Drug Allergy Clinical and Research Program and Overview of Services Provided at VASAP

What is the mission of the drug allergy clinic?

The drug allergy clinic is a specialized service that provides expert advice on all types of immunologically mediated drug reactions (see figure 1 for classification of adverse drug reactions). A key mission of the clinic is to improve the efficacy, safety, and effectiveness of future drug therapy. Patients labeled as allergic to drugs or who have experienced one or more adverse drug reactions (ADR) associated with drugs often: 1) Receive drugs of inferior efficacy and/or significant additional side effects/toxicities; 2) do not have appropriate advice as to which drugs they can and cannot safely take in the future; 3) feel anxious or fearful of taking any drugs in the future even when there is a clear therapeutic indication.  

One of the most common types of drug allergy labels is that of penicillin allergy. Although 8% of patients engaged in medical care are labeled as penicillin-allergic, less than 1/100 in the population are truly allergic, and the clinic has a public health imperative to appropriately remove the label of penicillin allergy in these patients.

The clinic currently receives referral from the eight states neighboring Tennessee.

 

Drug Hypersensitivity Research Program

The clinic also has a significant research mission and feeds into the “Drug Hypersensitivity Research Program.” This program and its laboratory infrastructure currently consist of a cellular laboratory (MCN-A-2200) and a molecular laboratory. The focus of this program is studying the immunopathogenesis of severe T-cell-mediated hypersensitivity reactions such as Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). These drug reactions have significant short- and long-term morbidity and mortality (up to 50% in the case of TEN). Currently Vanderbilt IRB approval exists to collect and store PBMCs and DNA on patients with well-phenotyped drug reactions. In addition to studying the immunopathogenesis of these reactions, which may lead to preclinical strategies to predict and prevent these reactions in the pre-clinical phase of drug development, we are developing a number of biomarkers, in vitro and ex vivo assays that may be useful in ascertaining drug causality and in the early diagnosis of these severe T-cell-mediated reactions.

What services does the drug allergy clinic provide?

1. Consultation: Through full history and previous record review, a causality and risk assessment determines how likely it is that a specific drug has cause of ADR and the most likely ADR diagnosis. For example, for the most severe of reactions, the patient needs advice on not only future avoidance of a specific drug that may have caused the initial ADR, but also guidance as to any drugs structurally related to the implicated drug  that could be additionally harmful.

2. Testing: A variety of ancillary diagnostic procedures are offered that contribute to the causality and risk assessment and the ultimate diagnosis and recommendations given to patients regarding future drug therapy. Ultimately there are no diagnostic tests in isolation that have 100% negative predictive value; however, using combinations of testing techniques can often accomplish this (e.g., penicillin skin testing + penicillin oral challenge to “de-label” patients of penicillin allergy).​

What is the role of testing?

1. To remove the label of drug allergy where this label has been falsely applied or the drug allergy has been lost over time (e.g., penicillin allergy where 10% of patients per year can lose skin test reactivity, and only 10% of those labeled as penicillin-allergic are positive on testing).

2. To provide ancillary diagnostic information: Many times when patients are seen in clinic, details of the original reaction may be lacking, and the patient has not been seen during the acute allergic reaction. Ancillary tests that we use in clinic include: a) skin prick testing/intradermal testing (both immediate and delayed readings); b) oral challenges (usually either single-dose or 2-dose observed challenges;  c) patch testing; and d) blood tests (such as genetic testing or drug-specific cellular assays). These tests lack 100% negative predictive value; however, they often provide very useful information to establish a) the drug causing the allergic reaction; b) potential for cross-reactivity with structurally related drugs; and c) the type of immunologically mediated reaction that occurred.

What are the most common drug testing protocols used and services provided?

