Exanthematous (maculopapular) drug eruption

INTRODUCTION — Exanthematous (maculopapular) drug eruption, also called morbilliform (measles-like) drug-induced exanthem, is the most common drug hypersensitivity reaction [1,2]. It is characterized by a disseminated, and occasionally generalized, symmetric eruption of erythematous macules and/or papules (picture 1A-B) that occur approximately one to two weeks after initiating treatment with the causative drug or, in previously sensitized individuals, as early as 6 to 12 hours and up to three days after initiating treatment with the causative drug. The exanthematous drug eruption should be differentiated from more severe forms of drug hypersensitivity, where the mucous membranes (oral, conjunctival, nasal, anogenital) and/or internal organs may be involved [3,4]. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

This topic will focus on the clinical presentation, diagnosis, and treatment of exanthematous drug eruptions. Drug hypersensitivity in general, severe cutaneous drug reactions, cutaneous reactions to anticancer agents, and other types of cutaneous adverse drug reactions are discussed separately.

●Drug hypersensitivity

•(See "Drug hypersensitivity: Classification and clinical features".)

•(See "An approach to the patient with drug allergy".)

●Severe cutaneous drug reactions

•(See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

•(See "Acute generalized exanthematous pustulosis (AGEP)".)

•(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

•(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

●Cutaneous adverse reactions to anticancer therapies

•(See "Cutaneous adverse effects of conventional chemotherapy agents".)

•(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

•(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

•(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

•(See "Toxicities associated with immune checkpoint inhibitors".)

●Other types of cutaneous drug reactions

•(See "Fixed drug eruption".)

•(See "Lichenoid drug eruption (drug-induced lichen planus)".)

EPIDEMIOLOGY — Cutaneous drug reactions are estimated to occur in approximately 2 percent of individuals exposed to drugs [1]. Reliable and reproducible data on the relative frequencies of different types of cutaneous drug reactions are lacking. It has been estimated that maculopapular exanthems account for 80 to 90 percent of cutaneous drug reactions, whereas reactions in the drug-induced anaphylaxis spectrum account for approximately 10 to 20 percent. Drug-specific reaction rates range from near 0 to greater than 5 percent among exposed patients, with the highest rates reported for antibiotics (eg, aminopenicillins, sulfonamides) and specific anticonvulsants (eg, carbamazepine) [2].

PATHOGENESIS

Immunologic mechanisms — Many, but not all, cases of drug-induced exanthem are thought to be delayed-type, T cell-mediated (type IV) immune reactions accompanied by the activation of several nonspecific effector cell types (eg, macrophages, eosinophils, or neutrophils) [5]. The precise mechanism by which a low molecular weight drug (xenobiotic) elicits a specific immune response is not completely understood and may involve different types of interactions between drugs and immune receptors [6] (see "Drug allergy: Pathogenesis", section on 'Interaction of drugs with the immune system'):

●Drugs or their metabolites may act as haptens, form covalent bonds with an endogenous protein or peptide, and become antigenic. Haptenated proteins could then be processed by antigen-presenting cells (APCs) and bind to major histocompatibility complex (MHC) molecules. The hapten-peptide-MHC molecule complexes are then presented to T cells carrying an appropriate receptor, which together with costimulatory factors may activate and expand drug-reactive T cells.

●Drugs may directly interact with immune receptors and activate specific immune cells, proposed as the "p-i concept" (pharmacologic interactions of drugs with immune receptors). According to this concept, chemically inert drugs, unable to bind covalently to peptides or proteins, may activate T cells if they fit with sufficient affinity directly into T cell receptors or MHC molecules.

In delayed-type immune reactions, activated T cells of the CD4 T helper type 1 (Th1) cell or T helper type 2 (Th2) cell and CD8 cytotoxic T cell subtypes may orchestrate different forms of inflammatory reactions, depending on the type of cytokines produced, leading to four subcategories of type IV reactions (IVa, IVb, IVc, and IVd) (figure 1) [7]. Effector cells, such as CD4 Th1 lymphocytes, CD8 cytotoxic lymphocytes, macrophages, neutrophils, and eosinophils, may be involved in the elicitation phase, explaining to some extent the variability of the clinical reaction patterns of drug hypersensitivity [8,9].

