those with a very large surface area of epidermal detachment

 

·       Exfoliation is due to extensive death of keratinocytes via apoptosis; the latter is mediated via the cytotoxic secretory protein granulysin and interaction of the death receptor–ligand pair Fas–FasL

 

·       Optimal medical management of SJS and TEN requires early diagnosis, immediate discontinuation of the causative drug(s), and rapid initiation of supportive care

 

·       Additional therapies include IVIg, cyclosporine, pulse corticosteroids, and targeted immunomodulators, but to date none have proven efficacy based upon prospective controlled trials

 

 

Introduction

 

SJS and TEN are, acute life-threatening muco-cutaneous reaction that are almost always drug related, characterized by extensive necrosis and detachment of the epidermis and mucous membrane, accompanied by systemic disturbance. Because of the similarities in etiology, risk factors, histopathology, pathogenesis and clinical findings, these two conditions are now considered as severe variants of an identical process that differs only in the final extent of body surface involved. Therefore, it is better to use the designation epidermal necrolysis (EN) for both. TEN is a maximal variant of SJS differing only in the extent of body surface involvement. The disease runs an unpredictable course. An initially benign-appearing dermatosis can progress rapidly, and once overt skin detachment has occurred, it is difficult to determine when it will end.

 

As prognosis is correlated with the speed at which the culprit drug is identified and withdrawn, it is crucial to establish the correct clinical diagnosis rapidly, so the causal drug(s) can be discontinued and appropriate medical treatment begun as soon as possible.

 

High-quality supportive treatment, ideally in intensive care units with modern equipment and trained nursing staff, is the current standard of care and can improve outcome. No specific therapy for SJS and TEN has yet shown efficacy in prospective, controlled clinical studies, in part because the low incidence of SJS and TEN plus their life-threatening potential make randomized clinical trials difficult to perform.

 

EPIDEMIOLOGY

 

Incidence

 

The incidence of SJS/TEN is approximately one to two cases per million per year. But in India incidence could be much higher because the main etiologic agents of TEN, i.e. drugs such as antibiotics, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs) are easily available without any prescription.

 

Age of Onset

 

EN can occur at any age, with the risk increasing with age after the fourth decade, and more frequently affects women.

 

Risk Factors

Certain patient groups have an increased risk of developing SJS/TEN, including those who have slow acetylator genotypes, lupus erythematosus (systemic LE or subacute cutaneous LE),  immunocompromised (e.g. HIV infection, lymphoma), are undergoing radiotherapy while concomitantly receiving anticonvulsants, or have specific human leukocyte antigen (HLA) alleles. Examples of the latter are HLA-B*1502 in Asians and East Indians (but not Europeans) who are exposed to carbamazepine and HLA-B*5801 in Han Chinese exposed to allopurinol. Consequently, the FDA recently recommended genotyping of all Asians for the allele HLA-B*1502 prior to the administration of carbamazepine. In individuals with AIDS, the risk of developing TEN is 1000-fold higher than in the general population.

STEVENS–JOHNSON SYNDROME (SJS) AND TOXIC EPIDERMAL NECROLYSIS (TEN): EPIDEMIOLOGY AND RISK FACTORS
Annual incidence	1.2–6 per million (SJS)
	0.4–1.2 per million (TEN)
Ratio women : men	1.5 : 1
Risk factors	·       Slow acetylator genotypes
	·       Immunosuppression (e.g. HIV infection, lymphoma)
	·       Concomitant administration of radiotherapy and anticonvulsants (most commonly, those with brain tumors)
	·       HLA-B*1502: Asians (in particular Han Chinese, Thai, Malaysian populations) and East Indians exposed to carbamazepine
	·       HLA-B*5801: Han Chinese exposed to allopurinol
	·       HLA-A*3101: Europeans exposed to carbamazepine

 

 

ETIOLOGY

 

The reaction is independent of the dose of the drug and is idiosyncratic. More than 100 different drugs have been implicated to date, but about a dozen ‘high risk’ medications account for one half of EN cases. These high risk drugs are antibacterial sulphonamides, aromatic anticonvulsants, allopurinol, NSAIDs (primarily oxicam derivatives and diclofenac), lamotrigine and nevirapine. The risk seems confined to the first 8 weeks of treatment. Furthermore drugs with long half-lives are more likely to cause drug reactions and fatal outcome than those with short half-lives, even they are chemically related.

 

Medications and the Risk of Toxic Epidermal Necrolysis

 

High Risk

 

·       Antibacterial sulphonamides (Co-trimoxazole, Sulfadiazine, Sulfapyridine, sulfadoxine, Sulfasalazine)

·       Anticonvulasants ( Carbamazepine, Phenobarbital, Phenytoin, Lamotrigine)

·       NSAIDs (especially pyrazolon derivatives, e.g. phenylbutazone and oxicam derivatives such as pyroxicam)

·       Antitubercular- Thiacetazone

·       Allopurinol

 

Lower Risk

 

·       Acetic acid NSAIDs (e.g., diclofenac)                                                       

·       Non- sulphonamide antibiotics (Cephalosporins, Aminopenicillins, Fluroquinolones, Tetracyclins and Macrolides)      

 

Doubtful Risk

 

·       Paracetamol (acetaminophen)

·       Corticosteroids

·       Other NSAIDs (except aspirin)

 

No Evidence of Risk

 

Aspirin, Sulfonylurea antidiabetic, Thiazide diuretics, Furosemide, Aldactone, calcium channel blockers, B- blockers, ACE inhibitors, Angiotensin 2 receptor antagonists, statins, hormones and vitamins.                                                                                                                                                                                                                                                                                   

 

PATHOGENESIS

 

The reason why some individuals develop such marked immune reactions against medications has until very recently been obscure. A widely accepted hypothesis has been that patients suffering from severe drug reactions are exposed to increased amounts of reactive (oxidative) metabolites because of a lowered ability to detoxify reactive metabolites, due to defect of the detoxifying system in the liver and skin, either on a genetic basis, or on a some enzyme deficiency. Such metabolite acts as a heptan and binds with the surface of the keratinocytes and makes them antigenic. As a result, drug specific cytotoxic CD8+ lymphocytes are formed and are responsible for massive keratinocyte cell death via apoptosis leading to epidermal necrolysis.

