Current Perspectives on Severe Drug Eruption.

Adverse drug reactions involving the skin are commonly known as drug eruptions. Severe drug eruption may cause severe cutaneous adverse drug reactions (SCARs), which are considered to be fatal and life-threatening, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Although cases are relatively rare, approximately 2% of hospitalized patients are affected by SCARs. There is an incidence of 2 to 7 cases/million per year of SJS/TEN and 1/1000 to 1/10,000 exposures to offending agents result in DRESS. However, the mortality rate of severe drug eruptions can reach up to 50%. SCARs represent a real medical emergency, and early identification and proper management are critical to survival. The common pathogenesis of severe drug eruptions includes genetic linkage with HLA- and non-HLA-genes, drug-specific T cell-mediated cytotoxicity, T cell receptor restriction, and cytotoxicity mechanisms. A multidisciplinary approach is required for acute management. Immediate withdrawal of potentially causative drugs and specific supportive treatment is of great importance. Immunoglobulins, systemic corticosteroids, and cyclosporine A are the most frequently used treatments for SCARs; additionally, new biologics and plasma exchange are reasonable strategies to reduce mortality. Although there are many treatment methods for severe drug eruption, controversies remain regarding the timing and dosage of drug eruption. Types, dosages, and indications of new biological agents, such as tumor necrosis factor antagonists, mepolizumab, and omalizumab, are still under exploration. This review summarizes the clinical characteristics, risk factors, pathogenesis, and treatment strategies of severe drug eruption to guide clinical management.

Introduction

Adverse drug reactions are defined as unexpected and harmful reactions to a conventional drug dose [1]. They are generally divided into two categories: dose-related drug reactions, which are predictable and determined by the characteristics of the drug itself, and non-dose-related drug reactions, which are unpredictable and related to both personal constitution and the drug itself. Drug eruptions generally belong in the latter category. According to relevant literature reports, drug eruption accounts for 25%–30% of adverse drug reactions [2]. Drug stimulation, also known as dermatitis medicamentosa, refers to the inflammatory reaction of the skin and mucosa caused by ingestion of drugs into the human body through any of the following routes of administration: oral, injection, inhalation, suppository, perfusion, or absorption. Drug-induced dermatitis is a common disease in dermatology, and reportedly, drug eruption accounts for 2%–5% of all skin diseases [3]. Most patients can be cured by immediate withdrawal from the sensitizing drug and administration of an anti-allergic treatment. However, severe cutaneous adverse drug reactions (SCARs) not only have a sudden onset and extensive and serious skin lesions, which may even involve the oral mucosa, they may also cause systemic poisoning symptoms that involve multiple organs, serious damage to liver and kidney functions, and even life-threatening conditions, such as severe drug stimulation [4-6].

Patients with SCARs have severe conditions, which progress rapidly and are often life-threatening due to secondary infection, water and electrolyte disorders, and multiple organ failure. The etiology of a severe drug eruption is complex and remains unclear. The increased risk of allergic reactions to certain drugs may be associated with specific human leukocyte antigens (HLAs). Currently, the common pathogenesis of severe drug eruptions includes genetic linkage with HLA- and non-HLA-genes, drug-specific T cell-mediated cytotoxicity, T cell receptor (TCR) restriction, and cytotoxicity mechanisms [7, 8]. Although there are many treatment methods for severe drug eruption, controversies remain regarding the timing and dosage of drug eruption. Types, dosages, and indications of new biological agents, such as tumor necrosis factor (TNF) antagonists and mepolizumab, are still under exploration. Understanding the clinical characteristics, treatment, and prognosis of severe drug eruptions from common sensitizing drugs will help clinicians monitor and prevent severe drug eruption, avoid drug abuse, and reduce its incidence and mortality. This study reviews the research progress and discusses the most recent evidence to guide clinical management.

Epidemiology

Although cases are relatively rare, approximately 2% of hospitalized patients are affected by SCARs [9]. There is an incidence of 2 to 7 cases/million per year of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [10-13], and 1/1000 to 1/10,000 exposures to offending agents result in drug reaction with eosinophilia and systemic symptoms (DRESS) [14]. However, mortality rates are gradually increasing from SJS, SJS-TEN overlap, and TEN to DRESS, which are approximately 5%–10%, 30%, 50%, and 10%, respectively [15-19].

Many studies have confirmed that antiepileptic drugs are associated with a high risk of SCARs. In the European Registry of Serious Adverse Skin Reactions (RegiSCAR), carbamazepine is considered to be the most common reason for DRESS [19] and the second most common cause of SJS and TEN. Other antiepileptic drugs are also associated with SCARs [20]. The SCARs risk associated with various drugs depends on a number of variables, including genetic and non-genetic risk factors. The prevalence and pattern of SCARs vary widely among different races and geographic distributions. A strong connection between HLA alleles and drug-induced cutaneous reactions has been identified in numerous studies [21]. In European and Japanese populations, the HLA-A*31.01 allele has been linked to carbamazepine (CBZ)-induced adverse reactions [18]. However, among Han Chinese, Vietnamese, Taiwanese, and other Southeast Asian descendants, the HLA-B*15:02 allele has been associated with CBZ-induced hypersensitivity reactions. Furthermore, allopurinol-induced SJS and TEN were found to have a strong correlation with the HLA-B*58:01 genotype, as this study obtained consistent results in patients in Southeast Asia, Japan, and Europe [21, 22].

