Drug allergies/sensitivities

Definition

A drug allergy is an adverse reaction to a medication, often an antibiotic, that is mediated by the body's immune system. A drug sensitivity is an unusual reaction to a drug that does not involve the immune system.

Description

Adverse reactions to medication may be allergic reactions involving a child's immune system, individual sensitivities to a drug, or side effects of the drug itself. Some children are allergic or sensitive to drugs that are not harmful for most people. Some drugs, such as aspirin and penicillin or related antibiotics , may induce allergic reactions in some children and sensitivities in other children.

Drug allergies

Drug allergies account for 5–10 percent of all adverse reactions to medications. They occur when the immune system—designed to protect the body from foreign substances such as bacteria and viruses—recognizes a medication as a harmful substance that must be destroyed. Drugs often induce an immune response; however, the symptoms of an allergic reaction occur in only a small number of children. Although most allergic drug reactions have mild symptoms, on rare occasions they can be life-threatening.

Drug allergies are unpredictable. Most drug allergies develop within days or occasionally weeks of beginning a drug treatment. Although it is very unusual to develop an allergy after months of taking a drug, sometimes children develop a drug allergy after having received multiple doses of the drug.

Unlike other types of adverse drug reactions, the frequency and severity of allergic reactions to drugs usually are independent of the amount of drug that is administered. Even a very small amount of a drug can trigger an allergic reaction.

Many classes of drugs can induce allergic reactions, resulting in a wide variety of symptoms affecting various tissues and organs. The likelihood that a drug will cause an allergic reaction depends in part on the chemical properties of the drug. Larger drug molecules are more likely to cause allergic reactions than smaller drug molecules. Larger drug molecules include the following:

• insulin
• antiserum which contains large immune-system proteins called antibodies
• recombinant proteins produced by genetic engineering

Unlike most other allergens, such as pollen or mold spores, drug molecules often are too small to be detected by the immune system. Smaller drugs such as antibiotics cannot induce an immune response unless they combine with a body cell or a carrier protein in the blood. Furthermore, drug allergies often are caused by the breakdown products or metabolites of the drug rather than by the drug itself. Sometimes the same drug, such as penicillin, can induce different types of allergic reactions.

ige-mediated allergies Most allergies, including most drug allergies, occur because of a reaction with an immune system antibody called immunoglobulin E (IgE). The first exposure to the drug sensitizes the child's immune system by inducing specialized white blood cells to produce IgE that recognizes the specific drug. On subsequent exposure to the drug, the drug-specific IgE antibodies bind to the drug on the surfaces of certain cells of the immune system. This binding activates the cells to release histamine and other chemicals that can cause a variety of symptoms. Thus, a child who has no reaction on first exposure to a drug may have a severe reaction with subsequent exposure.

Drug-specific IgE antibodies may cross-react with other drugs that have similar chemical properties, thereby triggering an allergic reaction, as is the case in the penicillin family . For example, the antibodies of a child allergic to penicillin may cross-react with the antibiotic amoxicillin or nafcillin.

Insect stings and the intravenous injection of certain drugs are the most common causes ofanaphylaxis , the most severe and frightening allergic response. Anaphylaxis involves the entire body. Although it is rare, several hundred Americans die of anaphylaxis every year. Anaphylaxis is most common in children who are allergic to penicillins and similar drugs. These drugs cause 97 percent of all deaths from drug allergies.

other types of drug allergies Some drug allergies occur via immune system components other than IgE. Cytotoxic/cytolytic drug allergies occur when a drug allergen that is associated with a cell membrane, usually a blood cell, interacts with other types of antibodies—called immunoglobulin G (IgG) or immunoglobulin M (IgM)—along with other immune system factors. These interactions damage or destroy body cells.

Immune complex drug allergies occur when a drug combines with antibodies and other immune system components to form complexes in the blood. These complexes can be deposited in blood vessels and on membranes, causing inflammatory reactions that may be either localized or throughout the body. For instance, serum sickness typically causes a rash and joint swelling after the offending drug is administered.

T-cell-mediated allergic drug reactions require immune system cells called T-memory cells that are specific for the drug allergen. When exposed to the allergen, the T-cells are activated and cause an inflammatory response. The most common example of this type of reaction is allergic contact dermatitis that causes inflammations of the skin.

Drug sensitivities

Drug sensitivities (also called idiosyncratic reactions or unusual adverse reactions) do not involve the child's immune system or the release of histamine. However, the symptoms of drug sensitivities can be very similar to the symptoms of a drug allergy. Unlike drug allergies, sensitivities often occur upon first exposure to a drug and do not lead to anaphylaxis.

Demographics

Anyone can develop an allergy to any drug at any time. It is not clear why some children develop allergies to drugs that are well tolerated by most people. It is estimated that up to 10 percent of all people develop allergies to penicillin or other antibiotics at some point in their lives. Those taking multiple medications or frequent courses of antibiotics appear to be more at risk for developing drug allergies.

