Drug Allergy Assessment and Management

Timothy J. Sullivan, M.D.

Diagnosis

History & Physical Skin tests Laboratory tests

Challenges Treating through Acute Desensitization Slow Desensitization

May 5, 2012

Timothy J. Sullivan, M.D.

Drug Hypersensitivity

Disclosures: No relevant issues Genentech, Novartis, Baxter

ACAAI 2011

What do patients (and their doctors) want to know about drug allergy?

What am I allergic to? What drugs can I safely use?

What are the Goals for the Allergy & Immunology Specialist

What drugs have been associated with what kinds of problems Current drug allergy status Patient education and establishment of rapport Plans for alternative medications, when to treat through, when or if desensitization would be appropriate

Clinical Assessment

Nature of the reaction allergic? Exposures drugs, latex Temporal relationships Propensity of drugs to cause reactions Prior drug allergy history Family history of drug allergy Effect of drug withdrawal or re-exposure Immunodiagnostic tests

Antigen Generating Tissues

Hepatocytes Keratinocytes

Skin Tests for Specific IgE

Immunodiagnostic Tests

IgE to medications

Epicutaneous & ID skin tests In vitro tests for specific IgE

T-cells reactive with drug determinants

Patch tests Intradermal tests In vitro tests for lymphocyte reactivity

Skin Tests for IgE to Medications

Nature of the antigen

Complete antigen - e.g. insulin Direct hapten e.g. amoxicillin Haptenation by a drug metabolite e.g. sulfamethoxazole 10-fold dilution from irritant threshold used for highest ID dose

Irritant threshold

Skin Tests for IgE to Medications

Criteria for positive test for IgE to a penicillin drug determinant The wheal at the end of the period of observation is at least 2 or 3 mm greater in diameter than the initial wheal. Criteria for positive test may differ by drug and by investigator

Maximum Concentrations for ID Skin Testing with Drugs

Imipenem Penicillins Cephalosporins Aminoglycosides Vancomycin Cipro Insulin 1 mg/mL 3 mg/mL 3 mg/mL 1 mg/mL 0.005 mg/mL 0.01 mg/mL 100 u/mL

Brandt 1993. JACI 91:263

Maximum Concentrations for ID Skin Testing with Drugs

Clindamycin 15 mg/Ml Trimethoprim/SMX 0.8 mg/mL Levofloxacin 0.025 mg/mL Erythromycin 0.05 mg/mL Azithromycin 0.01 mg/mL

Empredrad 2003. JACI 112:629-30

Maximum Concentrations for ID Skin Testing with Drugs

Drug

Nonirritating Concentration

Cefotaxime Cefuroxime

10 mg/mL 10 mg/mL 33 mg/mL 10 mg/mL 10 mg/mL 0.8 mg/mL 0.025 mg/mL

Cefazolin

Ceftazidime Ceftriaxone Cotrimazole

Nafcillin

Drug Allergy Practice Parameter. 2010. Ann Allergy 273.e51

Elective Penicillin Skin Testing

Penicillin G generates the major determinant and many minor determinants, but alone detects only ~50% of penicillin allergic patients PrePen & penicillin G skin tests will detect ~93% of penicillin allergic patients Additional minor determinant precursors are needed to detect the remaining penicillin allergic patients
Google Elective Penicillin Skin Testing

Cap Assays for IgE to Drugs

Ampicillin Cephalosporin Erythromycin Penicillin G Penicillin V Sulfamethoxazole

Anesthesia & Drug Hypersensitivity

Obtain the anesthesiologists name and record Obtain hospital records Compile a list of exposures Write prescriptions for the drugs needed for testing Test with standard concentrations of the drugs

Levy JH 1992. Anaphylactic reactions in anesthesia & critical care. Butterworth-Heinemann, Boston, 2nd edition, p129.