Host factors that increase the risk of scarring include systemic lupus erythematosus, the presence of potential malignancies, and potential infections, such as tuberculosis, hepatitis [23], human immunodeficiency virus (HIV) [24], and coronavirus disease 2019 (COVID-19) [25]. Potential infections not only increase the risk of scarring but also lead to more severe disease phenotypes, including an increased risk of visceral system damage and ophthalmic complications [26]. In recent years, the use of more biological agents and anti-tumor drugs has also increased the risk of SCARs [27]. In addition, prescription habits can also affect the risk of scarring. For example, a dose greater than or equal to 200 mg of allopurinol per day is associated with a high risk of SJS/TEN [28]. In addition to the common drugs related to SCARs [29-32] (Table 1), Chinese materia medica and new sensitizing drugs have been reported [33], such as antihypertensive drugs (cannabinol [34], hydrochlorothiazide [35]), antifungal drugs (griseofulvin [36], terbinafine [37]), and non-steroidal anti-aromatase (letrozole) [38].

Table 1

Drugs most commonly reported to induce SCARs [29–32]

SJS/TEN	AGEP	DRESS
Anticonvulsants	Anticonvulsants	Anticonvulsants
Phenytoin, carbamazepine, lamotrigine, phenobarbitone	Phenytoin, carbamazepine, lamotrigine, phenobarbitone	Phenytoin, carbamazepine, lamotrigine, phenobarbitone
NSAIDs	NSAIDs	NSAIDs
Oxicam-NSAIDs, diclofenac, phenylbutazone	Oxicam-NSAIDs, diclofenac, phenylbutazone	Oxicam-NSAIDs, diclofenac, phenylbutazone
Antibiotics	Antibiotics	Antiretrovirals
Sulphonamides, penicillins, quinolones, macrolides	Sulphonamides, penicillins, quinolones, macrolides, tetracyclines, vancomycin	Nevirapine, abacavir
Antiretrovirals	Anti-leprosy	Anti-leprosy
Nevirapine, abacavir	Dapsone	Dapsone
Antituberculous	Anti-gout	Anti-gout
Isoniazid, ethambutol	Allopurinol	Allopurinol
Anxiolytics		Anti-leprosy
Alprazolam		Dapsone
Anti-gout
Allopurinol

Pathogenesis of SCARs

In recent years, great progress has been made in the study of the pathophysiological mechanisms of drug eruption, which are described below.

Because of their small molecular weight, drugs must form complexes with tissues to produce an immune response. Currently, there are three hypotheses regarding drug-tissue complex interactions, which are as follows [39]: in the hapten/prohapten precursor model, drugs or their metabolites covalently bind to endogenous proteins in the body to form “complete antigen complexes,” which are regarded as foreign substances and undergo treatment and processing by antigen-presenting cells (APCs) to form “major histocompatibility complex (MHC)-antigen peptide complexes” for TCR recognition; (2) in the pharmacological and immune receptor interaction model, inert drugs that cannot covalently bind to endogenous proteins in the body bind to TCR and trigger a T-cell response due to their special configuration; and (3) in the peptide model, drugs or metabolites are directly attached to the covalent slot of MHC proteins, thereby changing the specificity of MHC molecules to peptides. These altered MHC proteins are then considered foreign antigens by the body and trigger a series of immune responses designed to remove foreign antigens [40]. HLA molecules play a key role in T cell activation by presenting processed antigens to the TCRs expressed on T cells. HLA class I and class II molecules initiate immune responses by presenting antigens to CD8 + (cytotoxic) and CD4 + (helper) T cells [41]. Because HLA molecules present a variety of “self” and “non-self” peptides, HLA genes are significantly polymorphic [42]. Currently, HLA molecules with specific adverse drug reactions have been found, including abacavir, allopurinol, carbamazepine, and phenytoin [39].

Drug-tissue complexes induce the overexpression of cytotoxic molecules, FasL, on keratinocytes (KC), while cytotoxic T cells (CTL), natural killer (NK) cells, and monocytes secrete granulocytin and membrane-linked protein A1, and so on, that induce the apoptosis of KC in different ways [43]. The Fas/Fas ligand (FasL) complex binds to the Fas-associated death domain protein (FADD), which simultaneously recruits procaspase 8, a cell apoptotic protease, in a multi-copy manner, leading to intracellular DNA degradation. CD8 + T cells specifically recognize KC and secrete toxic molecules (perforin, granzyme B, granulysin) into the cytoplasm through tiny cell pores, mediating KC apoptosis and mutual separation. Membrane-bound protein A1 is a substance found in the supernatant of peripheral blood mononuclear cells of patients who naturally recover after SJS/TEN, which triggers KC apoptosis through the “membrane-bound protein A1 receptor.” In addition, Ichihara et al. observed increased levels of Mir-18a-5P in the skin of TEN patients and revealed that Mir-18a-5p could downregulate the expression of B-cell lymphoma/leukemia-2 like protein 10 (an anti-endogenous apoptotic protein) and induce intrinsic KC apoptosis [40]. Particles of lysin also directly induce KC apoptosis and, by activating a precursor of the normal T cells, secrete inflammatory cytokines and chemokine T cells, monocytes, and other inflammatory cells in the skin. These cytokines include CCL3 and CCL5, CCL20 and monocyte chemotactic proteins 1 and 3 (MCP-1–3), IL-10, IL-1, IL-6, IL-interferon alpha, IL-2, IL-18, CC-chemokine receptor (CCR) 3, CXC chemokine receptor (CXCR) 3, CXCR4, and CCR10.

