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Allergic reactions to therapeutic drugs.

Adverse drug reactions (ADRs) are defined as any unintended noxious or deleterious effect from the administration of a therapeutic drug at doses appropriate for standard therapy. These adverse reactions are common and often have an important impact on determining the safety and efficacy of pharmacologic agents. (1), (2), (3) Such reactions account for 5% of hospital admissions and occur in 10% to 20% of hospitalized patients. (4) This relatively high incident rate, coupled with current limited clinical-laboratory testing available for ADRs, has spawned significant interest and focus in actively researching new testing approaches.

It is important to recognize that not all ADRs are allergy related. The spectrum of adverse reactions to drugs includes both immune and non-immune pathological mechanisms as indicated in Table 1. The term drug allergy should be limited to those ADRs where an immune mechanism has been clearly demonstrated. Immune-based ADRs also are variable with respect to symptom and mechanism of action. The Gell-Coombs classification system describes these types of immune mechanisms of tissue injury (see Table 3).
Table 1. Adverse drug reactions (ADRs)

Immune mediated (true              Non-immue reactions
allergy)

Type I (lgE)                 Pseudo-allergic  Pharmacologic (toxic)
                                              reactions

Type II (lgG)                (Anaphylactoid)  Dose effect

Type III (Immune complexes)                   Multiple drug
                                              interactions

Type IV (T Cells)                             Genetic variation

Table 3. Gell-Coombs classification system

GELL-COOMBS       TYPE OF       IMMUNOPATHOLOGICAL      POSSIBLE
CLASSICIFICATION  RESPONSE      MECHANISM               TESTING

Type I            IgE-Mediated  Mast Cell/Basophil      Basophil
                                Degranulation           Histamine
                                                        Release
                                                        Leukotriene

Type II           IgG Response  FcR Dependent Cell      Drug-Specific
                                Destruction             IgG

Type III          IgG/IgM       Immune Complex          Drug-Specific
                                Deposition              IgG

Type IV           T Cell (Th1)  Monocyte                T Cell
                                Activation-IFN-[gamma]  Activation

                  T Cell (Th2)  Eosinophilic
                                Inflammation (IL5,
                                IL4)

                  T Cell (CTL)  CD4/CD8 -
                                Perforin/Granzyme B

                  T Cells       Neutrophil Recruitment
                                (IL8)


[ILLUSTRATION OMITTED]

Type I (IgE mediated) allergic reactions are of primary concern and most studied, since these reactions may lead to anaphylaxis, a life-threatening condition. One of the best-studied examples is penicillin allergy, which causes significant morbidity and mortality. Penicillin molecules are capable of combining directly with proteins in the body and stimulating immune cells. Once the person has been sensitized and has had time to produce IgE, the next administration of penicillin may activate the primed mast cells and basophils, and lead to the systemic release of histamine and other mediators (e.g., mast cell tryptase, leukotrienes--see Figure 1). To help confirm a presumptive diagnosis of allergy, clinical laboratories can provide tests for drug-specific IgE, including penicillin.

[FIGURE 1 OMITTED]

Penicillin allergy is an interesting case since it is capable of eliciting both Type) and IV Gell-Coombs hypersensitivities. (5) Type IV hypersensitivities are delayed and may occur after the patient has been taking the drug for multiple days. Type IV reactions are mediated by drug-specific T cells. Symptoms of Type IV reactions are generally cutaneous or skin-related in nature, with eczema and rashes as the typical clinical presentation. These patients may not demonstrate any Type I reactions.

