Drug hypersensitivity: Flare‐up reactions, cross‐reactivity and multiple drug hypersensitivity

Abstract

In drug hypersensitivity, change of drug treatment and continuation with a new drug may result in reappearance of drug hypersensitivity symptoms. This is not uncommon in patients with chronic infections requiring continued and long-lasting antibiotic treatments. For the clinician, the question arises whether these symptoms are due to crossreactivity, are due to a new sensitization or are a reflection of a multiple drug hypersensitivity syndrome. Based on the p-i concept (pharmacological interaction with immune receptors), we propose that the efficient stimulation of T cells by a drug is the sum of drug-T-cell receptor affinity and readiness of the T cell to react, and therefore not constant. It heavily depends on the state of underlying immune activation. Consequently, drug hypersensitivity diseases, which go along with massive immune stimulations and often high serum cytokine values, are themselves risk factors for further drug hypersensitivity. The immune stimulation during drug hypersensitivity may, similar to generalized virus infections, lower the threshold of T-cell reactivity to drugs and cause rapid appearance of drug hypersensitivity symptoms to the second drug. We call the second hypersensitivity reaction a ''flare-up'' reaction; this is clinically important, as in most cases the second drug may be tolerated again, if the cofactors are missing. Moreover, the second treatment is often too short to cause a relevant sensitization.

Immediate Reactions to More Than 1 NSAID Must Not Be Considered Cross-Hypersensitivity Unless Tolerance to ASA Is Verified

“…Coexistence of IgE antibodies in a specific immunological response, for example, in immediate reactions to BLs, has not been proven to date [23], except for anaphylactic reactions to amoxicillin-clavulanic acid, where clinical observations indicate that patients can experience an immediate reaction to both drugs [18]. With respect to T-cell responses to drugs, a number of studies have shown that nonimmediate reactions can occur with chemically unrelated drugs [24,25].…”

Sequential appearance of four clinical delayed drug hypersensitivity in the same patient

“…4 A flare-up reaction, characterized by rapid appearance of symptoms (1-2 days) after treatment with a potential allergic substance in a patient who already shows signs of ongoing drug hypersensitivity is also unlikely, as the patient had an intermittent improvement and as most cases of flare up reactions usually present with an enhancement of the same pre-existing skin lesions (mainly exanthemas). 6 Pustular eruptions or AGEP-like eruptions may appear in relatively few cases of DRESS , but normally at the start and not after remission of DRESS. 7 In severe cases of DRESS and AGEP, large tense bullae and TEN-like lesions can develop which are sometimes very difficult to distinguish among DRESS, AGEP and SJS-TEN.…”

A Study on the Clinico - Epidemiological Aspects and Evidence of Autoimmunity in Patients With Multiple Drug Allergy Syndrome

“…Flare up reactions are defined as the exacerbation of an existing drug hypersensitivity by introduction of an unrelated drug. [2] This has been reported in Severe Cutaneous Adverse Reactions (SCAR), especially Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and is attributed to the immune activation induced by a severe drug reaction, which predisposes the patient to manifest hypersensitivity to otherwise well tolerated drugs.…”

“…[2] Cross reactivity arises from structural similarities, common metabolic pathways or pharmacologic mechanisms shared by different drugs.…”

“…Documented literature suggest that 1%-10% of patients with drug allergy manifest hypersensitivity to multiple unrelated drugs. [1,2] In 1989 Sullivan et al [3] described multiple drug allergy syndrome (Also known as multiple drug hypersensitivity syndrome) as a distinct entity where the affected shows allergies to two or more chemically different drugs.…”