Exanthematous drug reactions appear to be predominantly caused by type IVc hypersensitivity (figure 1), in which T cells act as effector cells. CD8 effector T cells migrate to the skin and cause tissue damage through perforin/granzyme B-mediated, granulysin-mediated, and FasL-mediated mechanisms [10]. Immunohistochemical staining and functional experimental studies of drug-reactive T cells in patients with distinct forms of exanthems support the concept that distinct T cell subsets may lead to different clinical phenotypes [8,9].

In clinical practice, the chronology of the onset and evolution of the skin lesions may provide clues about the type of pathomechanism involved (table 1 and figure 2) [8].

Eliciting drugs — A large number of drugs may induce delayed-type, T cell-mediated immune reactions, but only a limited number of them can be identified as unambiguous triggers in allergy testing (eg, aminopenicillins [amoxicillin, ampicillin], sulfamethoxazole, clindamycin). Some drugs act as haptens, bind to endogenous proteins, and then become full antigens. Examples include penicillins, cephalosporins, and agents with sulfhydryl groups. Possible antigenic determinants of beta-lactams include the aminobenzyl side chains, methoxyimino side chains, as well as core parts of the molecule [11,12]. The exact antigenic determinant is not known for most drugs (eg, clindamycin, sulfonamides, anticonvulsants).

For some drugs, biotransformation is necessary to form reactive metabolites. Examples include sulfonamides (sulfamethoxazole), anticonvulsants (eg, carbamazepine, phenytoin), and reverse transcriptase inhibitors (eg, nevirapine, abacavir). For the latter, direct binding and transformation of the MHC has been shown [13], although the exact mechanism is not fully established.

Drugs that have been introduced within a timeframe of one to four weeks before the reaction or have been previously taken and are later reintroduced are more likely to be causative than drugs that have been taken for months or even years, especially when taken in an uninterrupted manner.

GENETIC PREDISPOSITION — Genetic studies based upon the frequency of specific human leukocyte antigen (HLA) alleles suggest that there may be a genetic predisposition for drug hypersensitivity. Although there is strong evidence that certain HLA types confer an increased risk of severe cutaneous reactions (eg, Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], drug reaction with eosinophilia and systemic symptoms [DRESS]) to certain drugs, data on a possible association between exanthematous drug eruption and specific HLA alleles are still sparse and inconsistent [14,15].

●(See "An approach to the patient with drug allergy", section on 'Risk factors for drug allergy'.)

●(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

CONTRIBUTING FACTORS

Underlying disorders — Concomitant diseases (eg, decreased liver or renal function) may predispose the patient to the development of an allergic drug reaction, presumably due to altered metabolic pathways, reduced excretion, or variations in the immunologic response to drugs. Viral infections, particularly Epstein-Barr virus, cytomegalovirus, and human herpesviruses 6 and 7, are associated with an increased risk of cutaneous drug eruptions [16-18]. Patients with hereditary immunodeficiencies, acquired immunodeficiency (eg, HIV infection, iatrogenic immunosuppression, cystic fibrosis), and some autoimmune disorders are also prone to develop drug-induced exanthem [3,16,19,20].

Comedication — The concomitant intake of multiple medications may result in a more frequent occurrence of drug-induced exanthem, although the specific mechanism is still unclear [21].

HISTOPATHOLOGY — In routine histology, exanthematous drug eruptions typically reveal a subtle, vacuolar interface dermatitis, with scattered, dyskeratotic keratinocytes along the dermoepidermal junction zone (picture 2) [22]. Usually, there is a superficial, perivascular, and interstitial infiltrate of lymphocytes, neutrophils, and eosinophils. Additional features may include pronounced extravasation of erythrocytes, accumulation of lymphocytes aligned along the dermoepidermal junction, and fibrin deposition within the blood vessel walls of the papillary vascular plexus.

Although histopathologic patterns may support the clinical suspicion of a drug-induced exanthem, they cannot be reliably differentiated from those seen in a viral exanthem [23]. Thus, a "histologically proven" diagnosis of drug-induced exanthem is not possible.

CLINICAL PRESENTATION

Latency — In patients not previously sensitized, the onset of the cutaneous eruption typically occurs within 7 to 10 days (range 5 to 21 days) after starting treatment. Thus, for short courses of treatment (eg, antibiotics), the eruption may appear two to four days after stopping treatment. This relatively short latency time also suggests that a drug introduced one to three weeks before the reaction is much more likely to be responsible than a drug taken regularly for months or even years. In patients previously sensitized to the causative drug or a cross-reactive substance, the reaction may develop as early as 6 to 12 hours, or typically one to three days, after renewed treatment initiation.