 

 

Cytotoxic T cells expressing the skin-homing receptor, cutaneous lymphocyte-associated antigen (CLA), are seen early in the development of cutaneous lesions. These are likely to be drug-specific cytotoxic T cells. Important cytokines such as interleukin (IL)-6, TNF-α, interferon-γ, IL-18, and Fas ligand (FasL) are also present in the lesional epidermis and/or blister fluid of patients with TEN, and their actions could explain some of the constitutional symptoms of TEN as well as the frequently observed discrepancy between the extent of epidermal damage and the paucity of the inflammatory infiltrate. Lastly, the typical interval between the onset of drug therapy and SJS/TEN is between 1 and 3 weeks, suggesting a period of sensitization and providing further support for the role of the immune system in disease pathogenesis. This period (“memory”) is considerably shortened in patients who are unfortunately re-exposed to a drug that previously resulted in SJS or TEN.

 

The tissue damage described by pathologists as epidermal necrolysis is a reflection of massive keratinocyte cell death via apoptosis. The apoptosis of individual keratinocytes is a hallmark of the early stages of SJS and TEN, and it is the first clear morphologic sign of specific tissue damage. The more classic histologic image of extensive epidermal “necrolysis” is, in fact, the aftermath of keratinocyte apoptosis. Indeed, the apoptotic state of cells is transient in nature, and it is followed by necrosis if the apoptotic cells are not rapidly phagocytosed. In SJS and TEN, within hours keratinocyte apoptosis becomes very abundant in lesional skin, thus rapidly overwhelming the phagocytic capacity of the affected skin. Over a period of hours to days, these apoptotic keratinocytes become necrotic and lose their cohesion to adjacent keratinocytes as well as the basement membrane. The entire epidermis then loses viability, creating the familiar histologic image of full-thickness epidermal necrolysis.

 

 

SJS/TEN is primarily a drug‐induced phenomenon, with a culprit drug being demonstrated in approximately 85% of cases. The disease is characterized by widespread epithelial keratinocyte necrosis of both skin and mucous membranes, a process initiated by drug‐induced cytotoxic T lymphocytes (CTLs). MHC class I‐restricted drug presentation leads to clonal expansion of CD8+ CTLs which infiltrate the skin, while soluble factors induce keratinocyte apoptosis. Pro‐apoptotic molecules, including tumour necrosis factor‐α, interferon‐γ, and inducible nitric oxide synthase, may link drug‐induced immune responses to keratinocyte damage. Soluble Fas ligand, perforin and granzyme have all been implicated in triggering keratinocyte death; however current evidence favors granulysin as the key mediator of apoptosis in SJS/TEN.

 

In at least 15% of SJS/TEN cases a culprit drug is not identified. In SJS, some cases, especially in children, appear to be triggered by infections, most notably by Mycoplasma pneumonia.

 

In summary, the current model for the pathogenesis of SJS/TEN is as follows: upon exposure to certain types of drugs, an individual with particular predisposing factors mounts a specific immune reaction to the drug or one of its metabolites. As a result of an interplay of cell types and cytokines that remains to be totally defined, there is a strong expression of the cytolytic molecule FasL on keratinocytes as well as secretion of granulysin from CTLs, NK cells and NKT cells and annexin A1 from monocytes. This leads to FasL- and granulysin-mediated apoptosis and/or annexin-dependent necroptosis of keratinocytes and subsequent epidermal necrosis and detachment.

 

Proposed pathomechanisms to explain apoptosis of epidermal keratinocytes in Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

 

A number of medications can trigger widespread apoptosis of epidermal keratinocytes in individuals with SJS or TEN, leading to skin blistering and denudation. Several theories have been proposed for this condition: (A) the medication might induce upregulation of FasL by keratinocytes constitutively expressing Fas, leading to a death receptor-mediated apoptotic pathway; (B) the drug might interact with MHC class I-expressing cells and then drug-specific CD8+ cytotoxic T cells accumulate within epidermal blisters, releasing perforin and granzyme B that kill keratinocytes; (C) drug activated monocytes could secret annexin A1, which induces necroptosis in keratinocytes via binding to formal peptide receptor1(FPR1); and (D) the drug may also trigger the activation of CD8+ T cells, NK cells and NKT cells to secret granylosin, with keratinocyte death not requiring cell contact. IVIg contains antibodies against Fas that can block the binding of Fas L to Fas.

 

 

CLINICAL MANIFESTATION

 

For most drugs time from first drug exposure to onset of symptoms: 1-3 weeks, but usually develops within the first week of antibiotic therapy and up to 2 months after starting an anticonvulsant. Prodromes with flu-like symptoms such as fever, headache, rhinitis, cough or malaise may precede the mucocutaneous lesions by 1–3 days. Pain on swallowing, burning or stinging of the eyes progressively develops, heralding mucous membrane involvement. About one third of cases begin with flu-like symptoms, one third with symptoms of mucous membrane involvement and one third with an exanthema. Whatever the initial symptoms are their rapid progression, the addition of new signs, severe skin pain and tenderness, which is often out of proportion to physical findings in early disease and constitutional symptoms, should alert one of a severe disease.

 

 

Skin Lesions

 

The earliest skin lesions appear as erythematous, dusky red or purpuric macules of irregular size and shape, and they have a tendency to coalesce. Lesions increase in size and number over 5–7 days, tending to coalesce. Large areas of confluent erythema may develop; either de novo, or from confluence of individual discrete necrotic macules. In the absence of spontaneous epidermal detachment, a Nikolsky sign should be sought by exerting tangential mechanical pressure with a finger on several erythematous zones. This sign is considered positive if dermal–epidermal cleavage is induced. In some patients, the macular lesions observed at the onset can have a dusky center and a slightly paler outer ring, giving them a target-like appearance (flat atypical targets). However, such lesions lack the three concentric rings characteristic of typical target lesions and are not papular as in atypical target lesions of EM.

