International Consensus on drug allergy Demoly, P.; Adkinson, N. F.; Brockow, K. ...
Allergy,
April 2014, Letnik:
69, Številka:
4
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DHRs) before showing the evidence of either drug‐specific antibodies or T cells. DHRs may be allergic or ...nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life‐threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under‐reporting) and overdiagnosis (due to an overuse of the term ‘allergy’) are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more‐expensive or less‐effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class‐induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the World Allergy Organization (WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of DHRs.
Background
Drug‐induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS) and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) represent ...contrasting poles of severe drug eruptions, and sequential reactivations of several herpesviruses have exclusively been demonstrated in the former. No previous studies, however, were extended beyond the acute stage. We sought to investigate whether herpesvirus reactivations could also be observed in SJS/TEN and beyond the acute stage of both diseases.
Methods
Patients with SJS (n = 16), SJS/TEN overlap (n = 2), TEN (n = 10), and DIHS/DRESS (n = 34) were enrolled. We performed a retrospective analysis of Epstein–Barr virus (EBV), human herpesvirus 6 (HHV‐6), and cytomegalovirus (CMV) DNA loads sequentially determined by real‐time polymerase chain reaction during a 2‐year period after onset.
Results
Persistently increased EBV loads were detected in SJS during the acute stage and long after resolution, but not in others. In contrast, high HHV‐6 loads were exclusively detected in DIHS/DRESS during the acute stage. The dynamics of herpesvirus reactivation varied in DIHS/DRESS according to the use of systemic corticosteroids: While EBV loads were higher in patients not receiving systemic corticosteroids, CMV and HHV‐6 loads were higher in those receiving them.
Conclusions
Distinct patterns of herpesvirus reactivation according to the pathological phenotype and to the use of systemic corticosteroids were observed during the acute stage and follow‐up period, which may contribute, at least in part, to the difference in the clinical manifestations and long‐term outcomes. Systemic corticosteroids during the acute stage may improve the outcomes in DIHS/DRESS.
•CMV reactivation in immunosuppressive settings is associated with fatal outcomes.•CMV reactivation is associated with fatal complications in severe drug reactions.•Monocyte-derived cytokines and ...Tregs are useful biomarkers for CMV reactivation.•Increased biomarker levels at baseline are blunted by systemic corticosteroids.•CMV reactivation can be predictable and preventable by using our algorithm.
Cytomegalovirus (CMV) reactivation in patients with severe drug eruption on immunosuppressive therapy often leads to fulminant disease and even mortality, yet there are no biomarkers to accurately predict CMV reactivation either before or after immunosuppressive therapy. We aimed to assess whether patients who develop CMV reactivation (CMV-positive cases) have distinct immunological profiles from CMV-negative cases before and after immunosuppressive therapy.
We performed serial cytokine/chemokine and regulatory T cells (Tregs) assessments of 45 patients with drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic syndrome (DRESS) during a follow-up period of nearly three years after onset.
Elevated IL-8, IL-10, IL-12p40, IL-15, TNF-α, G-CSF, and MIP-1α levels at baseline were associated with later development of CMV reactivation, while after starting treatment, IL-10 and IL-15 levels were associated with the onset of CMV reactivation; the use of corticosteroids obscured the large differences in these cytokines at baseline. CMV-positive cases were found to have normal Tregs frequencies at baseline, while negative cases had elevated frequencies. Higher eotaxin, IL-10, and G-CSF levels and lower IL-12p40 levels at baseline might be used for predicting the development of lethal CMV disease.
The algorithm based on these results showed an accurate association with CMV reactivation.