The epidermal chemokines of T cells expressed in patients’ skin can attract peripheral blood CTL to migrate to the skin and play a cytotoxic role. Navarini et al. found that a mutation in the gene encoding IL-36 causes it to lose regulation, and the secretion of IL-6, IL-8, and IL-1 is enhanced, driving neutrophils to penetrate the epidermis [5]. In addition, IL-17 is secreted by T helper type 17 (Th17) cells in the patient’s blisters to recruit neutrophils, and Th17 cells may differentiate and transform into Treg cells [44]. Virus reactivation, especially human herpesvirus 6 (HHV-6) reactivation, is a characteristic feature of DRESS. The interaction between the antiviral immune response and hypersensitivity to the drug increases the disease complexity and prolongs the disease course. Like SJS/TEN, DRESS is also a T cell-mediated immune response, with 90% of DRESS patients showing significantly increased CD4 + T cells in the acute phase. Takahashi et al. proposed that regulatory T cells (Treg) play a key role in the onset of the acute phase of DRESS [45]. In humans with latent HHV-6 infection, monocytes in the blood are the best place to hide. HHV-6, hidden in circulating monocytes, expresses the skin regression molecule CCR. These infected monocytes respond to high-migration protein-1 (HMGB-1) [46]. Monocytes containing the infected virus migrate into the skin and are presented to innate immune CD4 + T cells. Simultaneously, the number of memory T cells in the lesion increases. Large amounts of IL-4, IL-5, and IL-13 can promote the differentiation and maturation of eosinophils.

Several genetic factors causing a predisposition to severe drug eruption have been previously reported, including metabolic enzyme mutations or specific HLA-A, B, or C alleles. Strong associations have been established between the HLA-B*15:02 allele and CBZ-triggered SJS and TEN and between the HLA-B*58:01 allele and allopurinol-induced SJS and TEN or DRESS syndrome [47]. A mutation of the IL 36 receptor antagonist gene was suggested to be a genetic factor in acute generalized exanthematous pustulosis (AGEP) [48]. A restricted role of T-cell receptor clonotype has been proposed in CBZ-induced severe drug eruption since a T-cell receptor clonotype role has been connected with individuals positive for HLA-B*15:02 with SJS or TEN, which is absent in all carbamazepine-tolerant HLA-B*15:02 carriers [49]. In allopurinol-induced severe drug eruption, a specific T-cell receptor clonotype was identified as a reaction to its metabolite oxypurinol as well as the HLA-B*5801 allele [50]. Various severe drug eruption phenotypes with the same drug-HLA association have been identified, including allopurinol-induced SJS and TEN or DRESS syndrome and HLA-B*58:01; carbamazepine-induced SJS and TEN or DRESS syndrome and HLA-B*15:02; exclusive drug-HLA associations with one phenotype, that is, dapsone hypersensitivity with the HLA-B*13:01 allele; and phenytoin-induced SJS and TEN with the HLA-B*15:02 allele [51]. In addition, genome-wide association studies have identified a variant of the cytochrome P450 2C9 enzyme, which is an important genetic factor in phenytoin-related severe drug eruption, which is known to reduce drug clearance [52]. Other studies have proposed an ABC transporter and proteasome pathway mutation in non-drug-specific SJS and TEN [53].

Clinical Presentation of SCARs

SCARs include SJS, TEN, DRESS, and AGEP. The incubation period, clinical presentation, laboratory examination, main organs involved, death rate, and histological features are shown in Table 2.

Table 2

Main clinical and pathological features of SCARs

	Incubation period	Clinical presentation	Laboratory examination	Main organs involved	Death rate	Histological features
SJS and TEN [54–56]	4~28days	Erythema, macular papules, urticaria, purpura or target rash, loose blisters that can fuse into bullae, causing skin epidermis to peel off	Lymphocytopenia, transient neutropenia, mild cytolysis, renal damage	Oral and genital mucosa, liver, kidney, lung, gastrointestinal tract, eyes, urethra, etc.	25%	The whole layer of epidermis is necrotic, resulting in epidermal separation and a small amount of monocyte infiltration in the papillary layer of the dermis.
DRESS [58–62]	2~6weeks	Measles-like rash with small pustules and, in severe cases, erythroderma with extensive exfoliation of the skin, fever, enlarged lymph nodes, accompanied by fever and enlarged lymph nodes	Eosinophilia, monocytosis, and thrombocytopenia	Liver, kidney, lung, heart, lymph node, brain, eye, etc.	10%	Keratinocyte necrosis, lymphocyte extravasation, surface sponge edema, interfacial vacuolar degeneration, dermal lymphocyte and eosinophil infiltration
AGEP [65–69]	1~11days	Joint, face, rash is aseptic pustule, less mucosal involvement, body temperature often >38 ℃	White blood cells and neutrophils are mostly elevated.	Liver, kidney, lung, etc.	5%	Spongy pustules under the cornea and(or) epidermis, papillary dermis and perivascular edema, neutrophil and eosinophil infiltration. Individual cell necrosis with vasculitis or keratinocytes