 

As the epidermal involvement progresses towards full thickness necrosis, the dusky red macular lesions take on a characteristic grey hue. This process can be very rapid (hours), or take several days. The necrotic epidermis then detaches from the underlying dermis, and fluid fills the space between epidermis and the dermis, giving rise to blisters. These blisters are flaccid, break easily and extend sideways by slight pressure of the thumb as more necrotic epidermis is displaced laterally (Asboe-Hansen sign). Tense blisters are usually seen only on the palmoplantar surfaces, where the epidermis is thicker and, therefore, more resistant to mild trauma. The full-thickness epidermis is easily detached at pressure points, such as the back, shoulders or buttocks, or by frictional trauma like a boiled potato leaving areas of exposed dermis. The combination of both detached and detachable epidermis (positive Nikolsky sign) will produce large areas of dark red bleeding dermis, resembling second-degree thermal burn and can become secondarily infected. In other areas the pale necrotic epidermis remains in situ, with a wrinkled appearance that resembles wet cigarette paper.

 

 

Distribution

 

Skin lesions tend to appear first on the upper trunk, spreading to the neck, face and proximal upper limbs in a symmetrically distribution. Subsequently, lesions spread to involve the rest of the trunk and limbs and becoming confluent; involvement of the palms and soles with flat atypical target lesions is often prominent. Dusky erythema of periungual skin is commonly seen. Palms and soles may be less severely involved but the hairy portion of the scalp is never affected.  SJS: widely distributed with prominent involvement of trunk and face. TEN: generalized, universal.

 

 

Mucous Membranes

 

Involvement of the mucous membranes of the eyes, mouth, nose and genitalia is usually an early feature and leads to an erosive and hemorrhagic mucositis. Almost 90% of patients develop erosive mucous membrane lesions, and can precede or follow the skin eruption (nearly always on at least two sites). The most frequently affected mucosal membrane is the oropharynx, followed by the eyes and genitalia.

 

Oral

 

Oral involvement is characterized by painful mucosal erythema with subsequent blistering and erosions. Similar changes to the vermillion of the lips progress to the retention of thick adherent hemorrhagic crusts. The tongue and palate are frequently affected. In severe cases mucosal involvement may extend to the oropharynx, larynx, respiratory tract and esophagus. Drinking and eating are usually severely compromised by oral involvement in acute EN.

 

Eyes

 

Most patients develop intense conjunctivitis manifested by pain, photophobia, lacrimation, redness and discharge with a tendency to form adhesions. In less than 24 hours, the conjunctiva and cornea may become adherent. Severe forms may lead to epithelial defect with corneal ulceration, anterior uveitis, and purulent conjunctivitis. There may be shedding of the eyelashes.

 

Urogenital tract

 

Involvement of the urogenital tract in EN is characterized by mucosal erythema, blistering and erosions. During the acute phase, urogenital pain is prominent and urinary dysfunction (dysuria or retention) is common. Genital erosions are frequently overlooked in women, and may lead to synechiae.

 

 

Clinical variants

 

SJS must be differentiated from erythema multiforme major (EMM). In both EMM and SJS, there is mucous membrane involvement and cutaneous blistering with epidermal detachment of less than 10% body surface area (BSA). However, in EMM the lesions consist of typical targets or raised atypical targets, predominantly localized on the limbs and acral sites; in SJS, the lesions are atypical flat targets with predilection for the torso. Distinguishing EMM from SJS has causality implications: EMM is mostly related to herpes simplex virus reactivation and rarely to drugs; SJS is usually triggered by a drug, rarely by an infection.

 

Mycoplasma‐induced SJS is reported, and in some cases (mostly children) may be characterized by a predominance of mucous membrane involvement with little or no cutaneous lesions. This clinically atypical form of SJS has been termed Mycoplasma pneumoniae‐associated mucositis (MPAM).

 

Classification of severity

 

Patients are categorized according to type of cutaneous lesion and extent of maximal epidermal detachment. Measurements of epidermal detachment should include both detached and detachable epidermis (positive Nikolsky sign) but not purely erythematous areas (negative Nikolsky sign). The extent of skin detachment allows classification of the patient into one of four groups:

·       SJS is defined as: epidermal detachment less than 10% BSA, plus widespread purpuric macules or flat atypical targets.

·       Overlap SJS‐TEN: detachment of 10–30% BSA, plus widespread purpuric macules or flat atypical targets.

·       TEN with spots: detachment greater than 30% BSA, plus widespread purpuric macules or flat atypical targets.

·       TEN without spots: detachment greater than 30% BSA, with loss of large epidermal sheets without purpuric macules or target lesions.

 

 

EXTRACUTANEOUS FINDINGS

·       Fever.

·       Usually mentally alert but distress due to severe pain.

·       The epithelium of the respiratory tract (tracheobronchial tree) is involved with sloughing of epithelium caused by epithelial necrosis and erosions and clinically manifested by dyspnea, elevated respiratory rate, bronchial hyper secretion and cough. In most cases chest x-ray is normal on admission but can rapidly reveal diffuse interstitial pneumonitis that can progress to acute respiratory distress syndrome (ARDS) and is associated with poor prognosis. In the case of respiratory abnormalities, fiber optic bronchoscopy may be useful to distinguish a specific epithelial detachment in the bronchi from an infectious pneumonitis, which has a much better prognosis.

·       Gastrointestinal tract involvement: epithelial necrosis of the esophagus, small bowel or colon manifesting as esophagitis, profuse diarrhea with malabsorption, melena and even colonic perforation.

·       Renal involvement: Proximal tubular damage results from necrosis of tubule cells by the same process that destroys epidermal cells with proteinuria, micro albuminuria, hematuria and even azotemia. Glomerulonephritis is rare.

 

 

LABORATORY EXAMINATIONS

 

Laboratory examinations are essential, not for the diagnosis of EN, but to evaluate the severity of the disease and for daily management of the patient as for all life-threatening conditions in ICU. The following investigations should be done for all patients:

 

·       Evaluation of respiratory rate and blood oxygenation are among the first steps to take in the emergency room and any alteration (respiratory rate > 20/min and pO2 < 80 mm Hg) is a sign of hypoxia due to pneumonia and should be checked through measurement of arterial blood gas levels.

 

·       CBC (normocytic and normochromic anemia and thrombocytopenia are common). Neutropenia is often considered to be unfavorable prognostic factor. In the acute phase, there is a transient decrease of peripheral CD4⁺ T lymphocytes, associated with decreased T-cell function, which returns to normal in 7-10 days.