Do not forget about latex allergy

Maculopapular rashes

Relatively non-pruritic Resolve without residual damage Benign Drug associated may be specific lymphocyte mediated

DTH and Beta-Lactam Drugs

Maculopapular rashes Negative skin and in vitro tests for specific IgE Positive patch and ID skin tests read at 48 and 72 hours Positive oral challenges in patch test positives, not in negative controls
Patriarca et. al. Ann Allergy Asthma Immunol 1999;83:257-266.

Maculopapular Rashes and DTH

Patch tests often positive in drug associated cases Intradermal tests read at 48 to 72 hours just as good as patch tests and easier for A&I physicians to perform Positive test indicates presence of DTH. Much left to learn about interpretation of clinical implications.

Diagnosing Nonimmediate Reactions to Cephalosporins

105 patients with non-immediate reactions associated with cephalosporins. Patch tests (5% in petrolatum) and Intradermal skin tests (read at 48 & 72 hours) with diverse penicillins and cephalosporins ID tests more sensitive than Patch tests
Romano A, et. al. JACI 2012;129:1166-1169. Schnyder B, et. al. JACI 2012;129:1170-1171.

Diagnosing Nonimmediate Reactions to Cephalosporins

86 test negative patients challenged with suspected cephalosporin. All challenges were negative.

Romano A, et. al. JACI 2012;129:1166-1169. Schnyder B, et. al. JACI 2012;129:1170-1171.

Onset of Allergic Drug Reactions

Previously Sensitized or Unsensitized
18 16 14 12 10 8 6 4 2 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Onset

Graded Drug Challenges

When you do NOT think the problem is allergic, but the patient, family, other physicians think the patient is allergic Must be careful not to desensitize and then be misled by absence of reaction If you think allergy is a significant possibility, test or desensitize, or risk an avoidable tragedy.

Diagnosis of Drug Allergy

Complete epidemiologic history essential Ad hoc skin test procedures In vitro assays for some relevant antigens

Management of Drug Allergy

Avoidance, Premedication, Drug challenges, Treating through reactions, Acute Desensitization, Slow desensitization, Treatment of reactions

Opiate Sensitivity

When feasible use non-opiate medications or approaches to pain control When feasible use PCA pumps for opiate administration When feasible use fentanyl Diphenhydramine 1 mg/kg q4-6h. Possibly H2 and LT receptor antagonists Peripheral opiate receptor antagonists such as alvimopan (Entereg) P.O. or parenteral methylnaltrexone (Relistor) may be beneficial without interfering with central pain control

Tharp MD, Kagey-Sabotka A, Fox CC, Maroni G, Lichtenstein LM, Sullivan TJ. Functional heterogeneity of human mast cells from different anatomical sites: in vitro responses to morphine sulfate. JACI 1987;79:646-652.

Treating Through Reactions

In some instances continuing therapy is the best decision Urticarial reactions occurring greater than ~24 hours after the beginning of therapy will not progress to anaphylaxis Direct observation is necessary to assess and plan suppressive therapy

Acute Desensitization
Indications

Immediate (IgE) hypersensitivity

Not pseudoallergic reactions

Significant illness Best course of action Any class of medication, hapten generating or complete antigens, can be used

Imprimatur
Desensitization for drug hypersensitivity
(Now 814 citations, 20 years after CDC endorsement of desensitization for IgE sensitivity)

safe readministration of many if not most drugs associated with previous hypersensitivity reactions is not only possible but highly likely with experienced and qualified oversight by an allergyimmunology specialist.
Adkinson NF Jr. JACI September 2008. 122:581-2.

Imprimatur
Rapid desensitization should be implemented as standard of care because of their high success rates and outcomesdemonstrated safety profile. Castells, M. Rapid desensitization for hypersensitivity reactions to medications. Immunology & Allergy Clinics of America. 2009. 29(3):585-606. (Review with 97 references)

Imprimatur

Drug Allergy: An Updated Practice Parameter. Annals of Allergy, Asthma &

Immunology 2010. 105 (October): e273-e278.

