Multiple Drug Hypersensitivity Syndrome Research Articles

Characterization, epidemiology and risk factors of multiple drug allergy syndrome and multiple drug intolerance syndrome: A systematic review.

BackgroundMultiple drug allergy and multiple drug intolerance syndrome (MDAS/MDIS) labels are an impediment to clinical care and knowledge regarding these conditions is limited. This systematic review investigated the characterization, epidemiology, risk factors, clinical impact and pharmaco‐economics of MDAS and MDIS.MethodsSystematic literature search across 11 databases (01 January 2000–06 November 2020) for MDIS, MDAS and related terminology. Studies were reviewed for quality of evidence and risk of bias by employing Critical Appraisal Skills Programme cohort study checklist. A narrative synthesis approach facilitated by systematic textual descriptions, tabulation and thematic analysis was adopted.ResultsThere was heterogeneity in terminology and methodology. Few studies applied standard drug allergy diagnostic methods. There is some evidence to suggest that multiple drug hypersensitivity syndrome (MDHS; i.e., confirmed allergies in MDAS) is a distinct clinical entity. Prevalence of MDIS and MDAS labels in unselected & selected populations varied between 2.1%–6.4% & 4.9%–90% and 1.2% & 0%–36% respectively. Reported risk factors included female gender, increasing age, body mass index, anxiety, depression, co‐morbidities, concurrent allergies and increased healthcare utilization. Drugs commonly implicated were antibiotics and non‐steroidal anti‐inflammatory drugs. No studies relating to clinical impact and pharmaco‐economics were found.ConclusionThere is considerable burden of MDAS and MDIS labels. Data needs cautious interpretation as majority of studies described involved unverified labels. Despite this limitation and heterogeneity of studies, there is some evidence to suggest that MDHS is a distinct clinical entity. Well‐designed multi‐centre studies applying standardized terminology and diagnostic methodology are needed to gain further insight into these conditions.

Perioperative management of a patient with multiple drug hypersensitivity syndrome: Anesthesia perspective

Patients with multiple drug hypersensitivity often pose significant challenge during surgery because of the greater risk of developing anaphylactic shock that could be fatal. The use of novel pharmaceutical agents such as anesthetic drugs and medical devices made from a wide range of chemicals and materials with unknown antigenicity potentially predisposes this subset of patients to hypersensitivity reactions in the perioperative period.
 The authors encountered a 20-year-old patient with a history of multiple drug hypersensitivities, who had been diagnosed with a huge ovarian tumor. She underwent surgery successfully but faced a rather difficult recovery. Herein, we discuss the management of unexpected perioperative outcomes with the support of literature review. This article also highlights the use of drug provocation tests and the necessary precautions to be taken in the absence of standardized preoperative guidelines for patients with multiple drug hypersensitivity syndrome undergoing major surgical procedures.
 Key words: Multiple hypersensitivity; Perioperative; Anesthesia; Suture; Drug provocation test
 Citation: Sany S, Leow VM, Ghaffar ZA, Lim JA, Chong SE. Perioperative management of a patient with multiple drug hypersensitivity syndrome: Anesthesia perspective. Anaesth. pain intensive care 2020;24(6):__
 Received: 10 August 202-, Reviewed: 29 October, 1 November 2020, Accepted: 1 November 2020

Drug-related relapses in drug reaction with eosinophilia and systemic symptoms (DRESS)

BackgroundA drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe T cell mediated hypersensitivity reaction. Relapses of symptoms in the recovery phase are frequent and linked to the reduction of the corticosteroid treatment, to viral reactivations or to the exposure to new drugs. Here, we analyzed, how often the exposure to new drugs leads to new sensitization or drug-related relapses without detectable sensitization.Methods46 patients with DRESS treated in the allergy division of the Inselspital, Bern University Hospital, were retrospectively assessed. Drug-related relapses were analyzed in terms of frequency and whether a possible sensitization evaluated by skin tests and/or lymphocyte transformation tests (LTT) to the new drugs was detectable. Furthermore, drug tolerance was evaluated in a subset of patients.Results56 relapses were observed in 27 of 46 patients with DRESS (58.7%). 33 (58.9%) of these relapses were associated with the use of new drugs, 30 drug-related relapses were evaluated by patch test and/or lymphocyte transformation test. In 8/30 (26.7%) drug-related relapses, a sensitization to the new drug was demonstrated, suggesting the emergence of a multiple drug hypersensitivity syndrome (MDH). 14 patients experienced 22 drug-related relapses without any detectable sensitization and only 1/6 patients developed new symptoms upon reexposure.ConclusionPatients with DRESS frequently suffered from drug related relapses. Half of the patients with drug-related relapses developed a MDH with proven sensitizations not only to the DRESS inducing drugs, but also to newly applied drugs. When not sensitized, drugs involved in drug related relapses could be reintroduced, if needed. Here, we propose a procedure for drug testing and future management of drug-related relapses in DRESS.