 

·       Serum electrolytes Serum bicarbonate levels below 20 mg/L indicate a poor prognosis. They usually result from respiratory alkalosis related to the specific involvement of the bronchi and more rarely from metabolic acidosis.

 

·       Hypophosphatemia is nearly constant.

 

·       Urinalysis (hematuria and proteinuria indicate renal involvement).

 

·       Blood sugar (elevated blood sugar and glycosuria). Release of stress hormones leads to a hypercatobolic state and is responsible for inhibition of insulin secretion or insulin resistance in peripheral tissues, which results in hyperglycemia, and occasionally overt diabetes. A blood glucose level above 252mg/dl is one marker of severity.

 

·       LFT (SGOT and SGPT) and serum amylase (most probably of salivary origin) are slightly elevated in half of the patients, but frank hepatitis may develop, induced by drugs or sepsis.

 

·       RFT (blood urea nitrogen, serum creatinine levels may be raised due to dehydration). Massive transdermal fluid loss is responsible for electrolyte imbalance, hypoalbuminemia, and hypoproteinemia and prerenal azotemia. Raised BUN is one marker of severity.

 

·       Chest x-ray may show diffuse interstitial pneumonia.

 

·       Skin biopsy and HIV (ELISA test) can be performed if indicated.

 

A biopsy must be taken from lesional skin, just adjacent to a blister, for routine histopathology. A second biopsy taken from peri‐blister lesional skin should be sent unfixed for direct immunofluorescence to exclude an immunobullous ­disorder.

 

At presentation, swabs should be taken from lesional skin and sent for bacteriology. Clinical photographs of the skin should be taken to show the type of lesion and extent of involvement. The extent of erythema and the extent of epidermal detachment should be recorded separately on a body map; for each parameter the percentage of BSA involved should be estimated.

 

Blood tests needed at presentation in Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)

 

·       Full blood count

·       Urea and electrolytes

·       Amylase

·       Bicarbonate

·       Glucose

·       Liver function tests

·       Erythrocyte sedimentation rate

·       C‐reactive protein

·       Coagulation studies

·       Mycoplasma serology

·       Antinuclear antibody and extractable nuclear antigen

·       Complement

·       Indirect immunofluorescence

 

 

PROGNOSIS AND CLINICAL COURSE

 

Course of epidermal necrolysis (EN)

 

First symptoms of the reaction are non-specific like fever, sore throat, and reduced state of health (prodromal symptoms). Medications given for the prodromal symptoms are not associated with EN even if the clear sign (mucosal involvement, macules) appears after their intake (“protopathic bias”; 1-3D). After admission the progression of EN to maximum skin detachment continues for up to 5 days (5D).

 

The epidermal detachment progresses for the first 5 to 7 days. With appropriate supportive therapy, and intensive skin/mucous membrane‐directed treatment, re‐epithelialization should start once the disease stops extending. In most uncomplicated cases re‐epithelialization will take 2- 3 weeks to heal eroded areas. This process results from proliferation and migration of keratinocytes from “reservoir” sites, such as healthy epidermis surrounding denuded areas and hair follicles within the areas of detachment. Due to this conserved capacity for re-epithelialization, skin grafting is not required in EN. Delayed healing will occur in the presence of skin sepsis, systemic complications, or if the triggering agent (culprit drug) has not been removed. Pressure points and mucosa exhibit delayed healing.  Mortality rate for SJS is 5%, 10-15% for overlap and > 30% for TEN. On average, death occurs in every third patient with EN, and it is mainly due to septicemia. Massive trans- epidermal fluid loss associated with electrolyte imbalance, inhibition of insulin secretion, insulin resistance, and onset of a hyper catabolic state can also be contributive factors. All these complications of EN are best managed in intensive care units. They can unfortunately culminate in adult respiratory distress syndrome and multiple organ failure despite adequate supportive therapy. Other causes of death are pulmonary embolism and gastrointestinal bleeding. 

 

In EN, there are several factors that have been correlated with poor outcome, including increasing age and extent of epidermal detachment. In addition, the number of medications, elevation of serum urea, creatinine and glucose levels, neutropenia, lymphopenia and thrombocytopenia has been statistically linked to poor outcome. Late withdrawal of the causative drug is also associated with a less favorable outcome. It has been estimated that prompt withdrawal of the offending drug reduces the risk of death by 30% per day. The prognosis is not affected by the type or dose of the responsible drug or the presence of human immunodeficiency virus infection.

 

A prognostic scoring system is called SCORTEN. It should be calculated at admission and 3 days later.

 

Prognostic Factors   

 

SCORTEN
Prognostic factors	Points
Age >40 years	1
Heart rate >120 bpm	1
Cancer or hematologic malignancy	1
BSA involved on day 1 >10%	1
Serum urea level (>28mg/dL)	1
Serum bicarbonate level (<20 mmol/L)	1
Serum glucose level (>252mg/dL)	1
SCORTEN	Mortality rate (%)
0–1	3.2
2	12.1
3	35.8
4	58.3
≥5	90

                                                                            

 

 

COMPLICATION AND SEQUELAE

 

Acute complications

 

Acute complications are similar to those of extensive burns.

 

Patients develop acute skin failure, its main features are:

 

·       Barrier dysfunction: The total daily fluid loss averages 3–4 L in adult patients with TEN affecting 50% of body surface area. It induces a reduction of intravascular volume and functional renal failure. If not corrected, hypovolemic may lead to hemodynamic alterations and organic renal failure.

·       Temperature dysregulation: Patients are usually febrile and shivering, even in the absence of infection. Release of inflammatory cytokines (IL-1, TNF-a, IL-6) contributes to high fever. Hypothermia is infrequent and usually a marker of severe infection and irreversible septic shock. 

·       Immune impairment: selective depletion of CD4+ helper T cells and

·       Infection:  The commonest life‐threatening complication of acute SJS/TEN is septicemia. The denuded dermis in SJS/TEN acts as a substrate for microbial colonization, initially by Staphylococcus aureus and later by Gram‐negative rods from the digestive flora, especially Pseudomonas aeruginosa. Systemic sepsis can quickly follow skin infection and lead to multiorgan failure.

