Abdelbaset A. Elzagallaai

Patch testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review.

Anticonvulsant hypersensitivity syndrome (AHS), also known by the other names drug rash (reaction) with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS), is a rare and potentially fatal reaction that occurs in susceptible patients after exposure to certain drugs, including aromatic anticonvulsants. Because of its ill-defined clinical picture and resemblance to other diseases, the diagnosis of AHS is often difficult and requires a safe and reliable diagnostic test. The skin patch test has been proven to be very useful for prediction and diagnosis of some types of hypersensitivity reactions such as delayed drug eruptions to β-lactam antibacterials. However, the diagnostic value of patch testing for AHS is yet to be determined and its negative predictive values (NPVs) and positive predictive values (PPVs) are still unknown.This systematic review attempts to evaluate the usefulness of patch tests in the diagnosis of AHS and to examine different technical aspects of patch testing that may contribute to its performance. We included studies in which aromatic anticonvulsant drugs are the likely causes of the hypersensitivity reaction.Analysis of original publications from 1950 to August 2008 and cited in PubMed, MEDLINE and EMBASE has revealed contradictory findings, possibly due mainly to the use of unstandardized methods. Numerous factors have been suggested to affect the final result of the test, including the following: type of drug tested; concentration of drug and vehicle used; timing of the test after exposure; and the clinical picture of the reaction. The PPV of the test in optimal conditions was as high as 80–90% depending on the drug tested. On the other hand, this value is around 10–20% in many other published studies.Although patch testing may be a useful diagnostic test for AHS, accurate determination of its sensitivity and specificity is yet to be achievable due to the lack of a gold standard test against which the performance of patch testing can be measured. Its PPV appears to be higher than its NPV, a matter that necessitates the use of other confirmatory tests in case of negative patch tests (e.g. careful systemic rechallenge). The benefit of testing appears to be maximal with certain drugs (i.e. carbamazepine and phenytoin) and for specific clinical manifestations (strong reactions). It should be performed 2–6 months after recovery from the date of the ADR for best results, with adequate vehicle control.

In Vitro Testing for the Diagnosis of Anticonvulsant Hypersensitivity Syndrome

Anticonvulsant hypersensitivity syndrome (AHS) is a rare and potentially fatal reaction that develops in susceptible patients following exposure to certain drugs, including aromatic anticonvulsants. Because of its ill-defined clinical picture and resemblance to other diseases, the diagnosis of AHS is often difficult and requires a safe and reliable diagnostic test. Other than systemic rechallenge, which is not always ethically permissible and has its own limitations, no reliable diagnostic test is available for this type of disorder. This systematic review attempts to evaluate the usefulness of the available in vitro tests in the diagnosis of AHS — namely, the lymphocyte transformation test (LTT) and the lymphocyte toxicity assay (LTA) — and to examine the different technical aspects of these tests that may contribute to their performance. We included studies in which aromatic anticonvulsant drugs were the likely causes of the hypersensitivity reaction and either the LTT or the LTA was used to aid the diagnosis of AHS. Analysis of original publications from 1950 to the last week of March 2009 and cited in PubMed, MEDLINE and EMBASE has revealed that there are numerous factors affecting the final result of the test, including the following: the timing of the test after exposure; the clinical manifestation of the reactions; the specific drug; and the test procedure and read-out system. In vitro diagnostic tests have the advantage over in vivo tests of being safe to use; however, in vitro tests for the diagnosis of AHS are not well standardized and their sensitivity and specificity are not yet determined. From the reviewed literature, the sensitivity of the LTT and the LTA seem to be around 70% and 90%, respectively, and the positive and negative predictive values of the tests in highly imputable cases are quite high. However, the lack of a gold-standard diagnostic test to prove drug culpability, along with the paucity of large-scale studies, precludes accurate determination of the epidemiological characteristics of these tests. It appears that without further understanding of the mechanisms underlying the pathophysiology of AHS, and how specific drugs and metabolites differentially affect these mechanisms, the development of more reliable tools for AHS diagnosis will be compromised. Consequently, in the absence of further research, the predictability of these tests will remain questionable and they are unlikely to be utilized on a large scale.

