Perspective Chapter: Drug-Induced Severe Cutaneous Adverse Reactions, Diagnostics and Management

Abstract

Severe cutaneous Adverse Reactions (SCAR) are rare drug hypersensitivity reactions but can be life-threatening if not appropriately and timely managed. Many research studies have shed light on its pathomechanism and triggers that have helped us better understand SCAR. The presence of viral fever and genetics such as HLA genotype with certain drugs have been associated with the occurrence of SCAR. However, the basis of interaction of these causative agents needs further evaluation to understand the predisposition to the reaction occurrence. The different spectrum of SCAR needs to be clinically diagnosed appropriately which includes Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS), Steven Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), Acute Generalized Exanthematous Pustulosis (AGEP), and generalized bullous fixed drug eruptions (GBFDE). However, due to the rare occurrence of this reaction, there is not sufficient evidence for the best treatment for patients suffering from SCAR. Our review provides detailed information about the disease type, manifestation, pathophysiology, diagnostics, and current treatment aspects of SCAR.

1. Introduction

Since time immemorial, medications come with some benefits and risks. However the intention of treating patients to cure their ailments remains the utmost priority of all the physicians. Thus stands true, the famous dictum by Hippocrates (460–370 BC) that states “Primum non-nocere” which means first of all be sure you do no harm and benefit come next. The reality however is that at times, risk and benefit cannot be separated out so what we follow today is as long as the benefit outweighs the risk, we are ready to take risks in every walk of life similar to what we do for medicines. Severe Cutaneous Adverse Reactions (SCARs) are drug associated hypersensitivity reactions that involves skin and mucous membranes of various body orifices such as eyes, ears, the inner surface of the nose, buccal mucosa, and lips and may involve damage to internal organs usually mediated by drug specific T lymphocytes [1, 2]. The phrase “Skin is Like an Ocean’s Surface Which Tells Deep Stories If You Watch Carefully” goes very well for SCARs which is a multi-spectrum disease due to its variable manifestations. SCAR has been classified into five main types- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Drug-Induced Hypersensitivity Syndrome (DIHS), Steven Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), SJS/TEN overlap syndrome and Acute Generalized Exanthematous Pustulosis (AGEP) [3]. Severe Cutaneous Adverse Reactions (SCAR) terminology was proposed for such conditions, as they were (a) severe, (b) unpredictable, and (c) drug-induced [4]. The pathophysiology remains almost similar in all these five types of severe cutaneous adverse reactions. However, immunological trigger due to viral, drug, and gene interaction is still unknown that requires intensive research. Even the predictability, diagnosis, and treatment remains challenging and uncertain for most dermatologist, immunologists, and clinical pharmacologists.

1.1 Classification of severe cutaneous adverse drug reactions (SCAR) provided by the World Allergy Organization (2014)

1. Steven Johnson Syndrome

2. Toxic Epidermal Necrolysis

3. Steven Johnson Syndrome/Toxic Epidermal Necrolysis Overlap Syndrome [5].

4. Drug-induced Hypersensitivity Syndrome (DIHS) or Drug reaction with Eosinophilia and Systemic Symptoms (DRESS)

5. Acute Generalized Exanthematous Pustulosis (AGEP)

1.2 Coombs & Gell’s classification of hypersensitivity skin reactions

Table 1 is summarized below.

Hypersensitivity reaction	Predominant inflammatory cells	Clinical Conditions
Type I	Immediate, IgE-mediated mast cell activation	Anaphylactic reaction to bee sting, antibiotic like penicillin, latex allergy.
Type II	Antibodies, cytotoxic, IgG-/IgM-mediated, complement	Hemolytic reactions; Good pasture Syndrome; Hyper acute graft rejections
Type III	mediated by immune complexes and IgG/IgM, complement	Hypersensitivity Pneumonitis (HP); Systemic Lupus Erythematosus (SLE); Polyarteritis Nodosa (PAN); Serum sickness
Type IV	Delayed-type hypersensitivity reactions mediated by T‑helper and T‑cytotoxic cells	Chronic Allograft rejection; Purified Protein Derivative (PPD) test; Latex/Nickel/ Poison ivy allergy
Grading of Type IV hypersensitivity skin reactions by Gell and Coombs
Type IVa	Monocytes	Drug-induced maculopapular exanthems
Type IVb	Eosinophils	Drug Reaction with Eosinophilic Systemic Symptoms (DRESS)
Type IVc	Cytotoxicity of drug specific T cells	Steven Johnson Syndrome/Toxic Epidermal Necrolysis
Type IVd	Neutrophils	Acute Generalized Exanthematous Pustulosis (AGEP)

Table 1.

