Drug allergy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

A drug allergy, or immunologic drug reaction is a reaction to a drug that specifically occurs through immunologic activation in response to a drug. Drug allergy is a sub-classification of adverse drug reactions. Adverse drug reactions are classified into two categories; Type A (predictable), and Type B (unpredictable). Drug allergy falls under Type B adverse drug reactions, along with pseodoallergic drug reactions.

Drug allergies are classified using two main sets of criteria. One is set forth by the World Allergy Association, and classifies the reaction as to whether it occurs within one hour of treatment, or after one hour. The other set of criteria are based on the type of immunologic reaction that has occurred and the mediators involved.

An allergic reaction will not occur on the first exposure to a substance. The first exposure allows the body to create antibodies and memory lymphocyte cells for the antigen. However, drugs often contain many different substances, including dyes, which could cause allergic reactions. This can cause an allergic reaction on the first administration of a drug. For example, a person who developed an allergy to a red dye will be allergic to any new drug which contains that red dye. Medications can cause allergic reactions through various mechanisms. The drug can either act as a direct antigenic particle, or it can cause activation of immune cells by the direct interaction with immune cell receptors.

The types of drugs that can cause drug allergies vary. Drugs containing sulfa are common in causing drug allergy reactions. Other common drugs implicated in leading to an allergic reaction are antibiotics, insulin, and iodinated drugs.

A drug allergy is different from an intolerance. A drug intolerance, which is often a milder, non-immune-mediated reaction, does not depend on prior exposure. Most people who believe they are allergic to aspirin are actually suffering from a drug intolerance.

Adverse drug reactions may occur in up to 10% of the worldwide population, and also affect up to 20% of patients who are hospitalized. Of all the cases of fatalities caused by anaphylaxis, drugs may be responsible for 20% of the deaths.

There are known risk factors for the development of drug allergies. Some are based on the patient and include; female gender, being young or middle aged, genetics, presence of certain viral infections (HIV and EBV), and history of atopy or prior drug allergies. Other factors are based on the quality of the drug, and include; high molecular weight compounds, intravenous and intramuscular routes of administration, and frequent, prolonged, high doses of medication.

In general, screening for drug allergies is discouraged. To screen for drug allergy, one would have to be exposed to the drug, which may mean putting the individual at an uneccesary risk for a severe drug reaction through a screening test. Screening for drug allergy may be useful in patients who are in need of a specific medication, but are susceptible or carry risk factors for having a severe allergic reaction upon exposure to the drug. Testing is usually reserved as a confirmatory diagnostic test in individuals who have already been shown to have an allergic reaction to a drug.

In general, any allergic reaction will worsen with continued exposure to the offending agent. Anaphylaxis will most certainly progress to death if untreated, and the same is true for the severe allergic reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Symptoms of a drug allergy can range from mild itching and rash, to serious exfoliative dermatological conditions that can be life threatening. Symptoms can also include the respiratory system, to cause wheezing and trouble breathing, as well as cause anaphylaxis and anaphylactic shock.

Findings on physical examination will vary widely in drug allergy, depending on the specific manifestation of the type of drug allergy (Stevens-Johnson Syndrome, toxic epidermal necrolysis), and the severity of the allergic reaction. A full, comprehensive physical examination should be performed to distinguish drug allergy from any other causes and conditions, and particular attention should be given to the respiratory and cardiovascular systems to quickly recognize impending life-threatening reactions.

Drug allergy and it’s associated conditions is primarily a clinical diagnosis based on the patient history, and through physical exam. Certain laboratory findings may be seen during the acute phase of the reaction, but are not always specific. Skin testing and biopsies can be performed when there is not a clear diagnosis.

The management strategies for drug allergy include both acute and long-term treatment, as well as drug desensitization and graded challenges for patients in whom the drug they are allergic to is absolutely neccesary for treatment.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

Drug allergies are classified using two main sets of criteria. One is set forth by the World Allergy Association, and classifies the reaction as to whether it occurs within one hour of treatment, or after one hour. The other set of criteria are based on the type of immunologic reaction that occurred and the mediators involved.

There are recommendations on the classification of drug allergy reactions based on the World Allergy Association (WAO) guidelines.^[2] The two categories of classification are based on whether the reaction occurs less than one hour of medication administration, or more than one hour afterwards.