The In Vitro Platelet Toxicity Assay (iPTA): A Novel Approach for Assessment of Drug Hypersensitivity Syndrome

A drug reactions (ADRs) account for 5% of all hospital admissions and occur in 10% to 20% of hospitalized patients. Most ADRs (85%90%) are predictable, dose dependent, and related to the pharmacological action of the drug (type A), but 10% to 15% are unpredictable, unrelated to the pharmacological action of the drug, and do not have clear dose dependency (type B). A major category of the latter type is drug hypersensitivity syndrome (DHS). DHS is a rare but potentially fatal disorder that occurs in susceptible patients following exposure to the culprit drug. It is most commonly associated with aromatic anticonvulsants (eg, phenytoin, carbamazepine, phenobarbital, and lamotrigine) and antimicrobials such as sulfonamides. It has been difficult to establish a diagnosis of DHS because of its variable clinical presentation, overlap with other clinical conditions, and the often delayed temporal relationship between administration of the culprit drug and the appearance of symptoms. Lack of a reliable and safe diagnostic test plays a major role in the significant morbidity and mortality due to drug hypersensitivity. Other than systemic rechallenge with the culprit drug, no goldstandard diagnostic test is currently available. Unfortunately, systemic rechallenge is ethically problematic. Currently available in vivo and in vitro tests are not well characterized, and their sensitivity and specificity are unknown. Attempts to develop safe and reliable in vitro diagnostic tests for DHS have been under way for decades; however, recent systematic reviews of both in vivo and in vitro diagnostic tests for DHS have documented a paucity of large-scale studies to evaluate the usefulness of these tests. The lymphocyte toxicity assay (LTA) is an in vitro diagnostic test that was developed 3 decades ago to investigate patient susceptibility to drug hypersensitivity. The usefulness of this test in diagnosing DHS is yet to be determined as its negative and positive predictive values are still unclear. The main disadvantage of this test is the lengthy and complicated method used to isolate peripheral blood lymphocytes. This involves centrifugation of diluted blood samples over a gradient of synthetic high molecular weight polymer of sucrose (Ficoll) and isolation of a narrow layer that contains lymphocytes, monocytes, and a high number of attached and cosedimented platelets. This lengthy process complicates the assay, increases its cost, and may contribute to its poor reproducibility.

Predictive Value of the Lymphocyte Toxicity Assay in the Diagnosis of Drug Hypersensitivity Syndrome

AbstractBackground: Drug hypersensitivity syndrome (DHS) is a rare but potentially fatal adverse drug reaction that develops in susceptible patients following exposure to certain drugs. Because of the variable clinical picture of DHS and its resemblance to other diseases, the diagnosis of DHS is challenging. The lymphocyte toxicity assay (LTA) is an in vitro test that has been used in the diagnosis of DHS. However, its predictive values are still controversial because of the lack of a ‘gold standard’ test to measure it against. Objectives: To determine the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the LTA in the diagnosis of DHS due to different classes of drugs, based on systemic reexposure as a gold standard, and to evaluate the current clinical utility of the LTA in clinical practice. Methods: Potential participants were identified from their medical records and contacted to obtain their consent to participate in the study. One hundred forty-seven patients were recruited and interviewed by telephone to identify events of re-exposure and their consequences. These data were used to determine true positive, false positive, true negative, and false negative results of the test, which were then used to estimate the predictive value of the test. Results: We identified 26 re-exposure events in 22 patients: 4 were true positives, 17 were true negatives, 1 was a false positive, and 4 were false negatives, as determined by systemic re-exposure. Although the number of identified re-exposures limited the ability to calculate the predictive values, our data provide an estimate of the clinical value of the test for the diagnosis of DHS. The data also highlight the effect of the type of drug involved in the reaction on the predictive value of the test. Conclusion: The LTA is potentially a valuable diagnostic tool for DHS; however, its sensitivity, specificity, NPV, and PPV seem to vary according to the drug involved in the reaction.