 

Pathogenesis of altered temperature regulation in acute skin failure

 

 

Long‐term complications

 

Survivors from an acute episode of SJS/TEN may develop delayed sequelae which are associated with significant morbidity and reduced quality of life. The most common sequelae involve the skin and mucous membranes; the most disabling complications are ocular.

 

In EN patient’s sequelae tend to be more frequent and more severe than previously thought. So prevention and adequate management of sequelae are as important as saving the life in acute phase.

 

Long-term complications of acute skin failure   

 

Skin

 

In the skin, post‐inflammatory dyspigmentation persists in darker skinned patients from months to years following resolution of the acute dermatosis. Re‐epithelialization usually occurs without scarring but cicatricial healing may develop in areas which were infected during the acute phase and at sites of unrelieved pressure injury. Eruptive melanocytic naevi occur occasionally in the recovery phase, more commonly in children and young adults. Shedding of nails (onychomadesis) may occur a few weeks after the acute episode due to nail matrix arrest; occasionally, there is subsequent permanent anonychia. Involvement of the scalp in acute SJS/TEN is extremely unusual, however telogen effluvium occurs in about 20% of patients in the post‐acute phase. Other skin complications include: pruritus, abnormal photosensitivity, abnormal sweating and heterotopic ossification.

 

 

Eyes

 

Long‐term ocular sequelae are the most disabling complications of SJS/TEN. Late ophthalmic complications are reported in about 40% of EN survivors. The relationship between the initial severity of ocular involvement and the development of late complications seems now to be well established. Chronic complications include corneal and conjunctival ulceration and scarring, dry eye, distichiasis, entropion, trichiasis and ocular surface failure. In the conjunctiva, scarring of the fornix obstructs the ductal openings of lacrimal glands thus ­aggravating ocular ­dryness. Bulbar and forniceal cicatricial changes lead to ­symblepharon or ankyloblepharon formation with limitation of ocular mobility and interference of the tear meniscus. Scarring of the eyelid margin leads to ectropion, entropion and misdirected eyelashes. Patients with chronic eye involvement require lifelong management for dryness, conjunctival inflammation and ocular discomfort; many suffer permanent visual impairment or blindness. Such severe eye lesions occasionally develop in patients who had no patent ocular signs during the acute phase of EN.

 

 

Oral mucosa

 

A range of long‐term oral complications may occur resulting in functional impairments. Oral mucosal scarring can cause gingival synechiae resulting in food trapping and limitation of oral mobility. A Sjögren‐like syndrome has been reported (ANA/Ro/­La‐negative) and is believed to occur in up to 40% of survivors. Other complications include altered taste and late alteration of teeth.

 

 

Lungs

 

The most important late complication of pulmonary involvement is bronchiolitis obliterans, in which airway epithelial injury is followed by regeneration and scarring. It leads to severe airway obstruction and progressive dyspnea. Most cases present 3–4 months after the acute episode and are associated with a poor prognosis.

 

 

GIT

 

Long‐term complications in the gastrointestinal tract are rare but esophageal stricture is reported. Intestinal ulceration may occur in acute SJS/TEN and usually heals along with skin re‐epithelialization, however in some patients small intestinal ulcers can be persistent causing diarrhea and malabsorption.

 

Urogenital

 

Chronic urogenital lesions in SJS/TEN are mostly adhesions: vaginal and introital adhesions may be associated with dyspareunia. Other gynecological complications include vaginal adenosis which is the replacement of non‐cornified vaginal epithelium with metaplastic epithelium of endocervical differentiation. Phimosis occurs in male patients.

Because these late complications and sequel may develop insidiously, it is strongly suggested that all patients surviving EN have a clinical follow up for a few weeks after discharge and 1 year later, including examination by an ophthalmologist and by other organ specialists as indicated by abnormal signs and symptoms.

 

Pathology

 

Histopathologic examination of lesional skin is a very useful tool for confirming the diagnosis of SJS and TEN, as the morphologic findings are distinct from those observed in SSSS (subcorneal blister with cleavage located in the granular layer of the epidermis) and acute generalized exanthematous pustulosis (AGEP; a rich neutrophilic infiltrate, superficial epidermal pustules and spongiosis, but no full-thickness epidermal necrolysis). Frequently, immediate analysis of frozen cryostat sections is sufficient for this purpose.

 

In early lesions of SJS and TEN, apoptotic keratinocytes are observed scattered in the basal and immediate suprabasal layers of the epidermis. This is most likely the histologic correlate of the dusky to gray color that clinicians familiar with SJS/TEN consider as a warning sign of impending full-blown epidermal necrolysis and detachment. At later stages, lesional biopsy specimens show   

a subepidermal blister with overlying confluent necrosis of the entire epidermis and a sparse perivascular infiltrate composed primarily of lymphocytes. At an immunopathologic level, variable numbers of lymphocytes (usually CD8⁺) and macrophages are observed within the epidermis, whereas lymphocytes in the papillary dermis are primarily CD4⁺ cells.

 

MANAGEMENT

 

EN is a life threatening disease that requires optimal management:

·       Early diagnosis, and immediate withdrawal of suspected drug(s),

·       Supportive care and

·       Specific therapy.

 

Prompt identification and immediate withdrawal of the causative drug(s) is associated with increased rate of survival in patients with EN induced by drugs with short elimination half-lives. On the other hand, it is preferable to continue every important and nonsuspected medication. That will avoid reluctance on the part of the patient's physicians to prescribe them in the future. Currently, there is no reliable test for the identification of causative drugs, so the clinician, has to rely on previously reported associations and determine the probability (unlikely, possible, plausible, probable, very probable) for each drug based on their intrinsic ability to cause EN and extrinsic factors such as the onset of a given medication with respect to the onset of EN. In case of doubt, all non-life sustaining drugs should be stopped, and particularly those administered within the previous 8 weeks. In general, the medication list of patients with EN should be reduced to a strict minimum, appropriate substitution made and drugs with short half-lives favored.

 

 

Symptomatic Treatment

 

The fundamental elements of patient management in SJS/TEN are meticulous care of lesional skin and mucous membranes, coupled with intensive supportive care for the systemic complications of acute skin failure. ++Only patients with limited skin involvement, a SCORTEN score of 0 or 1, and a disease that is not rapidly progressing can be treated in nonspecialized wards. Others should managed in an appropriate care setting, usually an intensive care unit (ICU) or burns unit, by a team of clinicians experienced in treating SJS/TEN. There is no “specific” treatment of demonstrated efficacy and supportive measures are the most important. Supportive care consists of maintaining hemodynamic equilibrium and preventing life-threatening complications.