Coombs and Gell classification of hypersensitivity cutaneous reactions.

2. Epidemiology of severe cutaneous adverse reactions (SCARs)

The skin is the most common and easily visible body part that manifest symptom of adverse drug reactions [6]. Adverse Drug Reactions (ADRs) contribute up to 7% of the hospital admissions of which cutaneous ADRs alone contribute to 2–3% of the overall hospitalizations [7, 8]. Few of these cutaneous adverse drug reactions have disabling sequelae or can be life-threatening. The incidence of fatalities among inpatients due to systemic and cutaneous adverse drug reactions reported ranges between 0.1% to 0.3%. However, the mortality rates for SJS/TEN are approximately 5–10%, 30–50% in TEN, 10% in DRESS, and the common leading culprit drugs associated with SCARs, around the world are antibiotics, anti-epileptics, allopurinol, Non-steroidal anti-inflammatory drugs (NSAIDS), and antiretrovirals [9, 10, 11]. Incidence rates of SJS/TEN range from 1.4–12.7/million person-years in different studies [12, 13, 14]. A Nationwide Korean Study of Severe Cutaneous Adverse Reactions by Kang DY et al. based on the Multicenter Registry revealed total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs. The main causative drugs suspected were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and anti-tubercular agents (6.3%). Carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%) were common offending drugs for SJS/TEN whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were associated with DRESS. The overall mortality rate reported in this study due to SCARs cases was 6.6% (SJS/TEN-8.9% and DRESS-4.2%) [15]. The phase 1 of regiSCAR project by the European community (last updated on October 25, 2014), includes potential 1889 (69.39%) cases of SJS/TEN/GBFDE/EEMM, 364 (13.37%) cases of AGEP, 469 (17.22%) cases of DIHS/DRESS. Of these suspected cases, the definite or probable cases of SJS/TEN- 1232 (65.21%), EEMM- 251 (13.28%), GBFDE- 5 (0.26%), AGEP- 228 (62.63%) and HSS/DRESS- 281 (59.91%) [16].

3. Steven Johnson syndrome/toxic epidermal necrolysis (SJS-TEN) overlap syndrome

3.1 History of SJS and TEN

Steven Johnson Syndrome was first described in 1922 by American pediatrician named Albert Mason Stevens (1884–1945) and Frank Chambliss Johnson (1894–1934) who reported two cases of boys in New York City, United States, aged 7 years and 8 years presenting with an extraordinary generalized skin eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis [17]. Both these cases were misdiagnosed by primary care physicians as a case of “hemorrhagic measles” or “black measles”. Similarly, the first description of Toxic Epidermal Necrolysis (TEN) also called Lyell syndrome was given by Scottish dermatologist Dr. Alan Lyell (1917–2007) in 1956 in four patients. Initially, these were considered as the toxic eruption that resembled severe burn or scalding of skin associated with erythematous plaques and widespread areas of epidermal detachment and was referred to as necrolysis due to excessive apoptotic keratinocytes [18]. Skin and mucous membranes were involved but with very little inflammation in the dermis referred to as the phenomenon of “dermal silence” by the dermatologist. This was an acute, rare, life-threatening mucocutaneous disease with an annual incidence of approximately 0.4–1.2 cases per million individuals with a mortality rate of more than 30% [19]. SCAR and EuroSCAR pooled data analysis was performed for children under 15 years of age that revealed that anti-bacterials class of drugs such as sulphonamides, antiepileptics such as phenobarbitol, lamotrigine, and carbamazepine was found to be strongly associated with SJS/TEN in this pediatric population [20]. Following is the case of toxic epidermal necrolysis involving the face and neck (Figure 1), trunk, and all four limbs (Figure 2) in an elderly female on cefixime and paracetamol treatment for dengue fever with no pre-existing comorbidities.

Figure 1.

Epidermal involvement of the face and neck.

Figure 2.

Epidermal involvement of limbs.

4. Criteria for the diagnosis of SJS/TEN based on extent of epidermal detachment

Steven Johnson Syndrome is an immune complex-mediated hypersensitivity reaction that involves mucocutaneous body areas such as oral, nasal, ocular, vaginal, urethral, gastrointestinal, and lower respiratory tract mucous membranes. Moreover, gastrointestinal and lower respiratory tract infections may progress to necrosis. The diagnosis of steven johnson syndrome, Toxic epidermal necrolysis, or overlap syndrome totally depends on the afflicted skin body surface area with epidermal detachment (Figure 3) [21].

• Steven Johnson syndrome (SJS)- < 10% of the body surface area involvement

• SJS/TEN overlap syndrome- 10 − 30% of the body surface area involvement

• Toxic Epidermal Necrolysis (TEN)- >30% of the body surface area involvement

Figure 3.