SJS/TEN

Pleomorphic erythema drug eruption is characterized by soybean- to broad bean-sized round or oval edematous erythema or papules, with blisters at the center and redness on the edge, and often has a symmetrical occurrence. When accompanied by mouth, eye, and vulvar mucosal involvement, blisters can be eroded, which when accompanied by severe pain, high fever, liver, and kidney function damage, is considered SJS, the most serious type of drug eruption. Bullous epidermolysis drug eruption belongs to the same disease spectrum as SJS. The general incubation period from drug exposure to symptoms is about 4–28 days and is rarely more than 8 weeks. There is often a prodromal period before onset, which is characterized by fever, cough, fatigue, arthralgia, rhinitis, eye tingling, conjunctivitis, dysphagia caused by oral ulcers, or urine pain caused by genital lesions.

Clinical manifestations include erythema, macular papules, urticaria, purpura, or target rash. Within 3–4 days, skin lesions develop rapidly on the face, neck, and limbs, while the scalp is rarely involved. Blisters of different sizes then appear in the erythema and quickly fuse into bullae, resulting in the peeling off of the skin epidermis and positive Nissl’s sign, leaving a bright red eroded surface and exudation, which is susceptible to bacterial infection (Fig. 1). Sepsis is the leading cause of death. If the lesion continues to develop, mucosal erosion can occur in the lips, tongue, oral cavity, nasal cavity, pharynx, larynx, conjunctiva, vagina, urethra, gastrointestinal tract, and respiratory tract. Eye involvement may occur in 80% of patients [54]. The gastrointestinal tract can be involved, and gastrointestinal bleeding and colon perforation may occur. Approximately 30% of patients have respiratory involvement [55], including pneumonia, bronchitis, and obvious hypoxemia. Other complications include abnormal liver function, myocarditis, acute tubular necrosis, glomerulonephritis, acute renal failure, pulmonary edema, and acute respiratory distress syndrome (Table 3). Score of Toxic Epidermal Necrolysis (SCORTEN) is a rating system for the severity of the disease [56] (Table 4). Histopathological examination reveals a necrotic epidermal layer, resulting in epidermal separation and a small amount of monocyte infiltration in the papillary layer of the dermis.

Fig. 1

Skin damage. a Conjunctiva. b Labial mucosa. c Target erythema. d Epidermolysis

Table 3

SJS, SJS/TEN, TEN clinical differentiation [54–56]

Clinical	SJS	SJS/TEN	TEN
Target damage	+	+	+
Mucosal damage	+	+	+
Systemic symptoms	+	+  +	+  +
Exfoliated area	< 10%	10% ~ 30%	> 30%
Distribution	Torso based	Head, torso	Head, torso, limbs

Table 4

Severity of illness score for toxic epidermal necrolysis [56]

Clinical parameter	Point	Total score	Mortality rate
Age > 40 years	1	0–1	3.2%
Malignancy	1	2	12.2%
Tachycardia > 120/min	1	3	35.5%
Initial area of detachment > 10%	1	4	58.3%
Serum urea > 10 mmol/L	1	5 or more	90.0%
Serum glucose > 14 mmol/L	1
Bicarbonate < 20 mmol/L	1

In addition to systemic complications, severe drug eruptions incorporating a large skin area can also produce severe sequelae. In a large retrospective cohort study [57], follow-up of adult patients with SJS/TEN revealed that nearly half of them had long-term sequelae, involving the eyes (corneal ulcers, cicatricial lesions, and shortening of the fornix and symblepharon), skin, gastrointestinal tract, genitals (erosion of genital mucosa may lead to vaginal adhesion), kidneys, lungs, and nails [58] (Fig. 2). The most common sequelae are ocular, skin, genital, oral, renal, and gastrointestinal sequelae as well as depression, anxiety, chronic pain, tinnitus, and amputation [59].

Fig. 2

Nail damage in a patient with TEN. a Fingernails. b toenails

DRESS

DRESS is a serious and potentially fatal adverse effect of therapeutic medications, also known as drug-induced hypersensitivity syndrome (DiHS), with a fatality rate of approximately 10%. It can be accompanied by rash, fever, and internal organ involvement and usually manifests as a measles-like eruption, with small pustules and erythroderma with extensive skin peeling in severe cases (Fig. 3). Multiple internal organs can be damaged; patients with underlying diseases and the elderly are more likely to have internal organ involvement. Eosinophilia, thrombocytopenia, acute severe hepatitis, hepatomegaly, jaundice, lymphadenopathy, enteritis, intestinal bleeding, nephritis, and respiratory distress syndrome can occur. Neurological diseases, such as meningitis or encephalitis, can also occur within 2 to 4 weeks of onset [60]. In severe cases, liver failure may be the leading cause of death in DRESS. Some patients may have ocular complications, such as double-eye corneal infiltration and acute anterior uveitis [61]. There are also reports that patients with DRESS can have general alopecia. The histopathological examination may reveal keratinocyte necrosis, lymphocyte extravasation, surface sponge edema, interfacial vacuolar degeneration, dermal lymphocyte, and eosinophil infiltration.