 

 

Supportive care:

 

Aim of supportive care is to limit complications such as hypovolemia, electrolyte imbalance, renal insufficiency and sepsis which are the major cause of mortality.

·       Admit the patient to ICU or burn unit and the room temperature should be maintained at (30-32 degree C) to reduce heat loss through the skin.

·       Measure extent of epidermal detachment by ‘Rule of Nines’ or the simple rule that one hand (palm and fingers) corresponds to 1% of the BSA.

·       Place large bore intravenous line by venous catheter in a region of non involved skin to ensure adequate intravenous access and to prevent sepsis.

·       Replacement of IV fluids and electrolytes is same as for patient with a third-degree thermal burn. However, less fluid (about 70%) usually required as for thermal burn of similar extent, because interstitial edema is absent. For the first 24 hours average 4-6 liters/day fluid and electrolyte is required (isotonic saline 0.7ml/kg/% of body surface area (BSA) affected+ human albumin 1ml/kg/% BSA. Potassium phosphate is added to I/V fluids to prevent insulin resistance). Half the calculated fluid is administered in the first 8 hours and the other half in the next 16 hours. Thereafter, fluid requirement should be guided by the previous day urinary output.  After admission, an oral liquid diet or a nasogastric tube (Ryle’s tube) should be considered in the presence of severe mucosal involvement restricting oral intake until the oral mucosa has healed (1500 calories in 1500ml over the first 24hrs, increasing by 500 calories daily to 3000-4000 calories day).  Proteins (approx 1.5 g/kg/day) are given to avoid negative nitrogen balance as protein loss, from skin lesions and increased catabolism, may reach up to 150–200 g/day.

·       Daily urinary output measurement by Foley’s catheter and is maintained at more than 1500ml/day.

·       All lines should be checked daily for signs of infection, changed at least every 3 days, and the tips of all discarded lines and catheters sent for culture.

·       Monitor for infection. To reduce the risk of infection, aseptic and careful handing is required. Treat empirically with systemic antibiotics until c/s reports only for documented infections or signs of sepsis (sudden rise or fall of temperature, deterioration of consciousness, fall in urinary output, tachycardia, tachypnea, and increase in insulin requirement). Empirical coverage should include one antibiotic having anti- staphylococcal activity and one effective against gram negative bacteria.

·       Prophylactic anticoagulation is provided during hospitalization.

·       +An hourly record of the pulse, respiratory rate, blood pressure, and urine output is essential; glycosuria and body temperature should be recorded every 3 hours. An accurate daily intake-output chart should be maintained. A urine output of 50-100 ml/hour is indicative of adequate tissue perfusion whereas reduction in urine output may be an early indicator of hypovolemia or septicemia. A pulse rate of =/> 120 /minute, even in the presence of precipitating factors like septicemia and fever, indicates a negative fluid balance.

·       Sedation and pain therapy.

·       Lung involvement may be complicated by pulmonary edema during fluid replacement. Pulmonary care includes normal saline aerosols, bronchial aspiration and postural drainage by turning the patient to different sides.

·       Period culture of skin erosions, blood and urine for bacteria and fungi.

·       Physical therapy daily to preserve limb mobility and to prevent contractures.

·       Consult physician to manage co morbidities, pulmonary medicine for airway involvement and gastroenterology for alimentary involvement.

 

Skin care:

 

Skin care is important to minimize heat and fluid loss, prevent infections and provide a moist environment to promote re-epithelisation.

·       All manipulation should be performed sterilely. Move the patient as little as possible because every movement is a potential cause of epidermal detachment. Adhesive tape should not be applied directly to involved skin when possible.

·       Air-fluidized bed to minimize shearing forces.

·       Non detached areas are kept dry and not manipulated.

·       Detached or detachable epidermis should be left in position as a biological dressing, should not be debrided and that only denuded areas in contact with bed should be covered with non-stick dressing such as Vaseline gauze until re-epithelisation has occurred. Blisters are fragile, left undisturbed or may simply punctured.

·       Skin care should be focus on the face, nose, ears, ano-genital region, axillary folds and interdigital spaces. Clean serous and bloody crusts from these areas with sterile normal saline daily and apply antibiotic ointment e.g. mupirocin.

·       Regular examination of the eyes by an ophthalmologist to minimize the risk of conjunctival scarring and blindness. Regular installation of antiseptic eye drops and separation of newly formed synechiae are required.

·       Mouth should be rinsed several times daily with antiseptic (chlorohexidine rinses) and antifungal solution. For lip erosions apply white petrolatum ointment.

·       Avoid sulpha-containing topical or systemic preparation.

·       Consult ENT specialist to evaluate extent of upper respiratory tract involvement.

·       Consult Gynecologist and urologist for genitourinary involvement.

·       If extensive denuded areas, use biological dressings or skin equivalents.

 

Care environment and care provision

Patients with large areas of epidermal loss (greater than 10% of BSA) should be admitted to an ICU for critical care management and specialist nursing. Since the cutaneous defect in SJS/TEN is analogous to a large superficial burn, many patients are transferred to a burns unit which can deliver both ­intensive ­supportive management as well as skin‐directed therapy. Rapid admission to a specialist unit improves survival, whilst a delay in transfer is accompanied by increased mortality.

 

A number of specialist services are needed to manage EN effectively. A multidisciplinary team (MDT), coordinated by a specialist in acute skin failure (dermatologist or burns surgeon), should be convened to manage the patient. As well as dermatology and wound care expertise, the EN MDT must include clinicians from intensive care, ophthalmology and skin care nursing. Additional clinical input is often required from thoracic medicine, gastroenterology, gynecology, urology, oral medicine, microbiology, dietetics, physiotherapy and pharmacy. Within an ICU or burns care unit the patient must be barrier nursed in a side room on a pressure‐relieving mattress with the ambient temperature raised to 25–28 °C.