In vitro testing for diagnosis of idiosyncratic adverse drug reactions: Implications for pathophysiology

Idiosyncratic drug reactions (IDRs) represent a major health problem, as they are unpredictable, often severe and can be life threatening. The low incidence of IDRs makes their detection during drug development stages very difficult causing many post-marketing drug withdrawals and black box warnings. The fact that IDRs are always not predictable based on the drugs known pharmacology and have no clear dose-effect relationship with the culprit drug renders diagnosis of IDRs very challenging, if not impossible, without the aid of a reliable diagnostic test. The drug provocation test (DPT) is considered the gold standard for diagnosis of IDRs but it is not always safe to perform on patients. In vitro tests have the advantage of bearing no potential harm to patients. However, available in vitro tests are not commonly used clinically because of lack of validation and their complex and expensive procedures. This review discusses the current role of in vitro diagnostic testing for diagnosis of IDRs and gives a brief account of their technical and mechanistic aspects. Advantages, disadvantages and major challenges that prevent these tests from becoming mainstream diagnostic tools are also discussed here.

In Vitro Testing for Hypersensitivity‐Mediated Adverse Drug Reactions: Challenges and Future Directions

Drug hypersensitivity reactions (DHRs) are uncommon but potentially fatal adverse events. Their diagnosis and prediction are difficult given their variable presentation and the overlap of symptoms with those of other clinical conditions. Systemic rechallenge is considered the gold standard for the diagnosis of DHRs; however, this may have severe consequences. In vitro tests are currently not sufficiently reliable to provide the basis for clinical decisions. This article summarizes the challenges associated with in vitro testing for DHRs.

Hair cortisol analysis: An update on methodological considerations and clinical applications

BACKGROUND Hair cortisol analysis is increasingly being appreciated and applied in both research and medicine, aiding endocrinologists with diagnosis. CONTENT We provide an overview of hair cortisol research in general and an update on methodological considerations including the incorporation of cortisol into hair, hair growth rates, and sampling procedures, mincing vs. grinding of samples during preparation for extraction, various extraction protocols, and quantification techniques. We compare the clinical utility and application of hair cortisol with traditional methods of measurement while acknowledging the limitations of analysis including variations in hair growth parameters. We explore the value of hair cortisol in cases of Cushing syndrome (particularly Cyclical Cushing), Adrenal insufficiency (including Addisons disease), therapy monitoring, cardiovascular disease, stress, and mental illness. SUMMARY Hair cortisol provides a unique objective biomarker for the analysis of endogenous cortisol levels for not only clinical diagnostic purposes but also in research. The use of hair cortisol has great potential for advancing patient care.

The predictive value of the in vitro platelet toxicity assay (iPTA) for the diagnosis of hypersensitivity reactions to sulfonamides: a case-control study

Background Drug hypersensitivity reactions (DHRs) are rare but potentially fatal types of adverse drug reactions (ADRs) that develop in susceptible patients following exposure to certain drugs including sulfonamides. The diagnosis of this type of ADRs is challenging and currently depends on clinical expertise. A safe and reliable in vitro test to diagnose DHRs would be a major advance in patient care and in evaluation of possible serious ADRs during drug development and clinical trials. Current available in vitro tests including the lymphocyte toxicity assay (LTA) and the lymphocyte transformation test (LTT) are cumbersome and expensive, and their predictive values are undefined. We have recently developed a novel in vitro diagnostic test for DHRs, the in vitro platelet toxicity assay (iPTA) to test patient susceptibility to DHS. The aim of this study was to evaluate the predictive value of the iPTA in diagnosis of DHRs to sulfonamide antibiotics.