Desensitization: Induction of Tolerance

Definitions matter Factor VIII tolerance induction vs. effector cell desensitization or modified drug metabolism

Immunologic Tolerance

Acquired or induced tolerance refers to the immune system's adaptation to external antigen characterized by a specific non-reactivity of the lymphoid tissues to a given antigen that in other circumstances would likely induce cell-mediated or humoral immunity.

Acute Desensitization
Begin ~10 g, doubling doses

~4 hours

Acute Desensitization
Mast Cell

Mediators

Mast Cell

Acute Desensitization Skin Test Responses

Wheal (mm)

Complications of Desensitization

Patient with acute urticaria associated with fluconazole, on two separate occasions Rapid desensitization to fluconazole performed 6 different times Began with 20 g dose Increased by doubling q15min to a full dose within 4 hours

Randolph C, et.al. 2008 Ann Allergy Asthma Immunol 100:616-7.

Complications of Desensitization

On one occasion she had transient urticaria 2 hours after desensitization 4 hours after the 5th desensitization she developed a circular, macular, pruritic, generalized rash that became vesicular. Resolved with prednisone and diphenhydramine therapy and did not progress over 2 weeks of fluconazole therapy 5 months later developed a maculopapular vesicular rash after desensitization that responded to prednisone therapy

Randolph C, et.al. 2008 Ann Allergy Asthma Immunol 100:616-7.

Complications of Desensitization

Chemotherapy drug hypersensitivity 12 step IV or IP rapid desensitization with anti H1, H2; lorazepam, dexamethasone premedication

88% skin test positive 98 patients, 413 desensitizations Mild reactions in 111 (27%) - cutaneous Severe reactions in 24 (6%) - multisystem

First dose reactions common indicating pseudoallergic as well as allergic problems

Castells MC, et.al. JACI September 2008. 122:574-580.

Acute Desensitization

Antigen-specific mast cell desensitization can be achieved by any form of antigen Antigen presented to mast cells in a manner that allows cell control systems to extinguish or minimize responses to specific IgE Depends upon the continuous presence of antigen Anaphylactic sensitivity can return within 48 hours after discontinuation of the drug.

Acute Desensitization Complications

(PCN - 287 patients)

Anaphylaxis Urticaria

None ~30%
2% 28%

Early Late

Angioedema Serum sickness Cytopenia

None <2% <1%

Slow Desensitization
Begin ~10 g, doubling

Days

Full dose administration

Slow Desensitization Gradually increasing drug levels

Little or no haptenation occurs

Slow Desensitization
Complications

In approximately 85%, no immediate or later reactions In the remainder, reactions occur despite the procedure In some cases reactions can be suppressed with anti-inflammatory medications

Slow Desensitization Pitfalls

-lactam drug example

No drug metabolism involved, should not work

Insulin example

A complete antigen, should not work

Practical problems of outpatient desensitization

Doses under observation Follow-up after desensitization

Protocols for drug allergy desensitization

Go to Google or Bing or other search engine

Search scribd.com/timothy sullivan md Click on the Scribd.com citation you want

Or go to Scribd.com

Search Protocols for drug allergy desensitization

Or go to Google and search Protocols for drug allergy desensitization Several dozen sample protocols for rapid or slow desensitization

Protocols for drug allergy desensitization

Protocols for desensitization for >40 common and some unusual medications

Download all or copy specific protocols >20,000 reads (US, Australia, Iran, Canada, UK, Turkey most frequent visitors)

All of the protocols have been used successfully Address the practical aspects of desensitization
Scribd.com/timothy sullivan md

Drug Allergy Syndromes

Many specific syndromes reviewed in practice parameter on JCAAI site: http://www.allergyparameters.org/file_depot/0-1

Drug Allergy Syndromes

Multiple drug allergy syndrome

Propensity to have allergic reactions to medications ~10-fold more often than the general population. HIV + patients ~20fold higher incidence of allergic reactions to medications. 4 to 15-fold increased prevalence if a family member is affected

Familial drug allergy syndrome

Drug Hypersensitivity and the Allergy & Immunology Physician

Accurate Diagnosis Avoidance Treating through Acute desensitization Slow desensitization Therapy of drug reactions