Severe Delayed Drug Reactions: Role of Genetics and Viral Infections.
ABSTRACT: Adverse drug reactions (ADRs) are a significant source of patient morbidity and mortality and represent a major burden to health care systems and drug development. Up to 50% of such reactions are preventable. Although many ADRs can be predicted based on the on-target pharmacologic activity, ADRs arising from drug interactions with off-target receptors are recognized. Off-target ADRs include the immune-mediated ADRs (IM-ADRs) and pharmacologic drug effects. In this review, we discuss what is known about the immunogenetics and pathogenesis of IM-ADRs and the hypothesized role of heterologous immunity in the development of IM-ADRs.
Project description:Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose-dependent. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug's interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast, off-target ADRs, including immune-mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B-cell-mediated (Gell-Coombs type I-III reactions) and T-cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life-threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms and drug-induced liver disease. T-cell-mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which are in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.
Project description:Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell-mediated ADRs.
Project description:Off-target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drug's therapeutic effect. Off-target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off-target drug-induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune-mediated (IM)-ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM-ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.
Project description:Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.
Project description:Adverse drug reactions (ADRs) are commonplace and occur when a drug binds to its intended pharmacologic target (type A ADR) or an unintended target (type B ADR). Immunologically mediated type B ADRs, such as drug hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms syndrome, and Stevens-Johnson syndrome/toxic epidermal necrolysis, can be severe and result in a diverse set of clinical manifestations that include fever and rash, as well as multiple organ failure (liver, kidney, lungs, and/or heart) in the case of drug hypersensitivity syndrome. There is increasing evidence that specific HLA alleles influence the risk of drug reactions. Several features of T cell-mediated ADRs are strikingly similar to those displayed by patients with autoimmune diseases like type I diabetes, such as strong HLA association, organ-specific adaptive immune responses, viral involvement, and activation of innate immunity. There is a need to better predict patient populations at risk for immunologically mediated type B ADRs. Because methods to predict type 1 diabetes by using genetic and immunologic biomarkers have been developed to a high level of accuracy (predicting 100% of subjects likely to progress), new research strategies based on these methods might also improve the ability to predict drug hypersensitivity.
Project description:Medication errors are the second most common cause of adverse patient safety incidents and the single most common preventable cause of adverse events in medical practice. Given the high human fatalities and financial burden of medication errors for healthcare systems worldwide, reducing their occurrence is a global priority. Therefore, appropriate policies to reduce medication errors, using national data and valid statistics are required. The primary objective of this study was to provide a national 'characteristic profile' of medication error-associated adverse drug reactions (ADRs), which are also known as preventable ADRs (pADRs). A retrospective study of pADR reports submitted to the national pharmacovigilance center (PCV) within Iran's Food and Drug Administration was conducted over a 2-year period (2015-2017). Preventability Method (P-Method), which is a standardized tool developed and recommended by the World Health Organization (WHO), was used for preventability assessment. The results of the analyses revealed that while the number of pADRs increased from year one to two (601 to 630), their proportion out of all ADRs per year decreased (7.32% to 6.44%). The percentage of pADRs was higher in females (61.01%) and adults (83.27%), and the highest number of reports were received by nurses (71.57%). Having 'a documented hypersensitivity to an administered drug or drug class' was the most common preventable factor in both years (61.23% and 54.29% respectively), and 'anti-infectives used systemically' were the medication class which primarily contributed to both serious (53.29%) and non-serious pADRs (39.19%). The specific characteristics of medication errors associated with ADRs from this study, especially the preventable criteria which led to their occurrence, can help devise more specific preventative policies.
Project description:ADRs are immune mediated skin reactions of diverse severity and etiology. The patho-mechanisms are however not well understood. We used a gene expression array for the comparison of the gene expression profile of 2 cutaneous adverse drug reactions (MPR and AGEP) to normal skin. Overall design: Total RNA was extracted from 6 mm skin biopsies and subjected to Affymetrix gene expression profiling.
