Adverse drug reactions are the fifth leading cause of death among all diseases, accounting for 5% to 10% of hospitalizations worldwide. They remain a challenge in modern healthcare, particularly with increasingly complex comorbidities and therapeutics.
By definition, adverse drug reactions are unintended harmful events attributed to the use of medications in clinical practice. They are associated with prolonged hospitalizations, increased readmission rates and costs of care, and death. 30% to 45% involve the skin. Risk factors include female sex, older age, higher number of medications, immunocompromise, and autoimmune disorders.
Identifying the type of rash due to medications is very problematic. Clinicians are familiar with the clinical features of the 2 most common drug-induced skin reactions, morbilliform eruptions and urticaria:
• Morbilliform drug eruption, also called exanthematous or maculopapular rash, is the most common, classically presenting with an erythematous maculopapular rash 1-2 weeks after drug exposure.
• Urticarial rash, the second most common, presents as migratory, pruritic, annular plaques, usually within hours of initial drug exposure.
Skin reaction rates are higher with penicillins, sulfonamides, anticonvulsants, and nonsteroidal anti-inflammatory drugs (NSAIDs). The latter and salicylates are those that are more associated with urticaria than with morbilliform drug exanthema. Serious drug eruptions are less common but can be life-threatening. They can be recognized early, allowing the suspected drug to be immediately suspended.
| Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) |
SJS and TEN are overlapping diseases characterized by mucocutaneous reactions with epidermal necrosis and sloughing of the affected skin. Conditions are classified into 3 categories according to their severity, based on the percentage of body surface area involved:
• SJS : lesion area is <10%
• SJS/TEN overlap : lesion area is 10% to 30%
• NET : lesion area is >30%.
The estimated global incidence of SJS/TEN in Europe and the USA reaches 6 cases per million person-years. Rates are higher in adults, women and people of Asian or black ethnicity.
The most common triggering drugs are allopurinol, antibiotics (particularly sulfonamides), antiepileptics, and NSAIDs.
Immune checkpoint inhibitors, which are increasingly prescribed for malignancy, are associated with serious drug rashes, including SJS/TEN.
> Symptoms begin after 1-3 weeks
The onset of the rash is usually 1 to 3 weeks after the introduction of the drug. Lesions usually appear first on the face and chest and then spread symmetrically. They begin as macules and target lesions with erythema and dark necrotic centers that become vesicles, erosions or ulcerations, with epidermal detachment. They usually have a positive Nikolsky sign, that is, traction pressure causes epidermal shear and erosion.
> Systemic manifestations
Systemic manifestations are common and include flu-like symptoms, fever, lymphadenopathy, and mucosal involvement (conjunctival, oropharyngeal, esophageal, and genital). This affectation occurs in up to 90% of patients. Oral ulcers, grit in the eyes, odynophagia and dysuria are common.
The most clinically significant elements of mucosal involvement are the sequelae of mucosal ulceration, resulting in scarring and stenosis, affecting several organ systems—cornea, urethra, esophagus, and pulmonary tract.
Serious complications of SJS/TEN are respiratory failure, shock, functional volume depletion, and infections. The average mortality rate is 1% to 5% in SJS and 25% to 35% in TEN.
> Diagnosis
The diagnosis of SJS/TEN is based on a history of drug exposure along with clinical evidence of classic mucocutaneous lesions. The gold standard for diagnosis is skin biopsy with routine histopathology and direct immunofluorescence studies.
If the diagnosis is uncertain, biopsy may be useful, even in early stages, but is more definitive in later stages, when the distinctive manifestations of full-thickness necrosis and subepidermal detachment already exist. At this stage, subsequent biopsy helps to exclude diagnoses that mimic SJS/TEN, such as staphylococcal squamous skin syndrome and other generalized blistering rashes, such as exfoliative erythroderma, bullous pemphigoid, pemphigus vulgaris , and skin dermatosis. linear immunoglobulin A.
> Supportive measures and rapid referrals are important.
The first and most important step in the management of a patient with SJS/TEN is the immediate identification and discontinuation of suspected medications.
Immediate discontinuation of the causative agent before the development of erosions and blisters means reducing the risk of death. The SCORTEN (Severity-of-Illness for Toxic Epidermal Necrolysis) tool includes prognostic indicators such as heart rate, age, and kidney function, and can be used to determine a patient’s risk of death with SJS/TEN.