Fig. 3

a Facial edema. b Measles-like rash over the body

DRESS patients may also develop late sequelae after cure, which most often involve the liver. An enlarged liver and spleen are common, and liver failure can lead to death. Renal dysfunction is most common in elderly patients with renal disease, which may eventually progress to renal failure; thyroid disease, diabetes, lupus erythematosus, and myocarditis may also occur [19, 62–64].

At present, DRESS does not have a unified diagnostic standard, and diagnosis is mainly based on clinical manifestations and laboratory tests. In 1992, some scholars proposed that patients meeting the following three criteria could be diagnosed with DRESS: drug-induced rash; eosinophilia (> 1.5 × 109/L) and abnormal lymphocytes; symptoms of systemic involvement, including lymphadenopathy (diameter > 2 cm, hepatitis, or transaminase at more than twice the normal value), interstitial nephritis, interstitial pneumonia, or carditis [65]. The diagnostic criteria proposed by the RegiSCAR also comprise the following three prerequisites for diagnosis: acute rash, suspected drug-related reactions, and hospitalization. Alternatively, three of the following four criteria can be used for diagnosis: fever (body temperature > 38 °C); enlargement of at least two lymph nodes; involvement of at least one internal organ (liver, kidney, heart, pancreas, or others); and at least one of the following hematological changes (increased or decreased lymphocytes, increased eosinophil percentage or absolute count, or decreased platelets).

The Japanese Research Committee on Severe Cutaneous Adverse Reaction (J-SCAR) [66] proposed the following diagnostic criteria: skin rash occurring after 3 weeks of application of certain drugs; symptoms persisting more than 2 weeks after stopping the disease-causing drugs; body temperature > 38 °C; liver damage (transaminase > 100 U/L) or involvement of other organs; one of the following hematological changes: white blood cell count > 11 × 109/L, abnormal lymphocytes > 5%, eosinophil counts > 1.5 × 109/L; enlarged lymph nodes; and reactivation of the HHV-6. Typical DRESS patients manifest all the abovementioned seven items above, while atypical DRESS patients may have between 1 and 5 of these items.

AGEP

AGEP is another severe drug eruption that may cause serious systemic involvement. The rash is mostly distributed on the joints and face, mainly manifested as small aseptic pustules, which are distributed on the basis of the edematous erythema (Fig. 4). Desquamation at the pustules may occur in approximately 1 week, accompanied by burning pain, itching, and discomfort. The Nikolsky sign may be positive or target erythema, purpura, blisters, bullae, and other rashes may occur. The genital mucosa is less affected; however, the oral or buccal mucosa may be affected and may be accompanied by fever (body temperature > 38 °C), and elevated white blood cells and neutrophil counts. Based on early manifestations, some may be misdiagnosed as acute infections [67]. Studies have reported that 17% of patients suffer from internal organ damage, such as liver insufficiency, renal insufficiency, and lung insufficiency [68]. Increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels indicate liver damage; abdominal ultrasound can detect liver steatosis or liver enlargement [69]. Damage to the respiratory system may lead to the formation of pleural effusions, which can lead to dyspnea and hypoxemia in severe cases [70]. There are case reports of lymphadenopathy occurring in patients with AGEP [71]. The overall prognosis of this disease is good, and the fatality rate is less than 5%. However, if system damages result in multiorgan failure or diffuse intravascular coagulation or if a large area of the mucosa is involved, there is a very high risk of death [72]. The typical histopathology of AGEP reveals spongy pustules under the cornea or epidermis. There is often obvious edema in the papillary dermis and surrounding blood vessels, accompanied by infiltration of neutrophils and eosinophils, as well as vasculitis or necrosis of individual cells of keratinocytes. Of note, this is different from the histopathology of psoriasis [73].

Fig. 4

Acute generalized exanthematous pustulosis

Differential Diagnosis

Pustules can appear in many skin diseases, and AGEP must be distinguished from many diseases, including pustular psoriasis, subcorneal pustulosist, and pustular vasculitis. While patients with AGEP may have a history of psoriasis, patients with pustular psoriasis have a history of psoriasis and usually have a generalized rash, long duration of pustules, high fever, and generally no history of drug allergy, and some patients will develop arthritis. Histopathologically, it manifests as the formation of large pustules, namely Kogoj pustules, mainly in the upper part of the epidermis, with neutrophils in the blisters, and the granular layer is significantly reduced or disappeared. The spinous layer thickens, the epidermal protrusion extends, the dermal papilla extends in a club-like shape, and the spinous layer above it becomes thinner.