General features — Exanthematous drug eruption typically presents with erythematous macules and/or papules, described as "morbilliform" (measles like) or "rubelliform" (rubella like), that predominantly involve the trunk and proximal extremities (picture 1A-D) [8]. In mild forms, acral sites are often spared, whereas in more severe cases, the face, palms, and soles may also be involved. Purpuric lesions may develop on the legs and other dependent areas or under therapy with anticoagulants.

Systemic symptoms are generally mild and may include pruritus and low-grade fever; slightly elevated, acute-phase proteins; and mild eosinophilia.

Intertriginous and flexural reaction pattern — Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE; formerly called "baboon syndrome") is an uncommon form of drug eruption, most often induced by antibiotics (picture 3) [24,25]. In rare instances, SDRIFE may be the manifestation of systemically elicited allergic dermatitis due to the systemic exposure to nickel or mercury. However, only limited data support this concept [26,27].

SDRIFE occurs a few hours to a few days after the administration of the offending drug (figure 2). The eruption presents as a sharply demarcated, V-shaped erythema in the gluteal/perianal or inguinal/perigenital area, often with involvement of at least one other flexural skin region, such as the axillae, antecubital fossae, or popliteal fossae of the knee (picture 3) [8,24,28].

SDRIFE should be differentiated from the so-called "malignant intertrigo," an intertriginous form of acral erythema (also called hand-foot syndrome) caused by conventional chemotherapy agents [29]. (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

CLINICAL COURSE — Most exanthematous drug eruptions are of mild to moderate severity and do not cause major morbidity. Typically, the eruption evolves rapidly, reaching the maximal extent approximately two to four days after discontinuation of the causative drug, and resolves in one to three weeks (figure 2). A mild eruption may subside within a few (three to seven) days.

Resolution often occurs with some desquamation. In patients with darkly pigmented skin, postinflammatory hyperpigmentation may occur. (See "Postinflammatory hyperpigmentation".)

DIAGNOSIS

General approach — The diagnosis of exanthematous drug eruption is primarily clinical, based on clinical and medication history, timing of initial drug administration and onset of symptoms, and physical examination (algorithm 1). Concurrent infections, comorbidities, and immunosuppression should be ascertained. Establishing a temporal association between drug administration and onset of the eruption remains a key element for the identification of the causative drug.

There is no specific or reliable laboratory test to diagnose a drug eruption (see 'Allergy testing' below). Routine laboratory tests (eg, blood count with differential, liver and kidney function tests) should be checked at least once, even if the clinical picture does not indicate a systemic reaction. However, whereas a mild elevation of liver transaminases is still compatible with the diagnosis of an (uncomplicated) maculopapular eruption, a more than twofold increase of liver transaminases or a decreased kidney function may indicate a more severe, systemic hypersensitivity reaction (ie, drug reaction with eosinophilia and systemic symptoms [DRESS]). A skin biopsy is not routinely performed, but it may be warranted if the diagnosis is uncertain or there is suspicion for a severe (bullous) drug reaction. (See 'Differential diagnosis' below.)

It should be noted that in the absence of specific diagnostic tests, exanthematous drug eruptions are often misdiagnosed, especially in childhood and adolescence, as they cannot be differentiated with sufficient reliability from viral or some other exanthems neither clinically nor histopathologically [3].

Identification of the causative drug — Establishing a chronologic association between first drug administration and onset of the cutaneous eruption provides an important clue to the identification of the causative drug. (See "An approach to the patient with drug allergy", section on 'Identification of the suspect drug'.)

Key elements to be considered include:

●Current and past medication history – The patient should be questioned about current and past (within the last four weeks) medications, including over-the-counter drugs, supplements, natural and herbal remedies, and topical preparations.