The extent of epidermal detachment in SJS/TEN. (adapted from fig 21.9 Bolognia and Bastuji-Garin S. et al. arch Derm 129: 92, 1993).

Distinguishing features of different severe bullous skin lesions are tabulated below (Table 2) [22].

Classification	Bullous Erythema multiforme (EM)	Steven Johnson Syndrome (SJS)	Overlap- Steven Johnson syndrome	Toxic epidermal necrolysis (TEN) with spots	Toxic epidermal necrolysis (TEN) without spots
Epidermal Detachment	<10% BSA	<10% BSA	10–30% BSA	>30% BSA	>10% BSA
Typical Targets	Yes	No	No	No	No
Atypical Targets	Raised	Flat	Flat	Flat	No
Spots	No	Yes	Yes	Yes	No

Table 2.

Distinguishing features of different severe bullous skin lesions.

Abbreviations: BSA- Body Surface Area, EM- Erythema Multiforme, SJS- Steven Johnson Syndrome, TEN - toxic epidermal necrolysis. Adapted from Bastuji-Garin S et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129(1): 92–96 (adapted from Bastuji-Garin S et al.).

5. Proposed immunological models of T cell activation in Stevens-Johnson syndrome/toxic epidermal necrolysis

There are three proposed models of T cell activation in Stevens-Johnson syndrome/toxic epidermal necrolysis due to drugs (Figure 4) [23].

1. Hapten/pro-hapten model: drugs/drug metabolites form complex with carrier proteins and are presented as haptenated peptides in the peptide-binding groove of HLA molecules (covalent).

2. p-i concept: drugs directly bind to HLA & TCR non-covalently.

3. Altered peptide model: drugs bind to the peptide-binding groove of HLA, resulting in alteration of HLA-binding peptide repertoire.

Figure 4.

Models of T cell activation in Steven Johnson syndrome and toxic epidermal necrolysis. Abbreviations: APC- antigen presenting cells, HLA- human leukocyte antigen, TCR- T cell receptor, HLA- human leukocyte antigen. Adapted from: Hasegawa a and Abe R. recent advances in managing and understanding Stevens-Johnson syndrome and toxic epidermal necrolysis (version 1; peer review: 2 approved). F1000Research 2020, 9(F1000 faculty rev):612.

6. Pathophysiology of occurrence of SJS/TEN

1. Drug induced upregulation of Fas-ligand by keratinocytes expressing Fas lead to activation of death receptor-mediated apoptotic pathway [24, 25].

2. Drug interaction with MHC class I-expressing cells leads to drug-specific CD8 + cytotoxic T cells accumulating within the epidermal blisters releasing perforin & granzyme B that kill keratinocytes [26].

3. Drug-activated monocytes secrete annexin A1, which induces necroptosis in keratinocytes [11].

4. Drug triggers activation of CD8 + T cells, NK (Non-Killer) T cells to secrete granulysin leading to keratinocyte death without the need for cell contact [27].

6.1 Histopathologic features

Histopathologic features in SJS/TEN show apoptotic keratinocytes present individually and in clusters within the epidermis. It may also show dendritic cell infiltration, spongiform superficial epidermal pustules, edema of the papillary dermis, and perivascular infiltrates of lymphocytes (Figure 5). Subtle vacuolar changes along the basal layer are accompanied by minimal inflammation with scattered lymphocytes within the epidermis [28].

Figure 5.

Histopathologic features in SJS/TEN show apoptotic keratinocytes present individually and in clusters within the epidermis.

6.2 SCORTEN scale (SCORe of toxic epidermal necrosis) for predicting mortality risk in SJS/TEN

SCORTEN scale is the severity-of-illness scale that measures the severity of certain bullous conditions and can be helpful in systematically determining the disease/reaction prognosis. The table below (Table 3) provides details of seven independent risk factors that need to be evaluated within the first 24 hours of admission or within the first 5 days of reaction that will add to accuracy in predicting mortality. The presence of prognostic factors is given a score of 1 and if not present then assign the score of 0. SCORTEN score is the summation of these individual scores allotted to each of the seven prognostic factors based on their presence or absence that gives the overall prognosis in terms of percentage mortality. More risk factors present, the higher the SCORTEN score, and the higher the mortality rate [29].

Serial number	Prognostic Factors	Score	SCORTEN score	% Mortality rate
1.	Age > 40 years	1	0–1	3
2.	Tachycardia >120 bpm	1	2	12
3.	Neoplasia	1	3	35
4.	Initial detachment >10%	1	4	58
5.	Serum Urea>10 mmol/l	1	>4	90
6.	Serum Bicarbonate<20 mmol/l	1
7.	Blood glucose >14 mmol/l	1

Table 3.