The mainstay of treatment is supportive measures: intravenous fluids, electrolyte replacement, nutritional support, pain control, and infection prevention. Periodic skin cultures and blood cultures can help detect and treat superinfection. Immediate referral to burn units and specialists (e.g., ophthalmology, urology) is indicated based on organ involvement.
Treatment with corticosteroids is controversial, but therapy with intravenous immunoglobulin alone or in combination with corticosteroids has shown varying degrees of success. Other options are plasmapheresis, immunosuppressive agents (cyclosporine, cyclophosphamide, thalidomide) or various combinations of these options, and any of the above treatments. Prophylactic systemic antibiotics should be avoided unless an infection study raises concern about bacterial superinfection.
| Drug reaction with eosinophilia and systemic symptoms (DRESS) |
DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) is a late-onset multiorgan reaction, usually occurring 2 to 6 weeks after the start of medication, although the rash may be seen earlier with some medications such as antibiotics.
The incidence is 1 in 1,000 to 10,000 drug exposures, being responsible for almost 18% of adverse reactions to drugs that affect the skin, in hospitalized patients. The most common offending medications include antiepileptics (carbamazepine, phenytoin, lamotrigine, phenobarbital), allopurinol, sulfonamides (sulfasalazine, dapsone, trimethoprim-sulfamethoxazole), minocycline, vancomycin, and antituberculosis drugs (isoniazid, rifampicin, ethambutol, pyrazinamide).
| Severity of Toxic Epidermal Necrolysis (SCORTEN) Score | |
| SCORTEN parameters | Score |
| Age ≥40 years | 1 |
| Malignancy | 1 |
| Heart rate >120/min | 1 |
| Initial detachment fraction >10% dermal | 1 |
| Uremia >65 mg/dl | 1 |
| Blood glucose >252 mg/dl | 1 |
| Bicarbonate ≥20 mEq/l | 1 |
| Total score | % predictive of mortality risk |
| 0-1 2 3 4 >5 | 3.2 12.1 35.8 58.3 90 |
> Fever, rash, facial edema, eosinophilia
DRESS often begins with fever and severe, pruritic, nonspecific skin rash affecting >50% of the body surface area. Patients usually develop central facial edema with periorbital sparing. The rash is usually maculopapular, but the lesions are polymorphic and may present as plaques, blisters, target lesions, urticaria, exfoliation, eczema or, rarely, lichenoid eruptions).
In addition to rash and fever, other manifestations may include lymphadenopathy, hematologic abnormalities, and involvement of internal organs (commonly liver, kidney, lungs, and heart). Up to 95% of patients with DRESS have eosinophilia. Throughout a prolonged clinical course, sequential reactivation of several human herpesviruses (particularly types 6 and 7) and, less frequently, infections by Epstein-Barr virus and Cytomegalovirus can be observed.
The course may wax and wane with multiple outbreaks. The average mortality rate is 4% to 10% due to multiple organ failure (most commonly liver necrosis), with long-term complications including exfoliative dermatitis, acute necrotizing eosinophilic myocarditis, and autoimmune sequelae such as thyroid disease, vitiligo, alopecia areata , lupus. erythematosus, autoimmune hemolytic anemia and fulminant type 1 diabetes mellitus.
> RegiSCAR: Diagnostic Criteria Resource
The clinical presentation of rash and eosinophilia involving internal organs should raise suspicion of DRESS and initiate the corresponding studies. The RegiSCAR (Registry of Severe Cutaneous Adverse Reactions) criteria are the most detailed and frequently used diagnoses. Follow-up blood tests should be obtained depending on the organ suspected to be affected.
The histopathology of DRESS is nonspecific and includes spongiosis, basal vacuolization, necrotic keratinocytes, dermoepidermal infiltrates, dermal edema, and perivascular lymphocyte infiltrates with or without eosinophils.
Identification of the causative agent can be challenging due to late presentation after drug exposure. The most reliable in vitro method to confirm the causative drug is the lymphocyte transformation test, which is particularly useful for confirmation when dealing with anticonvulsant and antituberculosis therapies. This test evaluates the activation of drug-specific T cells with 73% sensitivity and 82% specificity, but must be performed 2 to 6 months after the acute phase. In vivo skin testing , particularly patch testing and delayed intradermal testing, may also be useful in identifying the causative drug.