• Immediate- these reactions occur within one hour, and are most likely due to IgE mediated type I reactions. At times, type I reactions can occur after one hour if the absorption of the drug is delayed, for example due to an oral medication or ingesting a medication with food. These types of reactions have the risk of anaphylaxis if the patient is re-exposed.
• Delayed- these reactions occur after one hour, although most occur 6 hours after the administration of the drug, and some occur up to 7 to 10 days after treatment. Some reactions can even occur days after the treatment has been stopped.

One type of classification of drug allergies, is based on the type of autoimmune process. This is the same type of classification that is used for other types of immunological reactions, and is based on the Gell and Coombs system. Drugs usually cause type III and type IV reactions, however certain medications such as penecillin, can cause all four ^[1] .

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

An allergic reaction will not occur on the first exposure to a substance. The first exposure allows the body to create antibodies and memory lymphocyte cells for the antigen. However, drugs often contain many different substances, including dyes, which could cause allergic reactions. This can cause an allergic reaction on the first administration of a drug. For example, a person who developed an allergy to a red dye will be allergic to any new drug which contains that red dye.Medications can cause allergic reactions through various mechanisms. The drug can either act as a direct antigenic particle, or it can cause activation of immune cells by the direct interaction with immune cell receptors.

Most drugs do not act as antigenic particles in their mature form. This is because they are usually small, and therefore not recognized by immune receptors enough to actually activate T cells or B cells. However, drugs can act as antigens if they are presented to lymphocytes by antigen presenting cells such as dendrites. This response specific to the drug can be solely T-cell mediated, antibody mediated, or can have components of both.

• Stimulation of the antibody response– In general, antigens are processed by antigen presenting cells and presented to T-cells. This leads to t-cell activation and produces cytokines which then activate B cells. B cells then recognize the antigen through its IgG receptor, and becomes activated subsequently producing antigen-specific immunoglobulins. Modern pharmaceuticals that are proteins or resemble proteins, can stimulate antibody and T cell responses similar to other protein antigens. Examples of drugs that cause this type of reaction are:
  • Insulin
  • Enzymes
  • Antisera
  • Recombinant proteins (monoclonal antibodies)
  • Vaccines

Some of these compounds can induce antibody formation without any T cell interaction.

• Drugs as haptens or pro-haptens– Small drugs can become immunogenic by binding covalently to larger macromolecules such as host proteins on cell surfaces or in plasma. The drug is then called a hapten, and the antigenic compound is then called a hapten-carrier complex. These complexes can also induce a a T cell and antibody response. Drugs that give rise to metabolites that can act as haptens are called pro-haptens. For example, penecillin often acts as a hapten when the beta-lactam ring breaks open and reacts with lysine to form a hapten-carrier complex called penecilloyl determinant, which is capable of stimulating T-cells and antibodies ^{[1] [2]}. A few drugs which have this capability are
  • Penicillin and other beta-lactam antibiotics
  • Penicillamine
  • Gold and other heavy metals

• Reactive metabolites– Some drugs may not be reactive with macromolecules in their original state, however may form reactive particles after undergoing metabolism by CYP450 enzymes. As part of drug metabolism by hepatocytes, some drugs may not undergo correct detoxification and bind to or haptenate intracellular proteins. ^[3] Alternatively, they may be excreted by the cell and processed by antigen presenting cells. These antigen presenting cells can then present the drug on the surface of the cells to T cells. T cells would then produce cytokines and to stimulate B cells, and both T cell and antibody mediated responses would then occur. Glutathione usually neutralizes drugs that give rise to intermediates during metabolism. Some drugs escape neutralization. Examples of these drugs are:
  • Sulfonamide antimicrobials
  • Phenacetin
  • Phenytoin,carbamazepine, and lamotrigine
  • Procainamide
  • Halothane

The Gell and Coombs system separates immunologic reactions into four categories, and can be used whether the reaction is caused by drugs, infectious processes, or autoimmune disease. Types I, II, and III reactions are mediated by antibodies as the main immunologic component, whereas type IV is mediated by T cell response. Type IV can also be subdivided into four categories.