Although many patients will report to their physicians that they have a drug allergy, this diagnosis will be incorrect in many cases. It is problematic to rely solely on the patient's clinical history, since some ADRs may mimic allergic type reactions. These pseudoallergic (i.e., "anaphalactoid") reactions may be caused by direct effects of the drug on immune cells but are not the result of immune sensitization. Causes of pseudoallergic reactions commonly include opiates, aspirin, nonsteriodal anti-inflammatory drugs, and radiocontrast media. In addition, patients may have a rash or other inflammatory symptom caused by a coexisting medical condition, such as a viral infection, that may incorrectly be attributed to an adverse drug reaction or drug allergy. Of course, any ADR is clinically important and should be evaluated, whatever the actual mechanism.
Table 2. Examples of some biotherapeutic drugs with reported ADRs

Drug names           Class of biological  Clinical use

Cetuximab (Erbitux)  Monoclonal antibody  Cancer

Rituximab (Rituxan)  Monoclonal antibody  Lymphoma, rheumatoid
                                          arthritis

Interferon beta-1 a  Cytokine             Multiple sclerosis
(Avonex)

Etanercept (Enbrel)  Receptor             Rheumatoid arthritis

* Giezen TJ, Mantel-Teeuwisse AK, et al. Safety-Related Regulatory
Actions for Biologicals Approved in the United States and the European
Union. JAMA, 2008; 300(16):1891.


Correctly making a drug allergy diagnosis is further complicated if the drug must undergo some bioactive transformation before it can be immunogenic and stimulate the immune system. Most small molecule drugs are not immunogenic in their native state and must be coupled in vivo to a protein in the body before they can activate the immune system. For example, the sulfa drugs are believed to require the formation of a sulfonamide-protein complex before sensitization can occur. In this case, the sulfa drug must be converted by liver enzymes to a reactive molecule that can link to proteins in the body to be of sufficient size to effectively stimulate immune cells. Finally, it also is possible that the patient's adverse reaction is due to an additive or excipient in the final drug formulation, such as gelatin, rather than the drug itself. Such sensitivities can be difficult to sort out.

New biological drugs present unique challenges

Allergic reactions to new biotherapeutics, such as monoclonal antibody drugs, are being increasingly reported. (6) These biologically-derived drugs, especially monoclonal antibodies, are an important class of new drugs that have provided many new options for cancer treatment and other difficult-to-treat diseases. While the incidence of ADRs is low in most new biotherapeutic drugs, these monoclonal antibody drugs consist of large glycoprotein molecules; therefore, they have the potential for stimulating the immune system. The table "Examples of some biotherapeutic drugs with reported ADRS" lists examples of several important biological drugs for which the U.S. Food and Drug Administration (FDA) has required the manufacturers to provide a specific warning in the labeling because of reported ADRs.

It is important to recognize that most new biotherapeutic drugs provide great benefit to the patient. The incidence of ADRs is low but the severity of the reaction can be life threatening. Therefore, drug developers continue to develop improved methods to reduce the immunogenicity of this important new class of drugs.

In addition to the risk of anaphylaxis from drug-specific IgE, the patient's immune response to a biological drug or biotherapeutic can have other undesired consequences. Drug-specific IgG may be a significant problem in the management of the patient for two primary reasons:

* IgG that binds the drug and neutralizes the desired treatment effects; and

* IgG that alters the pharmacokinetics and leads to an increased clearance rate of the drug.

The clinical laboratory of the future will likely be asked to measure the patient's drug-specific IgG for many of these new biotherapeutics. These tests are already an important part of FDA-required testing being performed during clinical trials for many biotherapeutics.

When an ADR occurs during the initial exposure to a biotherapeutic drug, one usually predicts that the reaction was not an immune mediated reaction, since there was not sufficient time for the immune system to generate IgE. In the case of the important cancer biotherapeutic drug cetuximab (trade name, Erbitux), however, a serious, immediate anaphylactic reaction (IgE-mediated) following the initial infusion of a drug was actually observed in small percentage of the patients. Since these patients had not previously been exposed to the drug, the basis for the reaction was at first problematic. This unique medical mystery was eventually solved, however, by Thomas A. E. Platts-Mills, MD, and colleagues at the University of Virginia. (7), (8) They found an interesting link between beef allergy and the anaphylactic responses to cetuximab. When they tested the serum of all the patients who had reacted to cetuximab, they found these individuals had pre-existing IgE to cetuximab and beef allergen. The researchers also were able to detect specific IgE in a relatively high proportion of control subjects who had never been exposed to the drug. These individuals would possibly be at risk for an ADR if infused with cetuximab.