Seven independent risk factors for calculating SCORTEN score and predicting mortality risk in SJS/TEN.

7. Algorithm for drug causality for epidermal necrolysis (AlDeN) scale for causality assessment

Table 4 is summarized below.

Criteria	Values	Rules to apply	Value range
Delay from initial drug component intake to onset of reaction (index day)	Suggestive +3	From 5 to 28 days	-3 to 3
	Compatible +2	From 29 to 56 days
	Likely +1	From 1 to 4 days
	Unlikely −1	>56 days
	Excluded −3	Drugs started on or after the index day
	In case of previous reaction to the same drug only changes for – Suggestive +3: from 1 to 4 days; Likely +1: from 5 to 56 days
Drug present in the body on index day	Definite 0	Drug continued up to index day or stopped at a time point less; than five times the elimination half-life before the index day	-3 to 0
	Doubtful −1	Drug stopped at a time point prior to the index day by more than; five times the elimination half-lifea but liver or kidney function; alterations or suspected drug interactions are present
	Excluded −3	Drug stopped at a time point prior to the index day by more; than five times the elimination half-life, without liver or kidney; function alterations or suspected drug interactions
Prechallenge/rechallenge	Positive specific for; disease and drug: 4	SJS/TEN after use of same drug	-2 to 4
	Positive specific for; disease or drug: 2	SJS/TEN after use of similar drug or other reaction with; same drug
	Positive unspecific: 1	Other reaction after use of similar drug
	Not done/unknown: 0	No known previous exposure to this drug
	Negative −2	Exposure to this drug without any reaction (before or after; reaction)
Dechallenge	Neutral 0	Drug stopped (or unknown)	-2 to 0
	Negative −2	Drug continued without harm
Type of drug (notoriety)	Strongly associated 3	Drug of the “high-risk” list according to previous case–control studies	-1 to 3
	Associated 2	Drug with definite but lower risk according to previous; case–control studies
	Suspected 1	Several previous reports, ambiguous epidemiology; results (drug “under surveillance”)
	Unknown 0	All other drugs including newly released ones
	Not suspected −1	No evidence of association from previous epidemiology; study with sufficient number of exposed controls
	Intermediate score = total of all previous criteria		−11 to 10
Other cause	Possible −1	Rank all drugs from highest to lowest intermediate score	−1
		If at least one has an intermediate score > 3, subtract 1 point; from the score of each of the other drugs taken by the patient; (another cause is more likely)
Final score − 12 to 10
Causality assessment scale; <0, Very unlikely; 0–1, unlikely; 2–3, possible; 4–5, probable; ≥6, very probable.

Table 4.

Details of AlDeN scale for causality assessment (algorithm for drug causality for epidermal necrolysis).

8. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Drug-induced Hypersensitivity Syndrome (DIHS)

This DRESS is a life-threatening drug hypersensitivity reaction that can manifest with fever, cutaneous eruptions, and internal organ involvement [30]. Though the disease has a 10% mortality risk, it involves more than 50% of body surface area with skin lesions showing infiltrative papules and plaques with purpuric changes. This may be associated with other clinical features such as facial edema, desquamation during the resolution stage, and mucosal lesion involving the mouth and lips most commonly. Systemic symptoms depend on the organ involved. Eosinophilia (66–95%) is the most common hematological abnormality noted followed by atypical lymphocytosis (27–67%), lymphadenopathy (54%), and the liver is the most common internal organ involved followed by kidney, lung, and heart. The onset of skin reactions is usually observed after 3–8 weeks of the start of suspect drugs. The drugs implicated in such drug reactions are anti-convulsants, anti-infectious agents (anti-tuberculosis, antibiotics, and antiviral agents), sulfonamides, and uric acid-lowering medications. Usually, DRESS lasts for more than 15 days with prolonged courses with flare-ups observed after Human Herpes Virus type 6 reactivation. The immunopathology blamed here is the antiviral and anti-drug immune responses contribute to the disease presentations but the exact interaction is still unclear. Sequelae of this disease could be fulminant type 1 diabetes mellitus, thyroid disorders, autoimmune diseases, or permanent renal dysfunction that needs dialysis [31].