• Type I (IgE mediated) – this type of reaction involves a drug specific IgE immunoglobulin. The drug or its metabolite can be a hapten, can act as part of a hapten-carrier complex, can be an antigen in its native form, or can be produced by an IgE mediated previous sensitization to a cross reacting substance. The sensitization stage involves the production of drug-specific IgE, and its binding to mast cells and basophils. It is clinically asymptomatic. The effector stage occurs when the already sensitized individual is re-exposed to the specific drug. The drug again couples to carrier proteins and then proceeds to cross-link IgE on mast cell surfaces. This results in an inflammatory cascade causing release of vasoactive mediators.
• Type II (antibody-mediated cell destruction)– This reaction usually occurs in the setting of high dose long-term drug exposure where the individual makes high titers of preformed drug specific IgG antibodies. These reactions are uncommon, and effect only certain individuals. They occur when the drugs bind to the surfaces of cells such as red blood cells, platelets, and neutrophils, and subsequently act as antigens. Binding causes the cells to be tagged for clearance. Drugs that cause a type II reaction are:
  • Cephalosporins
  • Quinidine
  • Penicillin
  • NSAIDs
  • Methyldopa
• Type III (immune complex deposition) – These reactions are caused by immune complex deposition reactions such as serum-sickness like reactions, vasculitis, and drug fever. Like type II reactions, type III reactions also occur in the setting of chronic, high dose drug exposure. The drug is solubilized and binds drug-specific IgG. These particles conglomerate and accumulate to form immune complexes which accumulate in areas such as the glomeruli, the joints, and the blood vessels. They then activate complement particles and cause a widespread inflammatory response. Exposing the individual again usually leads to more rapid and severe symptoms.
• Type IV – (cell mediated) – Type IV reactions involve T cells as well as the other cell types such as macrophages, eosinophils, and neutrophils. Unlike the other reactions, type IV mediated reactions do not involve antibodies. Reactions involving T cells present with prominent skin findings because the skin contains numerous T cells.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2], Jolanta Marszalek, M.D. [3]

The types of drugs that can cause drug allergies vary. Drugs containing sulfa are common in causing drug allergy reactions. Other common drugs implicated in leading to an allergic reaction are antibiotics, insulin, and iodinated drugs.

When a medication causes an allergic reaction, it is called an allergen. The following is a short list of the most common drug allergens

• Antibiotics
  • Penicillin
  • Sulfa drugs
  • Tetracycline
• Analgesics
  • Codeine
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
• Anticonvulsives
  • Dilantin
  • Tegretol

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

True drug allergy needs to be differentiated from other reactions caused by drugs, such as pseudoallergic reactions and drug induced autoimmune like reactions. Drug allergy also needs to be differentiated from other conditions and reactions that present similarly to drug allergy.

There are reactions called pseudoallergic reactions which, are in the category of adverse drug reactions. Although they mimic drug allergies, immunologic mechanisms have not been demonstrated as an underlying cause. There are also reactions called non-immunologic hypersensitivity reactions for which immunologic mechanisms of reactions have also not been demonstrated.

Some pseudoallergic reactions occur as a result of direct activation of immune cells and inflammatory cells, so the final steps of pathogenesis are the same and the clinical features are similar. Despite the similarities, the diagnosis, prognosis and future prevention are different.

Non-immunologic anaphylaxis can also occur. All types of anaphylaxis are life-threatening. The term “anaphylactoid reaction” often used for non-immunologic anaphylaxis can sometimes be interpreted as less severe, although this is not true. Some patients who show marked dermographism, have profound mast cell instability, which is thought associated with pseudoallergic reactions.

Some agents commonly implicated in pseudoallergic reactions are;

• NSAIDS
• Vancomycin
• Local anesthetics
• Radiocontrast agents
• Opiates
• Chemotherapeutics
• Monoclonal antibodies and other biologic therapies used in cancer treatment

Lupus like syndromes can be caused by the following medications;

• Penicillamine
• Procainamide
• Phenytoin
• Isoniazid
• Sulfasalazine
• Amiodarone
• Minocycline

A pemphigus like syndrome can be caused by penicillamine

IgA bullous dermatitis can be caused by:

• Vancomycin
• Ceftriaxone
• Ciprofloxacin
• Metronidazole

Certain IgE mediated conditions need to be differentiated from IgE mediated drug allergies (angioedema, urticaria, anaphylaxis, bronschospasm) ^[1];

• Insect bites and stings
• Carcinoid syndrome
• Asthma
• Food allergy
• Latex allergy
• Scombroid fish poisoning
• Mastocytosis
• Infection (EBV, gastrointestinal parasites, hepatitis A, hepatitis B, and hepatitis C

Certain non-IgE mediated conditions need to be differentiated from non-IgE mediated allergic reactions (exanthema, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

• Kawasaki disease
• Still’s disease
• Acute graft-versus-host disease
• Psoriasis
• Insect bites/ stings
• Streptococcal infection
• Viral infection

Drug allergy should be differentiated from other diseases causing papulosquamous or erythmatosquamous rash. The differentilas include:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

Adverse drug reactions may occur in up to 10% of the worldwide population, and also affect up to 20% of patients who are hospitalized. Of all the cases of fatalities caused by anaphylaxis, drugs may be responsible for 20% of the deaths. The incidence of toxic epidermal necrolysis is about 0.4-1.2 cases per million in a year.