Lymphocyte transformation test (LTT) is a safety and reproducible test to assess activation of drug-specific T cells in vitro; however, there are several practical concerns such as the time of ...testing and the influence of treatment. Our aim was to define the right timing to perform LTT for determining the causative agent in various types of drug reactions. Lymphocyte transformation test was performed at different time points during the evolution of three types of drug reactions, maculo-papular type of drug eruptions (MP), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug-induced hypersensitivity syndrome/drug rash and eosinophilia with systemic symptoms (DIHS/DRESS). Positive LTT reactions were obtained when the test was performed at the acute stage but not the recovery stage in MP and SJS/TEN, while positive LTT reactions were obtained at the recovery stage but not the acute stage in DIHS/DRESS, regardless of treatment with systemic prednisolone. Lymphocyte transformation test is a reliable method to define the causative agent, when LTT is performed at the right timing depending on the type of drug reactions. Lymphocyte transformation test should be performed within 1 week after the onset of skin rashes in patients with MP and SJS/TEN; and 5-8 weeks after in patients with DIHS/DRESS, respectively.
Summary
Background Drug‐induced hypersensitivity syndrome (DIHS) is a severe multiorgan systemic reaction. Numerous studies have linked reactivation of human herpesvirus (HHV)‐6 with the development ...of DIHS. Recent articles have suggested that reactivation of other herpesviruses besides HHV‐6 might also be involved in the development of DIHS. On the other hand, recent studies have provided evidence for a role of reactivation of various herpesviruses in the development of graft‐versus‐host disease (GVHD).
Objectives We attempted to determine whether sequential herpesvirus reactivation could be detected in four patients with severe DIHS, as observed in patients with GVHD, and be coincident with various clinical manifestations that developed after discontinuation of the causative drugs.
Methods Detection and quantification of viral DNA cytomegalovirus (CMV), Epstein–Barr virus (EBV), HHV‐6 and HHV‐7 in sequential blood samples were performed using real‐time polymerase chain reaction assays, based on TaqMan technology.
Results In these patients, the cascade of virus reactivation initiated by HHV‐6 or EBV extended to EBV or HHV‐7, and eventually to CMV. Clinical manifestations of this syndrome followed by failure of various organs occurring despite discontinuation of the drug were coincident with these herpesvirus reactivations.
Conclusions These results suggest that various herpesviruses can reactivate in the setting of severe drug reactions in a similar sequential order to that described in GVHD. The sequential reactivation of these herpesviruses is responsible for the development of multiorgan failure occurring after discontinuation of the causative drug.
Summary
Background
Although infectious agents have long been implicated in the induction or exacerbation of pemphigus vulgaris (PV), a convincing role for the agent in the aetiology of PV has not ...been established.
Objectives
To establish the association with PV and herpes simplex virus (HSV).
Patients and methods
We examined saliva for the presence of HSV DNA after the onset of PV initially localized to the oral lesions in addition to conventional serological tests and immunohistochemistry.
Results
We successfully detected high levels of HSV DNA in the saliva samples from six of 16 patients with PV at the earliest stage, who had no episodes of herpes simplex. The prevalence (37·5%) of detecting HSV DNA in the patients with PV was lower than that of eczema herpeticum (56·5%), but comparable to that in patients with herpes labialis (30·0%). Copy numbers of the HSV DNA were rather higher than those with herpes labialis and with eczema herpeticum. In general, detection of HSV DNA in saliva was transient and restricted to the earliest phase of the disease. In addition, anti‐HSV immunoglobulin (Ig) G titres in patients with PV were significantly higher than those in patients with virologically confirmed HSV‐induced disorders. All salivary HSV DNA‐positive patients with PV had run a more complex, intractable course refractory to conventional therapy.
Conclusions
Detection of HSV DNA in saliva is a useful and noninvasive, quantitative method for establishing the role of HSV in the pathogenesis of PV and for identifying individuals at greater risk for subsequently developing refractory PV.
What's already known about this topic?
Although infectious agents have long been implicated in the induction or exacerbation of pemphigus vulgaris (PV), a convincing role for the agent in the aetiology of PV has not been established.
What does this study add?
We successfully detected high levels of herpes simplex virus (HSV) DNA in the saliva samples from six of 16 patients with PV at the earliest stage, who had no episodes of herpes simplex.
These patients with PV have run a more complex, intractable course refractory to conventional therapy.
Detection of HSV DNA in saliva will alert physicians to the possibility of greater risk of subsequently developing refractory PV.
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