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 Biomarkers for drug hypersensitivity reactions show promise, but most require validation for clinical use, according to members of the EAACI Task Force.

Biomarkers for drug-induced immune reactions aid clinicians in diagnosing, risk-stratifying, and managing diseases. But the varied mechanisms and clinical presentations of drug hypersensitivity reactions  (DHRs) can make diagnosis and treatment challenging, and most biomarkers still require validation.

“The biomarkers of clinical utility are skin tests, specific IgE (sIgE), tryptase, and some HLA-DR genotyping. The diagnostic performance depends on the responsible drug,” lead author Cristobalina Mayorga, PhD, and fellow members of a European Academy of Allergy and Clinical Immunology (EAACI) Task Force reported in Allergy.

“The mechanisms underlying DHRs are complex and diagnosis requires a detailed in vivo and in vitro assessment on an individual basis. … Unfortunately, most biomarkers have not gone beyond analytic or clinical validity,” they added.

Biomarkers & Mechanisms

An ideal biomarker should be reliable and easily quantifiable; show quantitative demonstrable differences; correlate with a relevant clinical outcome; be consistent, fast, and economical; and increase treatment success, according to Dr. Mayorga and colleagues.

In their position paper, they outlined the mechanisms involved in DHRs and the most suitable biomarkers associated with each mechanism. They also described the biomarker qualification process.

The researchers explained the connections between various endotypes and biomarkers in immediate and delayed DHRs. They provided a comprehensive table, listing each specific biomarker, its relationship with phenotypes and endotypes, level of evidence, development stage, technical feasibility, and other key biomarker characteristics.

They noted that viral infections can exacerbate or trigger various DHRs through molecular mechanisms such as virally induced immune activation, molecular mimicry, viral modulation of drug metabolism, immune response, or enhanced drug uptake by infected cells, and that DHRs can lead to viral reactivation.

Biomarker Approval Workflow

The researchers listed the four workflow phases involved in biomarker development and approval as required by regulations in Europe and the United States:

1. Discovery: Large studies to identify and characterize candidate biomarkers
2. Analytic Validity: Case-control studies to evaluate a biomarker’s accuracy, precision, and reproducibility
3. Clinical Validity: Prospective studies to identify the feature of a disease or treatment outcome with data on sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios
4. Clinical Utility: Multicenter studies to provide benefit and risk ratio data on disease diagnosis, treatment, management, or prevention to determine how well a test balances benefits and harms.

Biomarker Qualification Steps

After advancing through these workflow states, each biomarker undergoes several additional qualification steps. The biomarker’s potential benefits and risks are evaluated along with the existing evidence that supports its context of use, any knowledge gaps, and how those gaps will be addressed. The measurement method is described.

The feasibility of and risks associated with the measurement are evaluated, as is the relationship of the measurement to the disease or population to be treated. If known, the rationale for using the biomarker is evaluated. Assay considerations include analytical validation and understanding of potential sources of measurement variability.

Advancing the Validation Process

Identifying biomarkers is difficult, the researchers said, for the following reasons: (1) different endotypes have similar clinical features; (2) to date, some endotypes with different mechanisms are diagnosed based on exclusion; (3) one drug might be associated with multiple coexisting endotypes; and (4) some identified biomarkers, such as tryptase, are not widely available.

“It is therefore important to set up multicentre translational studies to advance the validation process towards reaching a clinical utility phase,” the Task Force concluded.