Tackling the Patient with Multiple Drug “Allergies”: Multiple Drug Intolerance Syndrome

As populations age, the prevalence of reported drug "allergy" increases, often leading to suboptimal care and increased morbidity because of unnecessary avoidance of safe and effective medications. Evaluation by a drug allergy specialist is often warranted when a patient has more than 2 unrelated drug "allergies" listed in the medical record. In this commentary, we clarify and propose standard terminology to use when evaluating patients with multiple drug allergy labels including and more specifically when diagnosing multiple drug intolerance syndrome and the much rarer multiple drug hypersensitivity syndrome. We review epidemiology and key features of multiple drug intolerance syndrome and multiple drug hypersensitivity syndrome. We summarize the methodologic and practical diagnostic workup and management of individuals with MDIS to assist with the accurate delabeling of drug "allergies" in the electronic health record.

The role of drug, dose, and the tolerance/intolerance of new drugs in multiple drug hypersensitivity syndrome.

Multiple drug hypersensitivity syndrome (MDH) is used to describe persons with a drug hypersensitivity reaction (DHR) to at least two chemically unrelated drugs, confirmed by skin test or in vitro assay. Medical records of 25 patients with MDH, tested and confirmed at our allergy division, were retrospectively evaluated in terms of clinical course, involved drugs, daily drug dose, latency periods, test results of skin test and cellular assays, and tolerated drugs in subsequent pharmacological treatments. Multiple drug hypersensitivity syndrome almost exclusively appeared as a delayed, often severe DHR and started in 14/25 with a drug reaction with eosinophilia and systemic symptoms (DRESS). Penicillins (13/25, 52.0%) and cephalosporins (6/25, 24.0%), typical high-dose drugs, were most often identified as elicitors of MDH, especially at the first DHR, followed by aromatic antiepileptics (7/25, 28.0%), vancomycin (4/25, 16.0%), and antibiotic sulfonamides (4/25, 16.0%). Cephalosporins, clindamycin, and radio contrast media (RCM) were mainly involved in subsequent DHR. The median daily drug dose of all drug trigger was 1875.0mg (662.5; 2100.0) at the first DHR and 600.0mg (300.0; 1300.0) at subsequent DHR, P=.0420. High-dose drugs, especially beta-lactam antibiotics, RCM and clindamycin, are common elicitors of subsequent DHR in patients with MDH. Macrolides, quinolones, doxycycline, nonaromatic antiepileptics, and paracetamol were often tolerated. As the same drugs elicited both flare-up reactions and real DHR, drug-induced flare-up reactions may be precursors of a possible second DHR and MDH. The administration of highly dosed drugs should be avoided in patients at risk for MDH.

Multiple Drug Hypersensitivity Syndrome in a Large Database

Multiple drug hypersensitivity syndrome (MDHS) is defined as confirmed drug hypersensitivity (DH) to at least 2 chemically and pharmacologically unrelated drugs. Reports of MDHS are scarce and poorly specified, and studies that diagnose MDHS on the basis of positive allergy test results are lacking. To evaluate retrospectively the frequency and characteristics of patients with MDHS in a large database. We included all patients who consulted and were tested in our Allergy Unit between September 1996 and February 2018 for a suspicion of DH. Clinical history and allergy workup results compiled in our Drug Allergy and Hypersensitivity Database were reviewed, and data of patients with a diagnosis of MDHS were retrieved and analyzed. During this period a total of 9250 patients were explored and 1819 tested positive for at least 1 drug. Forty-five cases, 30 female and 15 male patients cumulating 92 DHs, were confirmed as having MDHS. An immunologic mechanism, as demonstrated by positive skin testing, accounted for 59 DHs. Drug provocation tests were performed to confirm the diagnosis for the remaining 33 DHs. Of the 92 DHs in this series, 38 were classified as type IV and 21 as type I allergies; 33 remained of undetermined mechanism. Drug class occurrences seem to differ from those in monoallergic patients. Our data support the concept of MDHS as a distinct and rare subgroup of DH. The prevalence in our database was 2.5% in the total DH alleged patient population and 0.5% of the demonstrated DHs. Skin testing and drug provocation tests are mandatory for confirming the diagnosis.