Cetuximab is a chimeric (i.e., mouse-human) monoclonal IgG antibody molecule and a large glycoprotein with many possible immunogenic structures or epitopes. The unique part on this monoclonal antibody drug responsible for these cross-reactions was determined to be the carbohydrate structure galactose-alpha-1,3-galactose; found on both the monoclonal antibody protein and beef proteins. Thus, patients who had acquired an allergy to beef, lamb, or pork, were also likely to have an allergic response to cetuximab. (9)

Tests available

Few FDA-cleared test kits are available to investigate drug allergy so testing options are limited. Currently, the most widely available tests are to confirm a Type I drug hypersensitivity by measuring drug-specific IgE. Skin and patch testing also can be done to evaluate other immune mechanisms, including tests for Type IV or T cell-mediated sensitivities.

The use of ex-vivo live blood-cell testing is being evaluated by a number of laboratories and has the potential to confirm an immune-mediated mechanism for many drugs. Such tests can be used to assess immediate reactions when drug-specific IgE tests are not available.

These tests involve the challenge of basophils and/or leukocytes with the drug of interest and the measurement of biomarkers released on the cell surface. Multiple markers of activation can be measured (e.g., histamine, sulfi-doleukotrienes, CD63, or CD203c). Drug-specific T cells that may be responsible for delayed drug reactions can be evaluated by T-cell proliferation, CD69 upregulation, or cytokine production. (9) Currently, ex vivo tests with live blood cells are not available in an FDA-cleared kit; they are only available at specialized reference labs.

References

(1.) Pichler WJ. Drug hypersensitivity reactions: classification and relationship to T-cell activation; n: Pichler WJ, ed. Drug Hypersensitivity. Basel, Switzerland; Karger; 2007:168-189.

(2.) Gruchalla RS. Drug Allergy. J Allergy Clin Immunol. 2003; 111:S548-S559.

(3.) Gruchalla RS. Pirmohamed M. Antibiotic allergy. NEJM. 2006;354:601-609.

(4.) Gruchalla RS. Drug-metabolism, danger signals, and drug-induced hypersensitivity. J Allergy Clin Immunol. 2001;108:475-488.

(5.) Pichler WJ. Delayed drug hypersensitivity reactions. Ann Internal Med 2003;139:683-693.

(6.) Pichler WJ, Campi P. Adverse side effects of biologic agents. In: Pichler WJ, ed. Drug Hypersensitivity. Basel, Switzerland; Karger; 2007:151-165.

(7.) Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. NEJM. 2008;358: 1109-1117.

(8.) Commins SP, Platts-MillsTAE.Anaphylaxis syndromes related to a new mammalian cross-reactive carbohydrate determinant. J Allergy Clin Immuno. 2009; 124:652-657.

(9.) Martin M, et al. In vitro detection and characterization of drug hypersensitivity using flow cytometry. Allergy In press.

Note: The CE test covers all articles in this section.

By John F. Halsey, PhD, and Michelle Altrich, PhD, HCLD(ABB)

John F. Halsey, PhD, founder and former CEO of IBT Laboratories, is currently a clinical associate professor at the University of Kansas School of Medicine's Department of Internal Medicine, Division of Allergy, Immunology, and Rheumotology. Michelle Altrich, PhD, HCLD(ABB), is clinical laboratory director at IBT Laboratories, and formerly held an appointment at the University of Virginia where she specialized in molecular and cellular immunology.
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Title Annotation:COVER STORY
Author:Halsey, John F.; Altrich, Michelle
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Dec 1, 2009
Words:1809
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