Skin handling, topical therapy and dressings

In EN, necrolytic epidermis readily detaches from underlying dermis and therefore careful handling of the skin is essential. Day‐to‐day bedside care should be delivered by specialist nurses familiar with skin fragility disorders. Shearing forces applied to the skin, a particular problem in patient positioning, should be limited. Other sources of skin trauma to be avoided include the use of sphygmomanometer cuffs, adhesive ECG leads, adhesive dressings and identification wrist tags.

 

Despite careful nursing, lesional epidermis (referred to as ‘detachable epidermis’) in EN often peels away, especially at pressure areas, to leave zones of denuded dermis. In the conservative approach, detached epidermis can be left in situ to act as a biological dressing for the underlying dermis. In cases where bullae are prominent, it can be decompressed by fluid aspiration and the blister roof retained to cover the underlying dermis.

 

The intact skin should be cleansed each day by gentle irrigation with warmed sterile water or sprayed with a weak solution of chlorhexidine (1/5000). If mobility permits, the patient may be bathed in a weak solution of chlorhexidine (1/5000). The whole skin, including denuded areas, should be treated with frequent applications of a greasy emollient, such as 50% white soft paraffin with 50% liquid paraffin (50/50 WSP/LP). Aerosolized formulations of 50/50 WSP/LP can be used to minimize shearing forces associated with topical applications. A topical antibiotic ointment should be used only on sloughy or crusted areas, or at sites of positive microbiology swabs.

 

The use of dressings on denuded areas in EN will reduce fluid and protein loss, limit microbial colonization, help pain control and accelerate re‐epithelialization. Silicone dressings are recommended for areas of exposed dermis, while an absorbent non‐adherent dressing should be applied as a secondary layer to collect exudate and protect lesional skin. Smear the surface of dressings with 50/50 WSP/LP prior to contact with the patient.

In the surgical approach, favored by burns specialists, biological dressings are applied to denuded areas under a general anesthetic.

 

Local therapy for eyes, mouth and uro‐genital tract

 

Eyes

 

The eyes should be examined by an ophthalmologist as a part of the initial assessment and daily thereafter during the acute phase. An ocular lubricant must be applied 2‐hourly. Ocular hygiene, to remove inflammatory debris and break down conjunctival adhesions, must be carried out each day. A broad spectrum topical antibiotic should be used in the presence of corneal fluorescein staining or frank ulceration. The use of topical corticosteroid drops, supervised by an ophthalmologist, may reduce ocular surface damage in the acute phase of EN. For patients in whom there is extensive loss of ocular surface epithelia which is unresponsive to conservative measures, then amniotic membrane transplantation (AMT) can be considered. The proposed benefits of AMT in the acute phase include reduced inflammation, enhanced re‐epithelialization, and reduction of scarring and symblepharon formation.

 

Mouth

 

Regular examination of the mouth must be undertaken. Apply WSP ointment frequently to the lips; protect ulcerated intra‐oral surfaces with a mucoprotectant mouthwash. Clean the mouth daily with warm saline mouthwashes. Use an anti‐inflammatory oral rinse containing benzydamine hydrochloride every 3 h, and an antiseptic mouthwash (e.g. chlorhexidine digluconate) twice per day. In the absence of secondary infection, consider using a topical corticosteroid four times per day (e.g. Betnesol mouthwash 0.5 mg in 10 mL of water as a 3‐min rinse‐and‐spit preparation).

 

Uro‐genital tract

 

Examine the uro‐genital tract regularly throughout the acute illness. Use WSP ointment as an emollient frequently. Use silicone sheet dressings to eroded areas in the vulva and vagina. Consider applying a topical corticosteroid cream with additional antimicrobial activity to the involved but non‐eroded surfaces. Catheterizing all patients will prevent urethral strictures.

 

Fluid replacement and nutrition

 

Extensive epidermal detachment will result in large insensible transcutaneous fluid losses, compounded by decreased oral intake due to disease involvement of the mouth. During the acute illness, replace fluids intravenously, using a crystalloid fluid at 2 mL/kg body weight/% of BSA epidermal detachment, or alternatively use urine output to guide fluid replacement. Establish ­peripheral venous access by inserting cannula through non‐lesional skin. Over‐aggressive fluid resuscitation may be associated with pulmonary, cutaneous and intestinal edema.

 

In EN cases with significant areas of skin involvement, a nutritional regimen must be initiated early to support metabolic disturbances, minimize protein losses and promote ­healing. Enteral nutrition is preferable to parenteral nutrition to reduce peptic ulceration and limit translocation of gut bacteria. Since buccal mucositis in EN often precludes normal oral intake, naso‐gastric feeding with a silicone tube should be instituted when necessary. During the early, catabolic phase of EN 20–25 kcal/kg/day should be delivered, while requirements in the recovery, anabolic phase increase to 25–30 kcal/kg/day.

 

Analgesia

 

EN is characterized by cutaneous pain which is most severe at sites of epidermal detachment. If the patient is in severe pain, then an opiate‐based analgesia regimen using morphine delivered by an appropriate route should be considered. Additional analgesia is often needed to address increased pain associated with patient handling, repositioning, dressing changes and physiotherapy: a bolus of 0.1 mg/kg of morphine may be given intravenously, 10–20 min before commencement of the procedure. Bolus ketamine analgosedation (0.5 mg/kg) may be useful for procedural analgesia. Adjuvants, including γ‐aminobutyric acid (GABA) analogues, may have an opiate‐sparing role. Topical anesthesia of mucous membranes may facilitate placement of naso‐gastric tubes and urinary catheters.

 

Additional supportive medication

 

Patients with EN are subject to stress‐related gastric or duodenal ulceration and, if immobile, at risk of venous thromboembolism. Gastric protection with a proton pump inhibitor is recommended if the patient is not absorbing food. Prophylactic anticoagulation with low‐molecular‐weight heparin is necessary, unless contraindicated.

Anemia and leucopenia are common complications of the acute phase of EN. Neutropenia will increase the risk of sepsis and therefore administration of recombinant human granulocyte–­colony‐stimulating factor (G‐CSF) has been used to resist infectious complications. It has been suggested that G‐CSF in EN may also be immunomodulatory and enhance re‐epithelialization.

