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Drug hypersensitivity reactions can lead to a great variety of different diseases. The main cause is a specific interaction of antibodies or T cells with a drug. In addition to the hapten concept, some drugs can bind directly to T-cell receptors and stimulate them. Based on recent investigation on different exanthemas, an extended classification of the Gell and Coombs type IV reaction is proposed.
BACKGROUND: Multiple drug hypersensitivity (MDH) was first described in 1989 by Sullivan et al. as drug allergies to two or more chemically different drugs. So far, the diagnosis of MDH was associated almost exclusively with antibiotics and was defined based on history alone. AIMS OF THE STUDY: The objective of this study was to prove MDH by two independent tests, namely patch (PT) and lymphocyte transformation (LTT) tests. METHODS: Here we present 7 patients matching the definition of a MDH which were documented by positive LTT as well as PT to different drugs. RESULTS: Three of the 7 patients developed sensitization to the different compounds during the same treatment period and had one longer-lasting allergic reaction. For another 4 patients sensitization to the different drugs occurred at distinct time points. CONCLUSIONS: Our data support the concept of a MDH syndrome. The multiple sensitizations can be proven by skin and in vitro tests. We propose two subtypes of MDH: MDH, which develops against different drugs given simultaneously, and a second subtype, where the sensitizations develop sequentially. Antibiotics are often involved, but we also found sensitization to antiepileptics, hypnotics, antidepressants, local anesthetics, corticosteroids and other drug classes.
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Since the first description by Saltzstein in 1959, the denomination of drug-induced pseudolymphoma was used to describe two cutaneous adverse drug reactions with a histological picture mimicking malignant lymphoma. On the basis of clinical presentation, this term includes two different patterns: (1) hypersensitivity syndrome which begins acutely in the first 2 months after the initiation of the drug and associates fever, a severe skin disease with characteristic infiltrated papules and facial edema or an exfoliative dermatitis, lymphadenopathy, hematologic abnormalities (hypereosinophilia, atypical lymphocytes) and organ involvement such as hepatitis, carditis, interstitial nephritis, or interstitial pneumonitis. The cutaneous histological pattern shows a lymphocytic infiltrate, sometimes mimicking a cutaneous lymphoma, and the mortality rate is about 10%. When organ involvement exists, corticosteroids are often prescribed with dramatic improvement. Relapses may occur. (2) drug-induced pseudolymphoma which has a more insidious beginning with nodules and infiltrated plaques appearing several weeks after the beginning of the drug without constitutional symptoms. A pseudolymphoma pattern is seen on cutaneous histological slides. Complete improvement is usual after drug withdrawal, but a delayed lymphoma is possible. To decrease the ambiguity of the denomination of hypersensitivity syndrome, we propose the term of DRESS (Drug Rash with Eosinophilia and Systemic Symptoms).
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Diagnosis of drug hypersensitivity is difficult, as an enormous amount of different drugs can elicit various immune-mediated diseases with distinct pathomechanism. The lymphocyte transformation test (LTT) measures the proliferation of T cells to a drug in vitro--from which one concludes to a previous in vivo reaction due to a sensitization. This concept of the LTT has been confirmed by the generation of drug-specific T-cell clones and the finding that drugs can directly interact with the T-cell receptor, without previous metabolism or need to bind to proteins. In this review, technical aspects and usefulness of this test for the diagnosis of drug hypersensitivity are discussed. The main advantage of this test is its applicability with many different drugs in different immune reactions, as drug-specific T cell are almost always involved in drug hypersensitivity reactions. Its main disadvantages are that an in vitro proliferation of T cells to a drug is difficult to transfer to the clinical situation and that the test per se is rather cumbersome and technically demanding. In addition, its sensitivity is limited (for beta-lactam allergy it is in the range of 60-70%), - although at least in our hands - it is higher than of other tests for drug hypersensitivity diagnosis. Consequently, drug hypersensitivity diagnosis needs to rely on a combination of history and different tests, as none of the single tests available has per se a sufficiently good sensitivity. Within this setting, the LTT has proven to be a useful test for the diagnosis of drug hypersensitivity reactions and helped to better understand these reactions. Further work on the simplification of this test and systematic evaluation of its sensitivity and specificity in some main groups of drugs are necessary to make this test more widely available.