●Simultaneous exposure to multiple drugs – Identifying a particular drug as the cause of an exanthematous eruption is especially difficult when the patient is taking multiple drugs. In such a situation, it may be helpful to know the relative frequency of cutaneous reactions for specific drugs [1,2,30-32]. Drugs that most commonly elicit exanthematous eruption are aminopenicillins (amoxicillin, ampicillin), allopurinol, other beta-lactam antibiotics (piperacillin, cephalosporins), non-beta-lactam antibiotics (sulfonamides, clindamycin, tetracyclines), anticonvulsants (carbamazepine, phenytoin, lamotrigine), antiretroviral drugs (abacavir, nevirapine), and radio contrast media.

●Previously sensitized patients – A short latency time (6 to 12 hours and up to a few days) between first administration of the potential, causative drug and onset of the eruption suggests that sensitization may have taken place with a past exposure to the same drug or to a cross-reacting drug component.

●Accidental re-exposure – In patients with a previous history of a drug reaction, accidental re-exposure may occur due to the use of a drug marketed under different brand names or use of over-the-counter products or "natural remedies" containing the offending agent.

●Resolution of the rash after drug withdrawal – Resolution of the maculopapular eruption after withdrawal of the suspected drug supports the diagnosis of drug etiology. However, it cannot be considered as proof of causality. Resolution is usually completed within one to two weeks after the causative drug is discontinued. In some cases with a prolonged course, resolution may take up to three weeks.

When to suspect a severe drug reaction — A severe cutaneous drug reaction, such as DRESS or Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), may appear at the very beginning as a maculopapular exanthem [3,33,34]. A severe reaction should be suspected if systemic symptoms are present (eg, fever >38°C/100.4°F, lymphadenopathy) and if blisters, erythroderma, erythematous facial swelling, or mucosal involvement develop (table 2). Laboratory testing and a skin biopsy are recommended for the diagnosis. (See 'Differential diagnosis' below and "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Laboratory testing — In case of suspected, drug-induced exanthem, liver and kidney function tests should be performed at least once, even if the clinical picture does not indicate a systemic reaction:

●Liver and kidney function tests – A more than twofold increase of liver transaminases and/or abnormal kidney function tests may indicate a systemic, inflammatory reaction and prompt surveillance for the development of DRESS or other severe drug reactions.

●Complete blood cell count with differential – Blood eosinophilia may support the diagnosis of a drug reaction, although it cannot reliably differentiate a drug-induced exanthem from an infectious exanthem. It is important to note, however, that a pronounced eosinophilia can be the heralding sign of DRESS. (See "Approach to the patient with unexplained eosinophilia" and "Infectious causes of peripheral eosinophilia".)

Skin biopsy — A skin biopsy is not routinely necessary for the diagnosis of exanthematous drug eruption. The histopathologic findings (vacuolar interface dermatitis and tissue eosinophilia (picture 2)) may support the diagnosis but are nonspecific [22]. (See 'Histopathology' above.)

However, a skin biopsy may be warranted if the diagnosis is uncertain or there is concern for a more severe hypersensitivity reaction. (See 'When to suspect a severe drug reaction' above and 'Differential diagnosis' below.)

Allergy testing — The clinical diagnosis of drug hypersensitivity based solely on the temporal relationship between drug intake and the development of an exanthem leads to a huge overestimation of the frequency of drug allergy [35-37]. Therefore, allergy testing, if available, is recommended for all patients with suspected, drug-induced exanthem to rule out or confirm drug hypersensitivity, ideally within a time frame of one to six months after complete resolution of the rash. If allergy testing is not performed, many patients will be unnecessarily labeled (lifelong) as being drug allergic:

●Skin testing – Methods include patch and intradermal testing; test fields should be evaluated for delayed reactions at days 2, 3, and 4. (See "Patch testing" and "An approach to the patient with drug allergy", section on 'Testing for delayed reactions'.)

●In vitro testing – In specialized laboratories, blood samples may be examined with cell-based methods, such as lymphocyte transformation/activation testing, assays for upregulation of activation markers on T cells, cytokine production, and drug-induced cytotoxicity assay. However, the diagnostic sensitivity and specificity of these tests are variable, depending on the drug type and laboratory. Therefore, they should be considered investigational.

●Provocation (challenge) testing – The sensitivity and specificity of skin testing are limited and primarily determined by the investigated drug/drug class. Therefore, especially in cases with negative skin test results, the suspicion of allergic drug hypersensitivity should be finally confirmed or excluded by drug challenge testing. (See "An approach to the patient with drug allergy", section on 'Graded challenge and drug provocation'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of exanthematous drug eruption includes viral and bacterial exanthems, secondary syphilis, and rashes associated with systemic or cutaneous diseases (table 3). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adds to the long list of viruses causing a maculopapular rash, which may closely mimic a drug-induced exanthem [38,39]. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care".)