9. Acute generalized exanthematous pustulosis (AGEP)

The clinical characteristics of Acute Generalized Exanthematous Pustulosis (AGEP) are typical with multiple sterile, non-follicular pustules on oedematous erythema mostly on major skin folds. It may be associated with facial edema, blisters, or atypical target lesions. Mucosal lesions are rare and mild. There may be fever and leukocytosis associated with cutaneous eruptions. Systemic involvement is rare (<20%) but may affect the liver followed by the kidney, lung, and bone marrow. The culprit drugs that are strongly associated with these reactions are pristinamycin, ampicillin/amoxicillin, quinilones, hydroxychloroquine, anti-infective sulfonamides, terbinafine, and diltiazem based on multinational case–control EuroSCAR study. The duration between drug intake and occurrence of skin eruption may take a median duration of 1 day in the case of antibiotics and 11 days for other medications. AGEP resolves without any sequelae and has a good prognosis as well [32]. The diagnostic criteria for Acute Generalized Exanthematous Pustulosis (AGEP) are as follows [33, 34] – 1) Acute pustular eruption 2) Fever >38 degrees Celsius 3) Neutrophilia with or without eosinophilia 4) Sub corneal or intradermal pustules on biopsy 5) Spontaneous resolution in less than 15 days.

10. Diagnostic tests for cutaneous drug hypersensitivity

Drug associated cutaneous hypersensitivity reaction requires an adequate clinical and physical examination approach with an evaluation of historical details. In addition to clinical history and examination, the diagnostic test will help to confirm the diagnosis of SCARs. Also, it will help us to determine if the initial reaction is IgE or non-IgE mediated. A diagnostic test can be classified into In Vitro tests and In Vivo tests.

In Vitro Tests: The quantification of various chemokines (histamine, tryptase, leukotrienes) from a different sample such as peripheral blood, nasal or bronchial secretions, urine sample serves as useful means to differentiate between the immediate and delayed types of hypersensitivity reactions (For details, refer Table 5). The Allergen challenge test may be formed to see the difference in the level of chemical mediators from the baseline levels. In case of acute anaphylactic reactions, the test can serially measure serum total tryptase levels, at 1 and 6 hours but is not completely reliable as normal levels may be detected in fatal cases of anaphylaxis. Even plasma histamine levels drop after 1 hour of anaphylactic symptoms making this test not reliable. Moreover, these test kits are expensive.

Function of type of in vitro test	Test name	Drug names/Disease Conditions	Limitation of the test/Inferences
Allergen-specific IgE levels	radioallergosorbent tests (RASTs) or radioimmunoassay (RIA) or fluorescent enzyme immunoassay (FEIA) tests (ImmunoCAP®)	penicilloyl, amoxicilloyl, ampicilloyl, cefaclor, protamine, insulin, suxamethonium, neuromuscular blocking agents (NMBAs), and chlorhexidine	specific, lack sensitivity compared to clinical history and/or skin tests.; (in clinical practice, a utility for these tests is limited).
CD 63 and CD 203c levels on activated basophils.	Flow cytometry-based basophil activation assays (also known as flow cellular antigen stimulation tests [CASTs])	beta-lactam, NSAIDs, fluoroquinolones, iodinated contrast media, proton pump inhibitors, NMBAs, and chemotherapeutical agents	technical concerns, false-positive results, and lack of sensitivity and specificity. (not widely used)
Peripheral blood eosinophilia or elevated total IgE levels- presence or absence.	Complete Hemogram profile and Serum IgE levels in the blood	drug hypersensitivity syndromes.	not useful in the diagnosis or exclusion of drug allergies.
Positive direct Coomb’s test		hematological manifestations of drug hypersensitivity e.g. immune-mediated haemolytic anemia, leukopaenia, thrombocytopaenia	no specific diagnostic test or serological test apart from recovery of the cytopaenia following the withdrawal of the putative drug, Drug-induced IgM and IgG have not been found to be clinically useful
Lymphocyte transformation test (LTT)	diagnosis of reactions in a wide variety of delayed reactions with a wide variety of drugs	T-cell mediated delayed hypersensitivity against a wide variety of drugs	positive LTT is useful in confirming the diagnosis, a negative test cannot exclude drug hypersensitivity. Positive LTT is usually drug-specific, and reaction-specific.

Table 5.

The following table provides information about the in-vitro tests.