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The DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) corresponds to a drug reaction generally including cutaneous eruption, fever, hematologic abnormalities such as eosinophilia and atypical lymphocytosis and one or more specific visceral lesions specially in the liver. We report a case of drug hypersensitivity syndrome or DRESS associated with intra and extra-hepatic biliary lesions. This syndrome was associated with sulfasalazine and naproxene therapy. A reactivation of HHV6 was documented in the continuations of the DRESS and could play a role in the symptomms.
BACKGROUND: Drug hypersensitivity reactions are common and can be life-threatening. Confirmation of the diagnosis should be rigorous and based on clinical history and a physical examination, possibly followed by skin tests and drug provocation tests. OBJECTIVE: To describe the outcome of drug provocation tests in evaluating patients with histories suggesting drug allergy. DESIGN: Retrospective analysis of clinic case series. SETTING: The department for drug allergy at a university hospital. PATIENTS: 898 consecutive patients with suspected immediate drug allergy referred to the clinic between September 1996 and August 2001. Patients with severe skin reactions and those with positive results on skin tests for beta-lactams were excluded. INTERVENTION: Single-blinded administration of increasing doses of the suspected drug, up to the usual daily dose, under strict hospital surveillance. RESULTS: 1372 drug provocation tests were performed using various drugs, including beta-lactams (30.3%), aspirin (14.5%), other nonsteroidal anti-inflammatory drugs (11.7%), paracetamol (8.9%), macrolides (7.4%), and quinolones (2.4%). There were 241 (17.6%) positive drug provocation test results. Drug provocation reproduced the same symptoms, albeit milder and of a shorter duration, in the following patients: 13 (5.4%) with a history of anaphylactic shock, 17 (7.0%) with a history of anaphylaxis without shock, 10 (4.1%) with a history of laryngeal edema, 19 (7.9%) with a history of bronchospasm, 160 (66.4%) with a history of urticaria, and 22 (9.1%) with a history of maculopapular eruption. All adverse reactions were completely reversed by prednisolone, H(1)-antihistamines, and epinephrine as needed. LIMITATIONS: Falsely negative results on drug provocation tests may have occurred because of loss of sensitization, rare cofactors not included in the diagnostic procedure, and tolerance induction during provocation. CONCLUSIONS: Drug provocation tests in individuals with suspected drug allergy performed in carefully controlled settings can confirm drug hypersensitivity.
Most drug reactions are pharmacological reactions rather than hypersensitivity reactions. In assessing drug reactions, a detailed clinical history and careful documentation of reactions are most important. Elucidating the nature and time course (first versus subsequent exposure, immediate versus non-immediate) of a reaction can help to distinguish immune from non-immune hypersensitivity, as well as IgE-mediated from T cell-mediated allergy. Skin testing and in-vitro tests are of predictive value for only a limited group of IgE-mediated drug allergic reactions. Drug provocation challenges can be used to eliminate suspicion of a low-probability drug reaction, find a safe alternative to a proven or probable drug reaction, or as a means of desensitisation. If a patient taking an angiotensin-converting enzyme (ACE) inhibitor develops angioedema, the cause must be assumed to be the ACE inhibitor until proven otherwise.
Adverse drug reactions are a major health problem in the inpatient and outpatient clinical setting. Although all of the immune mechanisms of drug reactions are not well characterized, a detailed medication history, knowledge of the signs and symptoms associated with known immune mechanisms, and knowledge of the types of medications typically associated with distinct immune reactions are helpful in implicating the causative drug. Standardized testing for drug reactions is limited, especially for non-IgE-mediated reactions. Management consists of stopping the offending drug, treating the acute reaction, and making a determination concerning future use of the drug.
Allergic drug reactions compose a small percentage of ADRs, yet they are commonly encountered in clinical practice, and physicians are taught routinely to question patients about these reactions during history taking. Among antibiotics, the immunochemistry of penicillins has been elucidated,leading to the development of validated skin test reagents to diagnose type 1 allergy. Currently, the temporary commercial unavailability of Pre-Pen makes accurate penicillin skin testing impossible; however, this important skin test reagent is expected to become available sometime in 2006. Type 1 allergies to most other drugs lack comparable diagnostic tests, and their diagnosis is therefore driven by the patient's history. When readministration of medications to which patients report previous reactions is indicated, it may be almost always successfully accomplished by means of either graded challenge or desensitization.