Dilation and congestion of capillaries in the subcorneal pustulosist form mainly large, loose blisters, and abscess formation is usually distributed in a ring. In addition, the evolution of the disease is far less dramatic than that of AGEP. Pustular vasculitis is a special type of leukocyte destructive small vasculitis, which is characterized by the formation of many small pustules, which, in contrast to AGEP, are mainly confined to the back of the hand. Histologically, it can manifest as leukocyte-crushing vasculitis [74].

SCARs in Pediatric Patients

The morbidity of SJS, SJS-TEN, and TEN in children is lower than that in adults, mainly due to antibiotics and antiepileptic drugs. The mortality of patients with TEN is significantly higher than that of children with renal failure, septicemia, and bacterial infection in SJS or SJS-TEN [75]. More female than male patients develop pediatric DRESS [63]. While facial edema is less common in pediatric patients than in adults, pediatric DRESS patients are more likely to have fever, enlarged lymph nodes, and internal organs involvement, including the liver, kidney, heart, lung, brain, thyroid, and pancreas. Visceral involvement usually determines the disease severity. Liver damage and kidney damage are more common, and the overall mortality rate of DRESS in children is similar to that in adults [76]. Although there are few studies on children with AGEP, the most common reported causes include drugs, viruses, bacteria, and antibiotics [77].

Therapy

Although the incidence of a severe drug eruption is rare, patients are usually in critical condition and have multiple complications. The reported mortality rate associated with severe drug eruption is between 10 and 30% [78, 79]. However, experts have not reached a consensus on certain treatments [80-82] (Table 5). Herein, we summarize the treatment status and research progress of severe drug eruptions.

Table 5

Guidelines for the treatment of SCAR in different countries

	Recommended treatment	Other treatment
TEN management in Japan [80]	• The initial dose of glucocorticoid used in the system is 0.5–2 mg/kg/day of methylprednisolone. If eye symptoms, respiratory symptoms or skin lesions are rapidly expanding, it can be treated with 500–1000 mg/day of methylprednisolone for 3 days. • IVIG 5 ~ 20 g/day, lasting 3 ~ 5 days, no more than 2 g/kg, currently 0.4 g/kg/day is used for treatment for 5 days • Plasmapheresis	Cyclosporine
Guidelines for the management of SJS/TEN in India [81]	• Early- and short-term system use of glucocorticoids. Intravenous infusion of methylprednisolone 20–30 mg/kg/day, intravenous infusion of dexamethasone 1.5 mg/kg/day, and methylprednisolone 1000 mg/day shock treatment for 3 days • Cyclosporine, orally 3 ~ 5 mg/kg/day, but the course of treatment has not yet reached a consensus. It has been reported in 2 weeks to 1 month • IVIG, dosage, and time of administration are not uniform	Cyclophosphamide Plasmapheresis G-CSF TNF-α inhibitor
U.K. guidelines for the management of SJS/TEN [82]	• Most studies support the use of IVIG, especially in children; the course of treatment is 3 to 5 days, and the dose ranges from 0.2 to 1 g/kg/day • Early administration of high-dose corticosteroids can suppress inflammation, but it also increases the risk of sepsis • Oral cyclosporine 3 mg/kg/day, gradually reduced after 7 days, the total course of treatment is about 2 to 4 weeks	Plasmapheresis G-CSF TNF-α inhibitor

Symptomatic and Supportive Treatment

Once a patient is suspected of or diagnosed with a severe drug eruption, the offending drug should be immediately withdrawn. Avoiding similar drugs (e.g., penicillin and amoxicillin) is highly recommended. The time of drug retention and drug half-life are related to the prognosis [83-85]. As severe drug eruption can cause a variety of complications, such as infection, hospitalization and a full examination, including routine blood and urine, erythrocyte sedimentation rate (ESR), liver function, renal function, and immunity tests, should be performed to obtain a clear understanding of the patient’s condition [86].

The principle of therapy is the same as for burns. An air-fluidized bed may reduce the incidence of pressure ulcers and thrombus [87, 88]. According to research, delayed treatment increases mortality [89]. Burn center consultation and debridement may be required [84, 90, 91]. To reduce fluid loss and prevent infection on the body surface, the room temperature should be maintained at 30 °C–32 °C, and the environment should be kept moist and clean. Patients likely experience a fluid and electrolyte imbalance due to the breakdown of the cutaneous barrier; therefore, moisturizers, oral intake of fluids, intravenous fluids, and nutritional support can be provided. Careful monitoring of heart function is recommended during treatment.

The destruction of the cutaneous barrier can also increase the risk of infection. Some studies have found that patients whose skin secretions showed a positive bacterial culture could develop sepsis [92]. Another study demonstrated that patients tended to have a lower risk of infection if treated with empirical antibiotics. However, given the small number of patients observed, the authors do not suggest excessive antibiotics at an early stage [93]. Therefore, the frequent culture of mucocutaneous erosions and blood, topical antiseptics, and appropriate use of prophylactic antibiotics might be a reasonable treatment plan [94]. Other options, such as skin grafts, cryopreserved cutaneous allografts, skin substitutes, and biological dressings, can be used to minimize pain and dehydration [95-98]. In case of ocular involvement, it is necessary to administer antibiotic eye drops and steroid drops to prevent infection, corneal ulcers, conjunctivitis, and even symblepharon [99, 100]. The most common complication of patients with severe drug eruption is hypovolemia caused by excessive body fluid loss. Other complications include cardiac insufficiency, respiratory inflammation, and peptic ulcer, which require multidisciplinary treatment [101]. Some patients may develop inferiority and anxiety during the course of illness, which could persist. It is important to address psychological complications to improve their quality of life [101-104].