In Vivo Tests: Many skin tests are available as useful tools in the diagnosis of IgE-mediated allergy. A skin prick test (SPT) is positive if the mean wheal diameter is≥3 mm after 15 to 20 minutes (associated with a flare response) compared to the negative control. Similarly, the intradermal test (IDT) is positive when meaning wheal diameter is ≥3 mm compared to the baseline diameter for the negative control after 15 to 20 minutes of the intradermal administration of allergen (0.02 to 0.05 ml). Though IDT is more sensitive than the skin prick test, there is still a higher risk of irritation, false positive reaction, and IgE-dependent anaphylactic reactions. The observation for immediate hypersensitivity reaction usually appears in 15 to 20 minutes while 24 to 72 hours’ evaluation is required for non-immediate (late) reactions. Patch tests are used for the diagnosis of delayed hypersensitivity drug reactions. In these tests, a patch embedded with the suspected allergen is fixed on the back of the patient for 1 to 2 days and the result is read after 1 day and/or after 2 to 3 days. A photo-patch test is a modified patch test used to diagnose suspected photoallergic or phototoxic reactions. This patch is removed after a day and a skin area of almost 10 J/cm2 is irradiated with ultraviolet A light and the results are read on days 2, 3, and 4. The use of non-irritating skin test concentrations is recommended for SPT, IDT, and patch tests. In very rare cases, a skin biopsy may be helpful in differential diagnoses of skin conditions with typical histological patterns. For instance, connective tissue disease is characterized by interface dermatitis with epidermal atrophy, focal parakeratosis, dermal mucinosis, and fibrinoid deposition in the dermis [35, 36]. Drug provocation (challenge) tests (DPTs) are performed using suspected agents and objectively reproduce the patient’s symptoms and signs of hypersensitivity. However, the positive test does not confirm an immune-mediated reaction. For DPTs, the drug is given using slow, incremental dose escalations at fixed time intervals and observing for the presence or absence of an objective reaction under the strict supervision of trained clinicians/nurses with well-equipped resuscitative tools. The DPT can help to exclude drug hypersensitivity when the history is nonsuggestive or the symptoms nonspecific. To definitively diagnose drug allergy when the clinical history is suggestive but allergological tests are negative, inconclusive, or unavailable. Specific contraindications to DPT include pregnancy; comorbidities in which DPT may provoke the medical situation beyond the ability to control it (e.g., acute infections; uncontrolled asthma; or underlying cardiac, hepatic, or renal diseases); immunobullous drug eruptions; and cases in which the initial reaction was a severe cutaneous and/or systemic reaction (e.g., SJS and TEN). The risks and benefits of any DPT must be explained to the patient and informed consent obtained. Short-acting antihistamines (e.g., chlorpheniramine or hydroxyzine) should be stopped for 3 days and long-acting antihistamines (e.g., cetirizine, loratadine, or fexofenadine) for 7 days before performing any DPT. Patients should also be fasted overnight and carefully observed at all times during the DPT for symptoms or signs of an adverse reaction. Resuscitation equipment should be available at all times, and staff should be trained in the management of acute anaphylaxis [37].

11. Management of Severe Cutaneous Adverse Reactions

11.1 Treatment of SJS/TEN

11.1.1 General management/supportive care

Correct identification of the causative drug and immediate withdrawal of potentially causative drugs. May use the ALDEN algorithm to determine the culprit drug. Supportive management of skin wounds with anti-shear dressings, nutrition status, electrolyte balance, renal and airway function, and adequate pain control, prevent or treat the wound infections. Refer to the specialized unit/burn center for supportive care, silver wraps, apply emollients, air fluidized beds, and prevent infections. Fluid balance is very important to prevent end-organ hypo perfusion with daily monitoring of urine output (maintain 0.5–1.0 ml/kg/hr) or intra-arterial hemodynamic monitoring. Adequate nutrition supplement for protein loss- 20-25 kcal/kg/day in the early phase and 25–30 kcal/kg/day in the recovery phase is recommended either through oral intake or nasogastric feed. Analgesic care with acetaminophen in mild cases or opiod-based analgesics based on the severity of pain [38, 39].

11.1.2 Specific treatment for SJS/TEN

Corticosteroids- Systemic corticosteroids have shown non-inferiority when compared with supportive care in treating patients with SJS. However, in cases of TEN, many studies have shown survival benefits to the patient but some studies have also shown a lack of efficacy and also an increase in mortality. High doses of systemic steroids have shown to be more effective in TEN patients as recommended by Japanese experts. Araki et al have successfully used corticosteroid pulse therapy (methylprednisolone 500 mg/day for 3 days in 5 patients of TEN and all survived also supported by one recent published meta-analysis suggesting systemic corticosteroids as promising immunomodulating therapies for SJS/TEN [40].

Intravenous Immunoglobulin- some studies have shown the survival benefit of Intravenous immunoglobulins (IVIG) with a dose of 2.8 g/kg up to 4 g/kg [41, 42]. Those studies with no survival benefit used doses mostly up to 2 g/kg or lower [43]. Huang et al. performed the first meta-analysis on the efficacy of IVIg for the treatment of TEN showing the benefit of the use of high dose IVIG over low dose IVIG [44]. But recent published reviews and meta-analyses showed no differences in mortality with IVIG compared with only supportive care [45, 46].