1. Testing for patients who have had immediate or accelerated reactions (often histories consistent with an IgE-mediated reaction – anaphylaxis, angioedema, urticarial):

  • Skin prick testing/intradermal testing with immediate readings at 15 minutes followed by single-dose oral challenge (with 2 hours of observation)
  • Single-dose oral challenge (without preceding skin testing and with 2 hours of observation) – often for lower risk reactions that are accelerated (>1 hour) and have only skin involvement
  • Two-dose oral challenge (usually 10-25% of the full challenge dose followed 1 hour later if no reaction by the regular dose followed by 2 additional hours of observation) – used for higher risk patients where it is necessary to ascertain whether the implicated drug has caused the problem
  • Examples of drugs testing: 1) penicillin + cephalosporins and other beta-lactam antibiotics; 2) fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin); 3) corticosteroids; 4) radiocontrast dyes; 5) other antibiotics (e.g., metronidazole, Bactrim); 6) biological agents; 7) heparins; 8) local anesthetics; 9) chemotherapeutic agents; 10) proton pump inhibitors

​2. ​Testing for patients with histories of delayed reactions: often consisting of a nonspecific rash or delayed urticarial rash occurring >72 hours from dosing. Some patients in this category have a history of very serious immunologically mediated drug reactions, and it is urgent for them to have an appropriate causality assessment with clear recommendations even prior to any additional testing.

  • Skin prick/intradermal testing with delayed readings generally at 24 hours from the time of application: In the setting of benign and non-serious rashes, this testing may be followed by a 5-7 day oral challenge.  For serious rashes there is never an oral challenge.
  • Patch testing with readings at 48 hours, 96 hours, and 7 days:  Wherever possible, now skin prick/intradermal testing with delayed reading at 24 hours should replace drug patch testing for 1) ease of administration and 2) convenience for patients. When this is not possible, patch testing can be utilized.
  • Blood testing: Many of these are still considered research tests, although they do provide additional diagnostic information. When we plan to do blood testing, we ask patients to consent for participation in our research study (research nurse). Examples of tests performed include genetic testing (HLA typing) and drug-specific cellular assays (ELISpot, flow cytometry, T-cell receptor sequencing).

3. Other services provided: 

  • Blinded oral/subcutaneous challenges: Many patients have reactions that are difficult to sort out. In select cases, we will move forward to n of 1 challenges of placebo double blinded challenges to sort out whether the reaction the patient has experienced is a real reaction to the implicated drug.
  • Desensitization: The preferred option for patients is definitive de-labeling such that they can receive an immediate full dose of the indicated drug. If this is not possible and either rapid (for IgE-mediated reactions) or slow reintroduction (for delayed reactions), desensitization procedures are available. We usually offer these procedures on an outpatient basis to minimize cost and inconvenience to the patient.

4. Services not currently provided onsite at VASAP:

  • Challenges to intravenous medications (in select instances this may be recommended in hospitalized patients but is not offered as part of the VASAP drug allergy clinical service)
  • Patients with reactions to aspirin and NSAIDS will be seen in clinic and given advice based on their history; however, challenges to aspirin and non-steroidal anti-inflammatory agents are not currently offered on site at VASAP as part of the drug allergy service. Reactions to these agents are often delayed and can be severe. They often require an extended period of monitoring (5 hours) beyond the 3 hours that can be offered in clinic. It is recommended that these services be provided on site at VUMC.

5. Inpatient consultation services: Consultation and advice for inpatients with drug allergies are provided in conjunction with the Allergy and Immunology service. Typically these patients are referred for follow-up in the drug allergy clinic; however, acute advice is often of utility with regards to 1) drug causality and recommended drug avoidance; 2) ancillary diagnostic tests; and 3) treatment and management of the reaction.

Examples of patient types referred to VASAP
  • Patients with severe T-cell-mediated drug reactions that require drug causality assessment and advice for future drug treatment (in vivo, in vitro testing and Bayesian causality techniques to give best advice). Counseling is an important part of this visit, as these patients have often not received detailed information about their drug reaction and the short- and long-term sequelae.
  • Patients with non-specific delayed rashes temporally associated with drugs
  • Patients with any unusual ADR or a reaction that is suspected to be an immunologically mediated ADR (e.g., hepatitis, pancreatitis, interstitial nephritis)
  • Patients with immediate reactions (e.g., anaphylaxis, urticarial, angioedema, etc.) that are temporally associated with a drug
  • Patients with a distant label of drug allergy (of any phenotype) who currently have a need for drug therapy or are at a high risk for needing drug therapy in the near future

 

Figure 1: Classification of Adverse Drug Reactions