Cutaneous Adverse Drug Reaction (CADR)

Article Author:
Daifallah Al Aboud
Article Editor:
Wissem Hafsi
3/25/2020 1:43:32 PM
PubMed Link:
Cutaneous Adverse Drug Reaction (CADR)


Toxidermia (Cutaneous adverse drug reactions (CADR)) are skin manifestations resulting from systemic drug administration, ranging from erythema to a much more severe reaction such as Lyell's syndrome. They represent a heterogeneous field, including various clinical patterns without specific features suggesting drug causality. The causative agent must always be searched.[1][2]

Issues of Concern

Most systemic drugs are potential causes of cutaneous adverse reactions, although certain classes can be incriminated more often than others, especially antibiotics, anticonvulsants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Antibiotics and anti-epileptics are complicated with toxidermia in 1 to 5% of treatments.[3][4]

The mechanisms are multiple which accounts for the great semiological variability observed; it includes an immediate or delayed immunologic mechanism which is the source of the manifestations most widely reported in the literature, it is mediated by the cellular or humoral effectors of the immune system; it is mainly a delayed-type IV reaction, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent, in this case, the drug directly exerts its effect on the target. In the case of an immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test, and the intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to a pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case, if the involved drug is a newly marketed one or unusually related to cutaneous reactions.[5]

Toxins are a common public health problem. They affect about 10% of hospitalized patients. Toxidermias occur in 1 to 3% of multi-medicated patients.

Severe reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), acute generalized exanthematous pustulosis (AGEP) and DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome).[6][7]

Clinical Significance

There are several types of toxicdermia according to their clinical presentation and with its own evolution.[8][9][10]

Exanthematous eruptions (also described as morbilliform and as ery­thematous maculopapular eruptions) are the most common type of drug reaction, accounting for approximately 40% of all reactions. The rash develops one day to 3 weeks after the offending drug is first given although the timing depends on previous sensitization. The lesions are maculopapular, polymorphic with no mucosal involvement. They resemble a viral exanthem. Lesions usually appear first on the trunk or in areas of pressure or trauma. They spread to involve the extremities, usually in a symmetrical manner. Drugs most frequently incriminated: antibiotics (beta-lactams, sulfonamides), non-steroidal anti-inflammatory drugs (NSAIDs), antiepileptics (carbamazepine, hydantoins), allopurinol.

Urticarial Toxidermia "Urticaria and Quincke's Edema": There are two mains types, immediate urticaria, occurring very rapidly after the start of treatment (within 1 hour or 2 maximum) formally contra-indicating the continuation of the drug since it may correspond to an anaphylactic reaction. Or well-delayed urticaria occurring several days most often after administration of the treatment and linked to the pharmacological properties of the medicinal product, not contraindicating its prosecution.

Fixed pigmented erythema (EPF) occurs 24 hours to a few days after taking drug inducer. The classic form is characterized by one or several rounded or oval-shaped plates, well limited, erythemato-purplisha with a pigmented evolution.

Drug reactions can be very serious; life-threatening and can cause death. It represents 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly identified in order to guide their management.