Systemic Corticosteroids

Glucocorticoids have anti-inflammatory and immunosuppressive effects. They can inhibit the inflammatory response caused by immunocompetent cells and inhibit the activation of transcription factors (activator protein 1 and nuclear factor-κB), thereby inhibiting the immune response, eosinophil proliferation, and the production of inflammatory factors and antibodies. On the other hand, high-dose glucocorticoids can inhibit T cell-induced apoptosis of keratinocytes [105]. Consensus has not been established on the use of corticosteroids in the treatment of drug eruption because the evidence is limited and the results of the research are different.

The recommended dosage of prednisone is 1.0–1.5 mg/kg/day, usually 40–60 mg/day. To avoid relapse, it is recommended to reduce the dosage gradually over a period of 2–3 months; some recommend tapering the dose for 3–6-months for DRESS. One report suggests that prompt short-term corticosteroid therapy appears to be the key to minimizing damage from TEN and DRESS [106]. Kocaoglu et al. found that pulse methylprednisolone at a dose of 30 mg/kg (maximum of 1 g/day) for 3 days could accelerate the recovery of liver function and fever [107]. Tetsuo Shiohara and others believe that the current standard treatment for DRESS is the systemic use of glucocorticoids, which can quickly control rash and fever [45, 65, 108–110]. By observing the treatment process of 91 patients with DRESS, Wei et al. found that patients who were treated with systemic glucocorticoids survived longer (36.3 versus 12.7 days). Of all the surviving patients, almost 3/4 of the patients used hormones, but their treatment duration was extended 8 days longer on average [111]. In addition, a long-term follow-up study in Singapore found that 25 of 27 DIHS/DRESS patients survived following treatment with glucocorticoids [112].

However, other studies have shown that treatment with glucocorticoids is related to an increase in morbidity and mortality. The death rate from infection in patients receiving steroid therapy is 66%, while the death rate from infection in patients not receiving steroid therapy is 33%, indicating that steroids increased the risk of sepsis, increased protein catabolism, and delayed epithelialization [113]. Guibal’s research results show that long-term steroid therapy can delay the onset of TEN, but it cannot prevent the development of the disease [114]. In addition, long-term treatment with glucocorticoids can occur. Based on these observations, we can conclude that the treatment of TEN with corticosteroids may be harmful. However, Patterson reported that the nosocomial infection rate of short-term high-dose intravenous steroid treatment with steroid therapy for SJS and TEN is lower than that of placebo-treated burn department inpatients, although that study was theoretically limited to the early treatment (such as within 20 days) of patients [115, 116].

Intravenous Immunoglobulin

According to research, intravenous immunoglobulin (IVIG) may block Fas-FasL binding, interrupting the signal transduction of apoptosis, thereby preventing drug-induced necrosis of keratinocytes. It can also be combined with circulating immune complexes to form insoluble complexes with prompt clearance by reticuloendothelial cells and can bind to specific B cell receptors to downregulate their functions and reduce pathogenic antibody synthesis [117]. Therefore, some experts recommended IVIG for patients with life-threatening DRESS [118]. Early administration of high doses (≤ 2 g/kg) is recommended in TEN. Moreover, in a study of 12 patients with SJS, 0.6 g/kg/day of IVIG administered over 4 days resulted in a shorter recovery time and a mortality rate of 0 compared to other patients treated with corticosteroids and supportive care [5]. A study in India suggested that low-dose IVIG combined with steroids reduced mortality and recovery time compared to treatment with only steroids [119]. Husain et al. suggested that DRESS patients with life-threatening signs (renal and/or respiratory failure, encephalitis, severe hepatitis) can be treated with steroids combined with IVIG at a dose of 2 g/kg over 5 days. IVIG should not be administered without associated steroids [86, 120]. In a systematic review and meta-analysis, high-dose IVIG treatment was not found to be beneficial to patients, but early use of IVIG can decrease mortality [121, 122]. More than one study found that IVIG at either low or high doses did not show benefit in terms of expected mortality at either low or high doses (< 3 g/kg vs ≥ 3 g/kg, respectively) [123, 124]. IVIG may have adverse reactions, such as pulmonary embolism and hemorrhagic syndrome, and the exact timing and dosage require further examination.