> Multidisciplinary management
Management of DRESS requires a multidisciplinary approach based on which organs are affected and the severity. If the patient has a mild disease, with a moderately elevated transaminase level (<3 times the upper limit of normal), treatment is symptomatic, with topical corticosteroids.
The treatment of choice for severe disease is systemic corticosteroids in moderate to high doses.
For patients who do not respond to corticosteroids, intravenous immunoglobulin and Janus kinase inhibitors can be used, which have shown some success. Other alternatives are immunosuppressive agents (cyclophosphamide, cyclosporine, interferons, mycophenolate mofetil, rituximab), antivirals and plasmapheresis. Antibiotics and antipyretics should be avoided unless there is definite evidence of infection.
| Acute generalized exanthematous pustulosis |
It is a severe rapid cutaneous pustular reaction that usually occurs within 48 hours of drug exposure. Its incidence is 1 to 5 cases per million person-years, and common causative drugs are antibiotics, antifungals, hydroxychloroquine, and diltiazem.
> Abrupt presentation
Its presentation is abrupt, with hundreds of pustules the size of a pinhead, on a diffuse base of erythema and edema. It usually begins in folds with intertrigo. on the face or both, and then spread to the trunk and extremities. The lesions may cause burning and itching. Mucosal involvement is rare.
The rash is associated with fever, leukocytosis (predominantly neutrophilic), elevated C-reactive protein, and, in 20% of patients, multiorgan involvement. The pustules resolve spontaneously in a few weeks followed by postpustular punctate desquamation in an annular shape. The overall mortality rate is <5%, mainly due to complications such as skin superinfection, multiple organ dysfunction, and disseminated intravascular coagulation.
> Dermatoscopy improves early diagnosis
To define the clinical and diagnostic criteria, the EuroSCAR (European Study of Severe Cutaneous Adverse Reactions) diagnostic score can be used. Pustules are often difficult to visualize, but dermoscopy with magnifying glass and polarized light can improve early diagnosis, with detection of pustules at an early stage. Skin biopsy usually reveals intracorneal and subcorneal pustules, and intraepidermal pustules with edema and infiltrates with neutrophils and eosinophils in the papillary dermis.
Sometimes epidermal alterations such as spongiosis with necrotic keratinocytes are included. When the cause of this pathology is unclear, an option may be patch testing after resolution of symptoms. During the pustular phase, prevention of infection with moist dressings and antiseptic solutions is recommended. In prolonged cases, topical corticosteroids can help relieve symptoms and reduce the duration of hospitalization. In the absence of superinfection, antibiotics should be avoided.
| Drug-induced vasculitis |
Typically, it is a small vessel vasculitis related to an immune complex-mediated reaction of the capillaries and venules of the dermis.
Generally, this vasculitis is limited to the skin. Arthralgias also occur, but rarely present as severe multiorgan involvement that can mimic systemic vasculitis.
Commonly, drug-induced vasculitis occurs 1 to 3 weeks after drug initiation and is usually self-limiting. The most common causative drugs are: antibiotics, sulfonamides, diuretics, allopurinol, NSAIDs, amiodarone, ß blockers, selective serotonin reuptake inhibitors and metformin. The usual presentation is palpable petechiae and purpura that do not blanch.
The rash is commonly bilateral and is distributed in areas, depending on the body area. They sometimes develop into hemorrhagic vesicles, blisters, pustules, nodules, crusted ulcers, or livedo reticularis . Koebnerization, which is the appearance of lesions in areas of trauma, is rare, but reverse koebnerization has been described, with the lesions disappearing by pressure dressing after skin biopsy.