Immediate hypersensitivity are over-reported and few patient reporting these have reactions on careful testing.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

There are known risk factors for the development of drug allergies. Some are based on the patient and include; female gender, being young or middle aged, genetics, presence of certain viral infections (HIV and EBV), and history of atopy or prior drug allergies. Other factors are based on the quality of the drug, and include; high molecular weight compounds, intravenous and intramuscular routes of administration, and frequent, prolonged, high doses of medication.

• Gender – Women are more likely than men to have both immediate and delayed reactions, and the risk is greater in women of childbearing age.
• Age– Drug allergy occurs more frequently in young and middle-aged adults than in infants and the elderly.
• Genetics – Drug allergies run in families, and is associated with genetic polymorphisms in human leukocyte antigen type B (HLA-B) alleles ^[1].
• Viral infections – Human immunodeficiency virus (HIV), and Epstein-Barr virus (EBV) are associated with an increased likelihood of developing immunologic reactions to drugs.
• Prior drug allergy – A drug allergy in the past causes a person to be at a higher risk for an allergic reaction to the same drug, as well to a different type of drug.
• Atopy – Patients with a history of atopy, such as allergic asthma or food allergy, are not at an increased risk of developing an allergic reaction to the drug, but are at higher risk for the severe clinical manifestations of drug allergy when it does occur ^[2].

• High molecular weight compounds – Large macromolecular drugs such as horse antisera and insulin, or drugs that are known to haptenate by binding to tissue and proteins to elicit an immune response, are more likely to cause drug allergies.
• Route of administration – Intravenous routes of administration are more associated with severe drug reactions, and along with topical and intramuscular routes of administration, are also more likely to cause allergic drug reactions compared with oral medications ^[3].
• Dose – Prolonged high doses of medication, or frequently dosed medications, are more likely to elicit an allergic reaction than one large single dose of medication.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]

In general, screening for drug allergies is discouraged. To screen for drug allergy, one would have to be exposed to the drug, which may mean putting the individual at an uneccesary risk for a severe drug reaction through a screening test. Screening for drug allergy may be useful in patients who are in need of a specific medication, but are susceptible or carry risk factors for having a severe allergic reaction upon exposure to the drug. Testing is usually reserved as a confirmatory diagnostic test in individuals who have already been shown to have an allergic reaction to a drug.

Neither allergy blood testing nor skin testing should be used for primary screening measures in healthy patients: they may be most useful as confirmatory tests when the patient’s history is compatible with an IgE-mediated reaction, and the patient is in need of a specific medication that carries the risk of inducing a severe reaction.

• Skin prick testing (SPT) and intradermal testing (a test where a small amount of allergen is injected into the dermal layer of the skin) are useful for predicting an allergic reaction mediated by IgE-mediated reactions (type I hypersensitivity). Skin testing protocols are standardized for drugs such as penicillin, and are also useful (but rarely positive) for local anesthetics,muscle relaxants, and very sensitive for high-molecular-weight protein substances such as insulin and monoclonal antibodies. Positive skin tests to these drugs confirm the presence of antigen-specific IgE, and supports the diagnosis of a type I hypersensitivity reaction. ^[1] The negative predictive value of penicillin skin testing is high, and therefore, a negative test is useful for ruling out a penicillin allergy.
• IgE Blood tests that measure levels of IgE against specific drug allergens, can confirm an allergic disorder. They are useful when skin testing cannot or should not be performed. The likelihood of an IgE-mediated clinical reaction often increases with the level of specific IgE, but these levels do not predict severity or guarantee a reaction will occur. In the appropriate setting, these tests can help in identifying specific allergens and assessing allergic disease. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2] Please help WikiDoc by adding more content here. It’s easy! Click here to learn about editing.

In general, any allergic reaction will worsen with continued exposure to the offending agent. Anaphylaxis will most certainly progress to death if untreated, and the same is true for the severe allergic reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

• Stevens-Johnson syndrome starts with a generalized macropapular rash, that will then progress to bullae, mucous membrane ulcerations, conjunctivitis, fever, sore throat, and fatigue.
• Toxic epidermal necrolysis will progress similarly to Stevens-Johnson syndrome, but will also cause large layers of the epidermis to detatch from the layers below, leading to extreme amounts of sloughing of the skin surface, and an appearance of the skin that looks like burns or scalding.

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