PURPOSE OF REVIEW: Drug hypersensitivity reactions are relatively rare but may result in severe morbidity and fatalities. Due to the idiosyncratic nature and multifactorial etiology of these reactions, development of a single animal model to study the immunosensitizing mechanisms of all drugs is impossible. This hampers the development of predictive screening models that are urgently needed to assess the immunostimulating capacity of newly developed drugs. The present review will focus on recent findings on mechanisms of drug hypersensitivity reactions obtained with murine models, and on the use of these models as potential screening tools to assess the immunostimulating capacity of drugs. RECENT FINDINGS: Mechanisms of drug-induced sensitization versus tolerance appear dependent on generally accepted immunological paradigms. For instance, co-stimulatory signaling by antigen-presenting cells is decisive in drug-induced immunosensitization and both T cells and antigen-presenting cells are important for the induction of tolerance to orally administered drugs. From recent studies it has been hypothesized that expression of stress-associated transcription factors and the expression of costimulatory molecules or cytokine production within hours or days after the initial exposure may be representative of drug-induced hypersensitivity reactions and may thus be used as predictive parameters to screen for immunosensitizing drugs. SUMMARY: The development of animal models to study mechanisms of drug hypersensitivity reactions is still in its infancy. Much effort has been made, however, to search for early indicators of immunostimulation in murine animal models that may eventually appear useful in a tiered strategy to assess drug-induced sensitization.
The drug hypersensitivity syndrome (DHS) is a drug-induced reaction of an extremely severe clinical course and serious prognosis. It poses major diagnostic problems and is frequently unrecognized by clinicians. Based on literature data, the authors have presented the information on epidemiology, etiology, pathogenesis, clinical picture, diagnostics and treatment of DHS. This is the first report in Poland concerning this clinical interdisciplinary syndrome.
Drug hypersensitivity reactions are a significant cause of iatrogenic-induced illness. (They were originally classified as type IV hypersensitivity, to describe the tuberculin skin reaction.) It now appears that the T-cell directs the entire inflammatory cascade induced by delayed drug allergy. Delayed drug hypersensitivity, usually manifested in the skin, is triggered when drug-specific CD4+ and CD8+ T cells recognize drugs through their T-cell receptors in a process that is dependent on a major histocompatibility complex. Drugs stimulate T-cell receptors by either covalently binding to peptides or using their structural features to interact via a more direct approach. Immunohistochemical and functional analysis of drug-reactive T-cell clones has shown that the phenotypic pattern of delayed drug hypersensitivity depends on the cytokine pattern induced. For example, maculo-papular exanthema may be either TH-1 or TH-2 in nature, depending on whether they are interferon- g /tumor necrosis factor- a or interleukin-4, 5 and 13 driven. Bullous reactions to drugs (i.e., Stevens-Johnson syndrome or toxic epidermal necrolysis) are characterized by widespread keratinocyte apoptosis, a consequence of high CD8+ T-cell involvement and the molecular cytotoxicity of Fas, perforin and granzyme B. Pustular exanthema reactions to medications are stimulated via the T-cell release of IL-8 and granulocyte-monocyte colony-stimulating factor (GM-CSF). With better understanding of these unique inflammatory cascades, delayed type IV hypersensitivity reactions have been re-classified into four main subtypes: IVa (TH-1/monocyte directed), IVb (TH-2/eosinophil directed), IVc (CD8+/ Fas/perforin/Granzyme B directed) and IVd (IL-8/GM-CSF/neutrophil directed). Clinically, delayed hypersensitivity eruptions are often an overlap of cytokine pathways, with one preferential reaction dominating the final picture.
Noncovalent drug presentation leads to the activation of drug-specific T cells. In some patients with hypersensitivity, such a response occurs within hours even upon the first exposure to the drug. Thus, the reaction to the drug might not be due to a classical, primary response, but rather mediated by existing, preactivated T cells that are cross specific for the drug, and have an additional (peptide) specificity as well.
Adverse drug effects on the myocardium are often classified into toxic and hypersensitivity forms of myocarditis, each with distinct histologic findings. In contrast, giant cell myocarditis (GCM) is generally not associated with adverse drug reactions and has unique histopathologic features. We report four cases of adverse drug reactions in which the histologic findings were characteristic of GCM. The clinical recognition that GCM may be a manifestation of an adverse drug reaction is important, since the prognosis and treatment of this entity may be different from that of other forms of myocarditis.