Project description:BACKGROUND:The high HIV prevalence in South Africa may potentially be shaping the local adverse drug reaction (ADR) burden. We aimed to describe the prevalence and characteristics of serious ADRs at admission, and during admission, to two South African children's hospitals. METHODS:We reviewed the folders of children admitted over sequential 30-day periods in 2015 to the medical wards and intensive care units of each hospital. We identified potential ADRs using a trigger tool developed for this study. A multidisciplinary team assessed ADR causality, type, seriousness, and preventability through consensus discussion. We used multivariate logistic regression to explore associations with serious ADRs. RESULTS:Among 1050 patients (median age 11?months, 56% male, 2.8% HIV-infected) with 1106 admissions we found 40 serious ADRs (3.8 per 100 drug-exposed admissions), including 9/40 (23%) preventable serious ADRs, and 8/40 (20%) fatal or near-fatal serious ADRs. Antibacterials, corticosteroids, psycholeptics, immunosuppressants, and antivirals were the most commonly implicated drug classes. Preterm neonates and children in middle childhood (6 to 11?years) were at increased risk of serious ADRs compared to infants (under 1?year) and term neonates: adjusted odds ratio (aOR) 5.97 (95% confidence interval 1.30 to 27.3) and aOR 3.63 (1.24 to 10.6) respectively. Other risk factors for serious ADRs were HIV infection (aOR 3.87 (1.14 to 13.2) versus HIV-negative) and increasing drug count (aOR 1.08 (1.04 to 1.12) per additional drug). CONCLUSIONS:Serious ADR prevalence in our survey was similar to the prevalence found elsewhere. In our setting, serious ADRs were associated with HIV-infection and the antiviral drug class was one of the most commonly implicated. Similar to other sub-Saharan African studies, a large proportion of serious ADRs were fatal or near-fatal. Many serious ADRs were preventable.
Project description:A prospective Drug Utilization Review (DUR) program has been implemented in Korea to improve the quality and safety of medication use.To evaluate the influence of the DUR program in reducing incidence of preventable adverse drug reactions (pADRs).This study was performed using administrative data from the Health Insurance Review and Assessment Service (HIRA). The claims data for all adult patients with adverse drug events (ADE)-related diagnoses from 2009 to 2014 were obtained. Incidence rates of first-time and repeat pADRs prior to and after DUR program implementation were evaluated. Quarterly trends in incidence rates of overall ADE, allergic reactions, and ADRs were analyzed.Data extraction covering the period from 2009 to 2014 led to the identification of 3,927,662 records. First-time pADR rates decreased gradually after implementation of the DUR program (change in slope: -0.016, p = 0.02). The program had a similar influence on repeat pADR rates (change in slope: -0.006, p?0.01). The program did not decrease rates of first-time or repeat allergic reactions (change in slope: 0.018, p = 0.07 and 0.003, p = 0.04, respectively). In the cohort aged ?65 years, first-time pADR rate reduction was significant (28.2% [27.1-29.3] in ?18 years, and 19.8% [18.1-21.5] in 19-64 years). In contrast, first-time pADR rate was increased by 0.6% [-0.7-1.9] in patients ?65 years.Implementation of the prospective DUR program effectively reduced the number of pADRs. In the future, to reduce non-preventable ADRs such as allergic reactions, provision of clinical information including allergy history should be added to the DUR program.
Project description:OBJECTIVES:Few studies have investigated the prevalence of adverse drug reactions (ADRs) leading to hospitalisation in Japan. The aim of this study was to determine the prevalence of ADRs leading to hospitalisation and to evaluate the preventability of these ADRs in Japan. DESIGN:A single-centre cross-sectional study using electronic medical records. SETTING:Acute care hospital. PARTICIPANTS:All 1545 consecutive hospital admissions to an internal medicine ward due to acute medical illnesses from April 2017 to May 2018. The median patient age was 79 years (IQR 66-87), and the proportion of women was 47.9%. OUTCOME MEASURES:The primary outcome was the proportion of hospitalisations caused by ADRs among all hospitalisations. All suspected cases of ADRs were independently evaluated by two reviewers, and disagreements were resolved by discussion. The causality assessment for ADRs was performed by using the WHO-Uppsala Monitoring Committee criteria. The contribution of ADRs to hospitalisation and their preventability were evaluated based on the Hallas criteria. RESULTS:Of the 1545 hospitalisations, 153 hospitalisations (9.9%, 95% CI 8.4% to 11.4%) were caused by 200 ADRs. Cardiovascular agents (n=46, 23.0%), antithrombic agents (n=33, 16.5%), psychotropic agents (n=29, 14.5%) and non-steroidal anti-inflammatory drugs (n=24, 12.0%) accounted for approximately two-thirds of all ADRs leading to hospitalisation. Of 153 hospitalisations caused by ADRs, 102 (66.7%) were judged to be preventable. CONCLUSIONS:Similar to other countries, one in every ten hospitalisations is caused by ADRs according to data from an internal medicine ward of a Japanese hospital. Most of these hospitalisations are preventable. Some efforts to minimise hospitalisations caused by ADRs are needed.