Toxic epidermal necrolysis (NET) or syndrome of Lyell and Stevens-Johnson syndrome (SJS) is the most serious of the toxidermia, causing 25% of deaths. There is a continuum between SJS and LyellNET which are only differentiated by the detached surface (<10% in SJS,> 30% in Lyell-NET and overlap syndrome between 10 and 30%). Symptoms appear 21 days after initiation of causative therapy. In a few hours or a few days, the complete picture is constituted. Dark red or purpuric macular rash with pseudo-cockades conflated into a detachment dermis made of large shreds exposing the oozing dermis. The eruption, often symmetrical, starts on the face and then gradually spreads to the rest of the body. The sign of Nikolsky is positive (friction reproduces detachment). The painful erosions of mucous membranes are constant and affect at least two sites (conjunctiva, nose, mouth, anal or genital area). The general state of health is seriously altered by high fever, rapid dehydration and the superinfection of the skin lesions. Respiratory, pulmonary symptoms with polypnoea and hypoxia which is evidence of the necrosis of the bronchial tree are correlated with poor clinical prognosis.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterized by a late-onset eruption 2 to 6 weeks after starting the medication. The eruption is not very specific; it manifests with itching maculopapular exanthema extended to more than 50% of the body surface area or a febrile erythroderma. In 30% of cases, it is associated with an infiltrated facial edema and more rarely small pustules, purpura or lesions erythema multiforme can appear. The diagnosis of DRESS is mentioned in the association of this eruption to voluminous adenopathies in several lymph nodes and visceral involvement (hepatitis, interstitial nephritis, pulmonary involvement, cardiac or pancreatic). The general condition is altered. This clinical picture is supplemented by eosinophilia (> 1500 PNN / mm3) and a mononucleic syndrome. The eruption of DRESS persists several weeks and serious sometimes delayed compared to the onset of the eruption. In addition, eosinophilia may be lacking during the initial phase of the disease. The exact pathogenesis is unknown. Patients suffering from this toxidermia must be hospitalized must require several clinical and biological follow-up weeks after hospitalization.

Acute generalized acute exanthematous pustulosis (PEAG) is most frequently triggered by antibiotics, most of all aminopenicillins and macrolides. It begins abruptly with scarlatiniform erythema which quickly overlaps with semi-small pustules superficial, non-follicular, predominantly amicrobial in the large pleats (armpits, inguinal folds). The most common symptoms were a burning sensation of the skin and pruritus. It appears 24 hours to 4 days after taking the medication inductor. Mucosal involvement is possible but limited. The coalescence pustules often lead to superficial cutaneous desquamation. The eruption regressed in about ten days. The diagnosis of an AGEP is established based on history, clinical manifestations, and laboratory findings. The main differential diagnosis of this toxidermia is generalized pustular psoriasis often occurring in patients with a history of psoriasis, with less brutal evolution and different histological aspect. The diagnosis of AGPE must be established because of its potential severe prognosis (5 % mortality).

Other Issues

The first approach is to incriminate all drugs and to recommend withdrawing the medication. This attitude can be used in the acute phase and only if the drugs can be replaced, or if the skin reaction is severe and requires the rapid cessation of suspect drugs (evaluation of the ratio risk/benefit).

The search for bibliographic information and the pharmacovigilance statement is essential.

Treatment is mainly symptomatic based on topical corticosteroids and oral antihistaminics. Oral corticosteroids (0.5 to 1 mg/kg/day of prednisone) are frequently used, but no evidence of their efficacy has been reported. Severe toxidermia may occur with a general corticosteroid. 

Hospitalization is indicated when there are signs of severity. They can be cutaneous: skin surface> 60%, erythema confluence, facial edema, skin pain, palpable purpura, skin necrosis, bullae or epidermal detachment, a positive Nikolski sign, mucosal erosions, urticaria and/or tongue edema; general: high fever, lymphadenopathy, arthralgia or arthritis, expiratory dyspnea, hypotension and biological: eosinophilia greater than 1000 / mm3, lymphocytosis with atypical lymphocytes, liver biological abnormalities.

Enhancing Healthcare Team Outcomes

Each year thousands of people develop adverse drug reactions (ADR), and some even die from them. Of all the ADR, the skin reactions are the most common and can be a diagnostic challenge. All healthcare workers including nurses and pharmacists must be vigilant about ADR as they can present at any time, in any patient and have a wide range of presentations. The skin reactions can confound even the most experienced dermatologist. Since some patients may be on multiple medications, this can make it even more difficult to know what the potentially offending agent is. Further, there are also genetic variations linked to skin reactions- usually from anti-epileptic medications. It is always important for healthcare workers to understand that just because a drug has been approved by the FDA does not mean it is completely safe. During the FDA approval process, the drug is usually studied in a small number of people for a short time, and hence, many side effects can be missed. These trials do not always determine the rare side effects of drugs, and often the ADR are picked up during post-marketing surveillance. Thus, the onus is on the healthcare worker and team to be vigilant about ADR and monitor the patient closely.[11][12]


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