Cyclosporine

Alternatively, recent studies have shown cyclosporine to be a promising treatment for drug eruption. Cyclosporine can inhibit nuclear transcription factor-kappa B (NF-kB), FasL, and TNF-α, including the inhibition of CD8 + cytotoxicity mechanism; thus, it has powerful immunosuppressive and anti-apoptotic effects [125, 126]. When patients were given cyclosporine orally at a dose of 3 mg/kg/day for 10 days, which was then tapered for over a month, both the death rate and the progression of detachment were lower than those of SCORTEN [127]. In a cohort study, it was found that the survival rate of patients treated with cyclosporine was higher than that of patients treated with IVIG [128]. Six DIHS/DRESS cases were treated with a low dose (150–350 mg/day) of cyclosporine for 7 days or less, and all were cured without recurrence [129-131]. According to reports, the therapeutic effect of cyclosporine may take over a month. However, severe drug eruption progresses rapidly and requires timely and early treatment. In addition, it is worth noting that cyclosporine may aggravate liver and kidney damage in patients with severe drug eruption. Therefore, it is recommended to avoid using cyclosporine A alone in the acute phase [101].

Plasmapheresis

More than one decade of research has reported plasmapheresis to be effective in patients with TEN and DRESS [104, 132–136]. The exact mechanism of plasmapheresis is not clear; it has been found that after plasma replacement therapy, the patient’s IL-2, IL-6, TNF-α, interferon-gamma, FasL, and toxin levels were significantly reduced [137]. El-Azhary et al. suggested that plasmapheresis can effectively remove pathogenic factors and improve prognosis [138]. However, studies have pointed out that the use of plasma exchange to treat TEN does not improve the mortality, duration of the disease, or skin healing time [124, 139]. Giudice G reported that the administration of cyclosporine A at a dose of 250 mg/day for adults (children dose at 4 mg/kg/day) for a total of 15 days, combined with seven cycles of plasmapheresis, greatly reduced TEN mortality, as compared to other supportive and topical therapies [140]. Whether blood purification is more beneficial if used alone or in combination with IVIG and/or glucocorticoids for patients with severe drug rashes requires confirmation from more randomized-controlled studies.

Other Therapies

Thalidomide can inhibit TNF-α [141]. However, a double-blind, randomized, placebo-controlled study using thalidomide to treat TEN was aborted because of the high mortality rate [142]. Laban et al. reported a case of DRESS with associated interstitial nephritis and eye involvement that was treated with glucocorticoid, plasmapheresis, and cyclophosphamide [143]. However, six patients with TEN treated with cyclophosphamide (150 mg every 12 h) and ≥ 1 mg/kg of 6-methylprednisolone every day had worse effects compared to 11 patients with TEN treated with 3 mg/kg of cyclosporine twice a day [144]. It is currently believed that Epstein-Barr virus (EBV) may be the key factor in the development of the secondary autoimmune disease of DRESS, and some studies have indicated that cytomegalovirus reactivation may be the cause of a variety of complications. Therefore, cytomegalovirus (CMV) and EBV should be detected and treated with anti-CMV/EBV as soon as possible [23, 45]. Valganciclovir targeting at HHV-6 and HHV-7 is recommended for DRESS with viral reactivation. However, the mechanism and dosage require further study [117].

Etanercept can inhibit lymphotoxin α and TNF-α. A previous study of 10 patients with DRESS demonstrated a median healing time of 8.5 days after a 50-mg subcutaneous injection of etanercept [145]. Ling et al. successfully cured one case of SJS by subcutaneous injection of etanercept (initial dose 50 mg, then 25 mg per day for 3 days). Hunger et al. treated a 69-year-old TEN patient with anti-TNF-α antibodies (infliximab, 5 mg/kg) and confirmed that their recovery time was significantly shorter than that of patients treated with immunoglobulin [145, 146]. Wang et al. found similar mortality rates in patients treated with etanercept and corticosteroids, but those receiving etanercept had faster recovery [147]. Mepolizumab has been used to successfully treat eosinophilic diseases, such as hypereosinophilic syndrome and severe asthma [148]. As DRESS patients are often accompanied by hyperplasia with eosinophilia or the emergence of abnormal lymphocytes, Ange et al. reported successful treatment of DRESS patients with mepolizumab [149]. However, whether mepolizumab contributes to the treatment of severe drug eruption needs further study. Uzun et al. first reported that TEN can be treated with omalizumab (anti-IgE antibody). They monitored changes in immunoglobulin (Ig), C-reactive protein, serum eosinophile cationic protein, IgA, IgM, IgG1, IgG2, IgG3, IgG4, IgA, and IgM; all of which showed a significant decrease after treatment. However, there is no other evidence on omalizumab treatment in drug eruption [150]. Granulocyte colony-stimulating factor may play a certain role in the treatment of DRESS by inhibiting hypersensitivity reactions and stimulating epithelial regeneration, but there is currently no strong evidence [151].

In summary, a standard treatment plan for severe drug eruption has not been established yet, but the basic treatment process is generally the same (Fig. 5). To decrease mortality and improve prognosis, more precise research is urgently needed.

Fig. 5

Basic management of SCARs

Conclusion

The pathogenesis of severe drug eruption is still being explored. Early diagnosis and management of severe drug eruption are very important for the prognosis of patients, and attention should be paid to possible long-term sequelae. There are various treatment options available, but traditional glucocorticoids and immunoglobulin therapies are still the first-choice treatments for severe drug eruption. Biological agents are emerging in the treatment of severe drug eruption, which may be the trend of the treatment of severe drug eruption in the future. The prevention of severe drug eruptions is also essential. The increasing number of studies on severe drug eruptions will be greatly beneficial and will guide the management of these patients.