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

This patient had a two-month history of four clinical manifestations of drug hypersensitivity reactions (DHR): maculo papular eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis (TEN). The eliciting drugs were rifampicin, possibly gabapentin, levofloxacin, meropenam and/or colistin. Thus, the patient might develop a multiple drug hypersensitivity syndrome. The TEN-like lesion appeared after stopping drugs for two days. A different manifestation of DHR in dependence of drug use suggests that the distinct manifestations of DHRs are due to the stimulation of T cells with distinct functions. The simultaneous appearance of AGEP and DRESS symptoms might be due to the simultaneous stimulation of two (or more) different T cell subsets, which are functionally dominant. Lastly, the appearance and further propagation of symptoms after therapy-stop is a common but somewhat neglected problem in DHR, which raises questions regarding the cause of persisting T cell activation.

Patterns of response and drug involved in patients with multiple drug hypersensitivity syndrome

A MDH was diagnosed in 48 (2.41%) of the 1989 patients evaluated, being 32 females, with a mean age of 50±14, 43 years. A total of 137 episodes were reported: 80 (58.39%) suggested an IgE-mediated reaction, 37 (27%) a non-immunologic mechanism (cross-reactive to NSAIDs) and 20 (14.55%) a T-cell mediated reaction. The percentage of MHD in patients with IgE-mediated reactions (9.78%) was higher compared to those with T-cell mediated reactions (5.23%) and non-immunologic reactions (1.91%) (p<0,0001). The drugs most frequently involved were dypirone (13.6%), ciprofloxacin (12.1%), amoxicillin-clavulanic acid (11.4%), amoxicillin (10%), ASA (8.6%), ibuprofen (7.1%) and moxifloxacin (5.7%). Sensitivity to 2 chemically unrelated drugs was diagnosed in 44 patients and to 3 drugs in 4. The most frequent clinical entities were anaphylaxis/shock (42.85%) and urticaria (34.92%). Conclusions Patients with IgE-mediated reactions have a higher risk for developing MHD. More studies are needed to confirm this finding.

Multiple Drug Hypersensitivity Syndrome In Our Allergy Service

Multiple Drug Hypersensitivity Syndrome In Our Allergy Service

Clinical Presentations of Severe Cutaneous Drug Reactions in HIV-Infected Africans

Sub-Saharan Africa is the epicenter of the HIV pandemic and HIV-infected people are more susceptible to inflammatory dermatoses, infections, and drug eruptions. Many of the drugs used for HIV-associated opportunistic infections are associated with a higher incidence of drug-related toxicities and drug interactions. This article discusses the epidemiology, pharmacogenetics, and clinical features of idiosyncratic drug reactions in HIV-infected Africans. Special considerations in this population, including immune reconstitution inflammatory syndrome, multiple drug hypersensitivity syndrome, drug reactions in pregnancy, drug rechallenge in lichenoid drug eruptions, and anxiety/depression after cutaneous adverse drug reactions, are also briefly discussed.

Multiple drug hypersensitivity syndrome

The multiple drug hypersensitivity syndrome (MDH) is a distinct clinical entity, different from cross-reactivity and flare-up reactions. Following its initial description in 1989 by Sullivan et al., several authors have addressed the issues surrounding this peculiar form of drug hypersensitivity. Whether this syndrome is single or can be further classified in several entities is still a matter of debate. Case reports, case series or studies involving large populations on MDH are few. The use of this term in the literature is heterogeneous, and the definitions variable. Given the major advances in the study of drug hypersensitivities in general, and ongoing research regarding severe cutaneous adverse reactions in particular, careful study of the subgroup of patients with demonstrated immunological basis of MDH has enabled the generation of possible pathogenetic hypotheses. Together with the studies (despite their limitations) to estimate the prevalence of this syndrome in adult and paediatric patients these emerging data need confirmation through larger studies with well defined populations. Bringing together the experience of groups involved in the field of drug allergy should help to move knowledge regarding this peculiar form of drug hypersensitivity forward.

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

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 cross-reactivity, 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.