Approximately 30% of patients present extracutaneous involvement, such as joints, kidney, gastrointestinal, lung or neurological symptoms. The mortality rate, around 2%, is usually related to systemic involvement.
| Registry of diagnostic criteria for DRESS | |||
| Criteriawa | Score | ||
| NO | YEAH | Indeterminate | |
| 1) Acute skin rash a) More than 50% of body surface affected b) Rash characteristic of DRESS c) Biopsy suggesting DRESS | 0 -1 -1 | +1 +1 0 | 0 0 0 |
| 2 ) Fever >38.5ºC | -1 | 0 | -1 |
| 3) Lymphadenopathy (> 1 site; > 1 cm) | 0 | ’+1 | 0 |
| 4) Compromise of internal organs | 0 | +1 | 0 |
| 5) Eosinophilia a ) Eosinophils 700–1499, or 10%–19.9% if leukocytes <4 x 109 L+1 b) Eosinophils > 1,500 or >20% if leukocytes <4 x109 Ll |
| +1 +2 | |
| 6) Atypical lymphocytosis | 0 | +1 | 0 |
| 7) Thrombocytopenia | |||
| Additional parameters | |||
| Resolution >15 days | 0 | 0 | -1 |
| Exclusion of: antinuclear antibodies, blood culture, serology for hepatitis A, B and C, Chlamydia or Mycoplasma | +1 | ||
| a: Requires ≥3 criteria b: Probability of diagnosis based on a total score: <2 = no; score 2–3 = possible; score 4-5 = probable; score >5 = defined. c: Maximum of 2 points | |||
> Consider alternative causes
The diagnosis of drug-induced vasculitis should be based on the clinical presentation considering other causes of systemic vasculitis.
A reasonable investigation includes basic laboratory tests, infectious serologies (hepatitis B and C, HIV), serum protein electrophoresis, direct immunofluorescence studies with immunoglobulins (IgG, IgA, IgM), antinuclear antibodies, rheumatoid factor, serum complement levels, antineutrophil cytoplasmic antibodies and cryoglobulins. The definitive diagnosis can be confirmed by skin biopsy which typically shows any of the following characteristics:
• Neutrophilic infiltration in and around the vessel wall, with signs of “clear dust” or leukocytoclasis (disintegration of neutrophil nuclei into fragments)
• Fibrinoid necrosis or fibrin deposition in and around the vessel wall
• Signs of damage to the vessel wall and surrounding tissues such as damaged endothelial cells or extravasation of red blood cells.
When drug-induced vasculitis is suspected, the causative agent should be discontinued immediately. In most cases, the condition is self-limiting and responds to supportive measures and symptomatic relief (rest, elevation of the extremity if affected, and use of compression stockings. Corticosteroids usually provide a rapid response. Other options include : colchicine, dapsone, hydroxychloroquine and NSAIDs. In patients with underlying systemic vasculitis, immunosuppressive drugs (azathioprine, methotrexate, mycophenolate mofetil), biologicals or plasmapheresis can be considered.
| General approach |
The most important clues to identifying and differentiating fatal drug eruptions are found in the history, timing of exposure, and bedside physical examination. While there is overlap, severe drug eruptions have distinctive characteristics. In general, when a serious drug eruption is suspected, immediate identification and discontinuation of the suspected drug is indicated.
To aid and support the diagnosis, especially in doubtful cases, the definitive diagnosis is often confirmed by a skin biopsy. Due to the possibility of potentially fatal complications and sequelae, management begins immediately with supportive measures: maintenance intravenous fluid, nutritional supplements, and consultation with burn units or other specialists, to minimize long-term sequelae such as ocular, renal, pulmonary, hepatic or genitourinary. Specific medical management is complicated and varied, depending on the patient and the specific rash.
| Prevention is a challenge |
Preventing serious drug eruptions is challenging but having a complete history of past adverse events and serious drug reactions is helpful as it reduces the future risk of harm . In preventing serious adverse drug reactions, human leukocyte antigen testing can be very useful, as shown in the following examples:
The HLA-B*5801 allele is associated with a markedly elevated risk of allopurinol hypersensitivity syndrome. The prevalence of this allele is highest among people of Han Chinese, Korean, and Thai ancestry (7.4%) and African Americans (3.8%). Before starting allopurinol in these higher-risk populations, the American College of Rheumatology conditionally recommends testing for the HLA-B*5801 allele. This allele is seen almost exclusively in patients of Asian ancestry, who are at increased risk for SJS and DRESS when treated with antiepileptic agents.
The US Food and Drug Administration recommends screening these at-risk populations before starting carbamazepine, oxcarbazepine, and possibly phenytoin. Future studies are likely to identify other genetic tests that could limit the provocation of serious cutaneous adverse drug reactions.