Cyclosporine- Inhibits CD8+ cytotoxic T cells with anti-apoptotic effect by inhibition of Fas ligand. Cyclosporine 3 mg/kg for 10 days with gradual tapering over 1 month revealed less skin detachment and a lower mortality rate in one of the pilot studies recruiting 29 patients of SJS/TEN. Chen et al in a meta-analysis found significantly lower mortality than calculated as per SCORTEN score in patients receiving cyclosporine (OR: 0.42, 95% CI- 0.19-0.95) [47, 48]. Zimmermann et al. meta-analysis also showed a better reduction in mortality with the use of cyclosporine when compared with just supportive care. However large-scale randomized controlled studies are required to confirm these findings [49].

Anti-TNF alpha agents: Increase in TNF-alpha in skin specimens, skin blister fluids, and in serum of SJS/TEN patients have been observed and hence the role of anti-TNF alpha agents may prove effective. Infliximab and Etanercept use have shown to be effective as published in many case reports and case series with better survival outcomes. Only one trial by Wolkenstein et al that used Thalidomide for treatment of SJS/TEN was prematurely terminated in view of the increase in mortality observed in patients [50, 51].

Plasmapheresis: Plasmapheresis is known to filter the harmful mediators in blood and have shown dramatic improvement in a patient with SJS/TEN. Narira et al study demonstrated that the use of plasmapheresis in patients refractory to conventional therapy treatment reduced the interleukin levels (IL-6, 8, and TNF-alpha) and is recommended for use by Japanese experts in TEN patients refractory to high dose corticosteroids [52].

11.2 Treatment for drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS)

• Supportive care is required with hydration maintenance in most of the cases except those with detected elevated levels of auto-antibodies.

• Systemic corticosteroids such as prednisolone with starting dose of 0.5 to 1 mg/kg/day gradually tapering over 2–3 months suggested by some experts known to decrease flare-up episodes and auto-immune sequelae.

• However, there is a risk for higher rates of infections, and septicemia and may require intensive care management. Hence suggested use only in those with severe presentations.

• French group of Dermatology recommends the use of systemic use of corticosteroids for those with a 5-fold increase in serum transaminases level or if there is the involvement of another organ such as kidney, lung, and heart.

• The results of the use of IVIG are conflicting and its use as monotherapy should be avoided. Several immunosuppressants like cyclosporine, cyclophosphamide, mycophenolate mofetil, and rituximab have been proposed in addition to systemic corticosteroids or IVIG in patients with severe disease and viral reactivation (Human Herpes virus −6 activation has been implicated as a trigger for this reaction) [33].

11.3 Acute generalized Exanthematous Pustulosis (AGEP)

• Identification and removal of the culprit drugs are sufficient and skin lesions resolve in 6–8 days after suspect drug withdrawal [53].

• Hospitalization may be required in some patients and may be treated with topical and systemic corticosteroids if required. The beneficial effects of systemic steroids need further evaluation.

11.4 Generalized bullous fixed drug eruptions (GBFDE)

• Prompt identification and withdrawal of causative suspect drugs remains the mainstay management of this reaction [54].

• Systemic corticosteroids may be beneficial in severe cases though there is a lack of sufficient evidence to compare with other treatment modalities and supportive care.

12. Future directions using pharmacogenetic tools to identify genetic predisposition to SCARs

The occurrence of SCAR is unpredictable but this uncertainty can be minimized to some extent by performing a pharmacogenetic assessment. If done before initiating patients on potential drugs, the occurrence of SCAR can be prevented as well. Human Leukocyte Antigens (HLA) genes have been evaluated in detail that has been found to have an association with SCAR variations observed in some patients on specific drugs (listed in Table 6). Having knowledge about genetic predisposition will help to detect patients at higher risk of developing SCAR. A study by Esmaeilzadeh H. et al study from Iran has shown Steven Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN) as the most common drug-induced SCAR presentation and the most common culprit drug as beta-lactam antibiotics followed by carbamazepine. The presence of HLA-A*02:01 and A*51:01 was also shown to increase the risk of SCAR while A*11:01 had a protective role against SCAR. Those with HLA-A*02:01, HLA-A*24:02, and HLA-B*51:01 were an increased SJS as observed in the same study [55].