 

Monitoring for infection

 

Cutaneous infection is a common complication of EN: it will impair re‐epithelialization and may lead to systemic sepsis. Swabs for bacterial and Candida culture should be taken from multiple sites, particularly sloughy or crusted areas, throughout the acute phase of EN. Prophylactic systemic antimicrobial therapy may increase skin colonization, particularly with Candida albicans; therefore antibiotics should only be given if there are clinical signs of infection. The EN disease process may be accompanied by a fever which complicates detection of secondary sepsis. Patients should therefore be monitored carefully for other signs of systemic infection such as confusion, hypotension, reduced urine output and reduced oxygen saturation. The detection of sepsis may also be indicated by a rise in CRP, a neutrophilia and an increase in skin pain.

 

Definite indications of antibiotic use

 

1. High bacterial count (single strain) from skin / catheter sample of urine

2. Sudden hypothermia in a relatively stabilized patient

3. Confused mental status, anxiety and excitement

4. Symptoms of infection pertaining to a particular system, e.g. pneumonia/urinary tract infection

 

Specific treatment in acute stage

 

Because of the importance of immunologic and cytotoxic mechanisms, a large number of immunosuppressive and/or anti-inflammatory therapies have been tried to halt the progression of the disease, most notably systemic corticosteroid, IVIG and cyclosporine. None has clearly proved its efficacy.

Systemic Corticosteroids

 

The use of systemic corticosteroids is still controversial. Some studies found that such therapy could prevent the extension of the disease when administered during the early phase, in high doses and for short period, not more than 4-5 days, especially as intravenous pulses, but late in the disease they are contraindicated.  Other studies concluded that steroids did not stop the progression of the disease and were even associated with increased mortality and adverse effects, particularly sepsis. Thus, systemic corticosteroids cannot be recommended as the mainstay treatment of EN, but a large study has suggested a possible benefit.

Intravenous dexamethasone 1.5 mg/kg or IV solumedrol 500mg for three consecutive days as pulse therapy within first 48 hours of onset of rash in patient with a still limited skin surface involvement to prevent widespread involvement.

 

Intravenous immunoglobulin

 

If within 48-72 h of bulla onset, use high-dose IVIG, 1gm/kg/day infused over 4 hours for 3 consecutive days. If 72 h have passed, but the patient is still actively progressing with new lesions, IVIG may still be used. It blocks keratinocyte necrosis by inhibiting the Fas‐FasL interaction and apoptosis through anti‐Fas activity. It should be avoided in patients with impaired renal function. 

 

Cyclosporine

 

Cyclosporine is a powerful immunosuppressive agent: activation of T helper 2 cytokines and inhibition of CD8+ cytotoxic mechanisms. It can halt the progression of EN without worrisome side effects when administered early. It is used in the dose of 3mg/kg/day orally for 10 days and then tapered. It can be administered by breaking the soft gel capsules, mixing the content in apple or orange juice and administered via a nasogastric tube.

 

Therapeutic ladder

First line

·       Withdraw culprit drug

·       If epidermal loss is >10% BSA transfer to a specialist unit (intensive care unit or burns unit)

·       Institute supportive care package, with particular attention to:

a.   Heated environment

b.   Fluid replacement

c.    Nutritional regimen

d.   Analgesia

e.   Preventing/treating infection

·       Specialist skin care nursing is essential for delivery of topical therapy/dressings

Second line

In the early stages of the acute phase consider using:

·       IVIG (0.5–1 g/kg daily for 3–4 consecutive days), or

·       Systemic corticosteroid (e.g. prednisolone 0.5–1 mg/kg daily for 10 days, and tapered; or IV methylprednisolone 500 mg on 3 consecutive days), or

·       Cyclosporine (3 or 4 mg/kg/day in divided doses for 10 days, and tapered)

 

Treatment of Sequelae

 

++Very promising treatments have now been developed for the ocular sequelae of EN, including gas permeable scleral lenses and grafting of autologous stem cells from contralateral limbus or mouth mucosa. With the exception of ocular sequelae, the literature contains only case reports related to treating sequelae. Photo protection and cosmetic lasers may help resolve the pigmentation changes on the skin.

 

SUMMARY OF DRUG REACTION

·       Every drug can cause almost every reaction, but 80% of drug eruptions are caused by B-lactam antibiotics, aspirin, NSAIDs, sulphonamides, allopurinol and antiepileptics.

·       In all cases, immediate identification and discontinuation of the offending agent is an essential first step. If patients are on multiple medications and definite causal identification is not possible, attempt to identify the most likely offending drug and discontinue it and all unnecessary drugs. Use alternative, pharmacologically-distinct agents. In most cases, the cutaneous reaction will resolve in 2-5 days without therapy.  Some patients, however, may require topical or systemic therapy to control the bothersome pruritus that may accompany the reaction such as topical corticosteroid ointment and oral antihistamines.

·       Patients who experience a simple, morbilliform drug eruption should avoid repeated exposure to the same drug or drug class in the future; however, in cases where this cannot be avoided, and then one can attempt a re-challenge of the medication with close monitoring. In some cases, adverse drug reactions do not occur upon repeat exposure.

·       Patients with a history of severe cutaneous eruption, especially with systemic complications, should avoid repeated exposure to the same drug or drug class in the future; their first-degree relatives should also be counseled to avoid the drug / drug class. Patients should wear a medical alert card that may aid patients in avoiding potentially dangerous medications.

·       In the future, we may be able to predict who is at risk of EN using genetic screening, as specific at-risk HLA alleles have been recognized in certain populations.

 

 

Pitfalls

·       If the cutaneous reaction does not resolve as expected, consider another diagnosis or the possibility that the offending agent has not been discontinued.

·       Many drugs cross-react, i.e., reactions to one medication typically predict cross-reaction to other medications in the same class. For example, hypersensitivity to anticonvulsants such as phenytoin results in cross-reactivity to phenobarbital and lamotrigine.

·       Look for liver, renal, and hematologic abnormalities, particularly if drugs such as dilantin and allopurinol are possible offenders.

·       In patients with renal or hepatic insufficiency, drug clearance may be impaired and the rash may persist longer than 3-5 days after discontinuation.

·       A morbilliform rash may rarely be a prodrome of Stevens-Johnson syndrome or toxic epidermal necrolysis. Monitor for skin tenderness, bullous and mucosal involvement.