The morphology, distribution, and spatial and temporal evolution of the rash and results of laboratory testing (eg, serologic tests, bacterial cultures) may be helpful in distinguishing a drug-induced exanthem from a viral or bacterial exanthem or a rash associated with a systemic or cutaneous disease (table 3) [9,40,41].

It is also important to differentiate an exanthematous drug eruption from the prodromal phase of a severe cutaneous drug reaction, such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) (table 2) [33,34]. (See "Acute generalized exanthematous pustulosis (AGEP)" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

MANAGEMENT

Drug withdrawal — Prompt withdrawal of the offending drug is the mainstay of treatment for maculopapular drug eruption. However, in patients taking multiple drugs, every effort should be made to stop only the most suspicious drug(s) and not several or all drugs. Moreover, if the drug is urgently needed and no suitable alternative is available, drug treatment may also remain unchanged under close medical supervision [42]. (See ''Treating through'' below.)

Symptomatic treatment — The treatment of exanthematous drug eruptions is supportive. For symptomatic relief of skin lesions and pruritus, we suggest a topical corticosteroid and an oral antihistamine. We generally use a high-potency topical corticosteroid (table 4) one to two times per day for one week or until resolution. We prefer second-generation, nonsedating agents (eg, cetirizine or loratadine).

Systemic corticosteroids are generally unnecessary. However, in patients with a more severe or widespread exanthem accompanied by intense pruritus, a short course of a moderate-dose systemic corticosteroid (eg, prednisone 0.5 to 1 mg/kg per day for three to five days) may be beneficial [43].

The efficacy of antihistamines and anti-inflammatory drugs for the treatment of exanthematous drug eruptions has not been evaluated in randomized trials, and their use is mainly based on clinical experience.

'Treating through' — "Treating through" means the continuation of a drug treatment in the setting of a mild, cutaneous hypersensitivity reaction. This strategy may be considered in particular clinical scenarios, specifically when the condition being treated is serious and an effective alternative treatment is lacking [44]. In such cases, the benefit of the continuation of an effective therapy has to be carefully weighed against the risk of worsening the exanthem or the progression of the exanthem. Comedication with a corticosteroid or an antihistamine may reduce the risk of the progression of the exanthem but has not been well studied.

There is limited evidence in support of "treating through" from case series of patients with HIV/AIDS who were treated with co-trimoxazole for prophylaxis or treatment of opportunistic infections [45]. In a series of 18 patients with severe, bacterial soft tissue infections who experienced a drug-induced, maculopapular eruption, urgently indicated antibiotic therapy was maintained under strict medical supervision. The eruption improved in 12 patients despite the continuation of treatment, while 6 patients required replacement with an alternative agent [42]. An algorithm to support the difficult and complicated decision leading to "treating through" has been published [44].

Patient education — During the acute phase of the drug reaction, patients should be educated about warning signs of more severe drug hypersensitivity reactions. These include high fever, facial swelling (edema), mucosal symptoms, skin tenderness, development of pustules or blisters, and jaundice (table 2). Patients should seek immediate medical attention if any of these signs develop. (See 'When to suspect a severe drug reaction' above.)

PREVENTION

Avoidance — Patients should be counseled to avoid the offending drug and possibly cross-reacting drugs in the future. They should be provided with a list (eg, in an allergy card or document [46]) including the generic and a selection of brand names of the causative drug as well as possibly cross-reacting drugs. (See "An approach to the patient with drug allergy", section on 'Long-term management of patients prone to drug allergy'.)

Premedication — We do not suggest premedication with a corticosteroid and/or an antihistamine for the prevention of an exanthematous drug eruption in a sensitized patient. The efficacy of this premedication regimen for preventing a delayed-type allergic drug hypersensitivity reaction in sensitized patients has not been evaluated in case series nor in randomized trials.

Desensitization — Desensitization to induce temporary drug tolerance is an established practice in the management of immediate-type hypersensitivity reactions [47]. (See "Rapid drug desensitization for immediate hypersensitivity reactions".)