Predisposing Infectious diseases	Drug-induced	Malignancy related	HLA allele associated with the risk to specific drugs
AIDS (Acquired Immunodeficiency syndrome)	Antiepileptics: Phenytoin, Carbamazepine, Oxcarbazepine, Valproic acid, Lamotrigine	Hematological	HLA-B*15:02- Carbamazepine
Coxsackie and Dengue virus infection	Barbiturates	Lung cancer	HLA-A*31:01- Carbamazepine
Influenza, Herpes Simplex virus	Anti-retrovirals: NRTI-Nevirapine; NNRTIs - Indinavir	Malignant Lymphoma	HLA-B*57:01- Allopurinol; Abacavir
Bacterial Infection: Gr A beta-hemolytic streptococci, Diphtheria, Brucellosis, LGV, Mycobacteria	NSAIDS: oxicams –meloxicam, piroxicam,; Paracetamol	Urothelial Carcinoma	HLA-A*32:01; Vancomycin
Fungal infection: coccidiomycosis, dermatophytosis, trichomoniasis	TNF alpha antagonist: Etanercept, Infliximab, Adalimumab	Hepatocellular Carcinoma

Table 6.

Predisposing factors for Steven Johnson syndrome/toxic epidermal necrolysis.

Abbreviations: AIDS- Acquired immune deficiency syndrome, LGV- Lymphogranuloma venereum, NRTI- Nucleoside reverse transcriptase inhibitors, NNRTIs- Non-nucleoside reverse transcriptase inhibitors, NSAIDs- Non-steroidal anti-inflammatory drugs, TNF alpha- Tumor Necrosis Factor-alpha, HLA- Human leukocyte antigens.

13. Conclusion

Among the various pathophysiology suggested for SCARs, T cells play a major role in the occurrence of delayed hypersensitivity reactions presenting as SCAR variants. There is a need to select structurally different classes of antibiotics in case of antibiotic-induced severe cutaneous adverse reaction (SCAR) to avoid recurrence. Furthermore, there is a need to conduct research and explore the immune mechanism of viral-drug-gene interaction and develop drugs to modulate T cells/other cell lineages/novel therapeutic targets. Animal models for SCAR variants may be an important step toward the development of new drugs but are understudied. Nevertheless, rational use of antibiotics should be promoted as well as implemented into practice by consumers and health care physicians. The important concern with Immunomodulators and targeted therapies is associated with long-term sequelae such as immune reactive inflammatory syndrome and polyglandular autoimmune syndrome III. Validation of more prognostic HLA and other biomarkers for guiding therapy may help to prevent the occurrence of scars. There is a need to develop multicentric, multi-ethnic, and multi-regional registries that will enable us to gather clinical and demographic profiles, along with histopathological, genomic, proteomic, and metabolomic evaluation supplemented with a data mining approach for a better understanding of signals generated. The metabolomic approach may be helpful to detect the drug or its metabolite may be the causative factor for SCAR severity.

Abbreviations

SCARs	Severe Cutaneous Adverse Drug Reactions
AGEP	Acute Generalized Eaxnthematous Pustulosis
SJS	Steven Johnson Syndrome
TEN	Toxic Epidermal Necrolysis
SJS/TEN Overlap	Steven Johnson Syndrome/Toxic Epidermal Necrolysis Overlap syndrome
GBFDE	Generalized Bullous Fluid Drug Eruptions
EEMM	Erythema Exsudativum Multiforme with Mucosal Involvement
EM	Erythema Multiforme
DRESS	Drug Related Eosinophilia with Eosinophilic Systemic Symptom
WAO	World Allergy Organization
DIHS	Drug Induced Hypersensitivity Syndrome
BC	Before Christ
CD	Clusters of Differentiation
Ig E	Immunoglobulin E
Ig G	Immunoglobulin G
Ig M	Immunoglobulin M
HP	Hypersensitivity Pneumonitis
PAN	Polyarthritis Nodosa
SLE	Systemic Lupus Erythematosus
PPD	Purified Protein Derivative
ADRs	Adverse Drug Reactions
NSAIDs	Non-Steroidal Anti-Inflammatory Drugs
RIA	Radioimmunoassay
TCR	T Cell Receptor
APC	Antigen Presenting Cells
FEIA	Fluorimetric Enzyme-Linked Immunoassay
SPT	Skin Prick Test
OR	Odds Ratio
IDT	Intradermal test
IVIG	Intravenous Immunoglobulin
TNF	alpha- Tumor Necrosis Factor-alpha
HLA	Human Leukocyte Antigen
AIDS	Acquired Immunodeficiency Syndrome
LGV	Lymphogranuloma Venerum
NRTI	Nucleoside Reverse Transcriptase Inhibitors
NNRTI	Non-Nucleoside Reverse Transcriptase Inhibitors
LTT	Lymphocyte Transformation Test
DPT	Drug Provocation Tests
CASTs	Cellular Antigen Stimulation Tests