There is little evidence for the efficacy and safety of desensitization in T cell-mediated, delayed-type drug hypersensitivity reactions [48]. However, in patients with a history of mild to moderate exanthem who are in repeated need of a drug (eg, trimethoprim-sulfamethoxazole in HIV infection or antibiotics in cystic fibrosis), desensitization may be an option [19,45]. (See "An approach to the patient with drug allergy", section on 'Desensitization to the culprit drug'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug allergy and hypersensitivity".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Exanthematous (maculopapular) drug eruption is by far the most common clinical manifestation of drug hypersensitivity, occurring in approximately 2 percent of individuals exposed to drugs. Most exanthematous drug eruptions are thought to represent delayed-type, T cell-mediated allergic hypersensitivity (table 1). Although these reactions may occur with a large variety of drugs, only a limited number of drugs can be regularly identified as unambiguous triggers by allergy testing (eg, aminopenicillins [amoxicillin, ampicillin], sulfamethoxazole, carbamazepine, and clindamycin). Genetic predisposition, concomitant viral infection (eg, Epstein-Barr virus, human herpesvirus), and the administration of multiple drugs may all increase the risk of an exanthematous drug eruption. (See 'Epidemiology' above and 'Genetic predisposition' above and 'Contributing factors' above.)

●Clinical presentation – Exanthematous drug eruptions are characterized by erythematous macules and/or papules that predominantly involve the trunk and proximal extremities (picture 1A-D). Mucosal involvement is usually absent. In the case of sensitization during ongoing treatment, the rash usually develops within one to two weeks after the beginning of drug administration, but in previously sensitized patients, it may occur as early as 6 to 12 hours and up to one to three days after starting treatment. Systemic symptoms are generally mild and may include pruritus, low fever, and mild eosinophilia. After withdrawal of the offending drug, resolution is to be expected within one to two weeks (figure 2). (See 'Clinical presentation' above and 'Clinical course' above.)

●Diagnosis – The diagnosis of an exanthematous drug eruption is suspected in patients with a characteristic rash that occurs in temporal relationship with the administration of a new drug (table 5 and picture 1A-D). Resolution of the rash after drug discontinuation may support the diagnosis but by no means can be considered as proof. For all patients with a suspected exanthematous drug eruption, thorough drug allergy testing, if available, is recommended for confirming or ruling out drug hypersensitivity. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of an exanthematous drug eruption includes viral and bacterial exanthems, secondary syphilis, and rashes associated with systemic or dermatologic diseases (table 3). An exanthematous drug eruption may rarely be the heralding sign of a severe cutaneous drug hypersensitivity reaction. Warning signs include evolution to erythroderma, high fever, erythematous facial swelling, mucosal erosions, skin tenderness, and blistering (table 2). (See 'Differential diagnosis' above and 'When to suspect a severe drug reaction' above.)

●Management:

•Drug withdrawal – Prompt withdrawal of the offending drug is the mainstay of treatment for exanthematous drug eruptions. (See 'Drug withdrawal' above.)

•Relieving symptoms – For symptomatic relief of exanthem and pruritus, we suggest a topical corticosteroid and an oral nonsedating antihistamine, such as cetirizine or loratadine (Grade 2C). We generally use a high-potency topical corticosteroid (table 4) one to two times per day for one week. Antihistamines are given orally until pruritus subsides. We suggest not routinely using systemic corticosteroids for the treatment of uncomplicated exanthematous drug eruptions (Grade 2C). However, in patients with very intense cutaneous symptoms, a course of a moderate-dose systemic corticosteroid for three to five days may be beneficial. (See 'Symptomatic treatment' above.)

•"Treating through" – "Treating through" means the continuation of a drug treatment in the setting of a mild, cutaneous hypersensitivity reaction. In select patients who develop an exanthem during treatment of a severe (oftentimes infectious) disease, the benefit of continuing an effective drug (oftentimes an antibiotic) under close medical supervision by a specialist in drug allergy has to be weighed against the risk of worsening the cutaneous eruption or progression of the cutaneous eruption. Given the very limited evidence from small case series, this approach should be pursued with great caution. (See ''Treating through'' above.)

●Prevention – Patients should be counseled to avoid the offending drug and cross-reacting substances in the future. They should be provided with an allergy card or document containing a list of the generic and brand names of the causative drug. (See 'Prevention' above.)