The most common drug sensitivity is to aspirin. Nearly 1 million Americans, primarily adults, are sensitive to aspirin. However, many medications, including aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin, and others), can trigger an asthma attack in children. Asthma is a common chronic respiratory condition in children. Attacks occur when the air passages from the lungs to the nose and mouth are narrowed causing difficulty breathing. Aspirin and aspirin-like medications are common triggers for asthma attacks in as many as 30 percent of asthmatic children.

Causes and symptoms

Drug allergies

Any drug (either prescription or over-the-counter) can evoke an allergic reaction; however, antibiotics, especially penicillin and related drugs, are the most common cause of drug allergies. Children also frequently (i.e. to these agents more frequently than to other agents) develop allergies to the following:

• aspirin
• sulfa-based drugs
• barbiturates
• anticonvulsants
• insulin preparations, particularly those from animal sources
• dyes that are injected into blood vessels before taking x rays

The symptoms of a drug allergy vary from quite mild to life-threatening anaphylaxis. Unlike other common allergies, drug allergies often affect the entire body. The most common symptoms of a drug allergy are skin conditions including rash, generalized itching , and urticaria (hives ; a very itchy rash with red swellings affecting only a small area of skin or the entire body; possibly the early symptom of anaphylaxis). The type of rash depends on the type of allergic response.

Less common symptoms of drug allergies include runny nose, sneezing, and congestion.

Uncommon but more serious symptoms of a drug allergy include the following:

• nausea, vomiting , diarrhea
• abdominal pain or cramps
• fever
• low blood cell count
• wheezing and difficulty breathing
• inflammation of the lungs, kidneys, and joints
• angioedema (a sudden swelling of the mucous membranes and tissues under the skin, anywhere on the body but especially on the face, eyes, lips, neck, throat, and genitals)

Angioedema occurs within a few minutes of exposure to the drug, often in conjunction with urticaria. Angioedema often is asymmetrical: for example, only one side of the lip may be affected. Swelling of the tongue, mouth, and airways can cause difficulty speaking, swallowing, or breathing. Angioedema can become life-threatening if the swelling affects the larynx (voice box) and the air passages become blocked. Emergency symptoms of a drug allergy include obstruction of the throat from swelling, severe asthma attack, and anaphylaxis.

Allergic reactions to drugs are the most common cause of an inflammation of the kidneys called tubulointerstitial nephritis. The allergic reaction and development of this acute condition may occur between five days and five weeks after exposure to penicillin, sulfonamides , diuretics (drugs to increase urination), and aspirin and other NSAIDs.

ige-mediated allergies IgE-mediated allergies can be caused by the following:

• penicillin when the allergic reaction is immediate
• blood factors, including antisera
• hormones
• vaccines (usually an allergic reaction to some component of the vaccine such as egg protein, gelatin, or neomycin, an antibiotic)
• very rarely, local anesthetics such as Novocain

The most common symptom of an IgE-mediated drug allergy is a rash that develops after the child has taken the drug for several days and produced antibodies against it.

anaphylaxis Anaphylaxis is a violent immune system reaction that can occur when a child who has large amounts of drug-specific IgE antibodies is re-exposed to the drug. The antibodies bind to the drug very rapidly causing an immediate, severe response. Anaphylaxis most often is caused by the following:

• penicillin and related antibiotics
• streptomycin
• tetracycline
• insulin

Analphylaxis usually begins within one to 15 minutes following exposure to the drug. Only rarely does the reaction begin an hour or more after exposure. Anaphylaxis can progress very rapidly leading to collapse, seizures, and loss of consciousness within one to two minutes. Without treatment, cessation of breathing, anaphylactic shock, and death can occur within 15 minutes. Any drug that has caused anaphylaxis in a child will probably cause it again on subsequent exposure, unless measures are taken to prevent it.

Symptoms of anaphylaxis include:

• urticaria on various parts of the body
• angioedema
• intense itching
• flushing of the skin
• coughing and sneezing
• nausea, vomiting, diarrhea
• abdominal pain or cramping
• tingling sensations
• ear throbbing
• heart palpitations
• uneasiness or sudden extreme anxiety
• swollen throat and/or constricted air passages causing a hoarse voice, wheezing, and difficulty breathing, the most characteristic symptom of anaphylaxis

Constriction of the air passages in the bronchial tract and/or throat, accompanied by shock, can cause a drastic drop in blood pressure that may lead to the following:

• rapid pulse
• paleness
• weakness
• dizziness, lightheadedness
• slurred speech
• mental confusion
• unconsciousness

other drug allergies Cytotoxic/cytolytic-type drug allergies can be caused by the following:

• penicillin
• sulfonamides
• quinidine
• methyldopa

Cytotoxic/cytolytic-type of drug allergy can result in the following:

• immune hemolytic anemia due to the destruction of red blood cells
• thrombocytopenia from the reduction in blood platelets
• granulocytopenia from a deficiency of a type of white blood cell called a granular leukocyte

Drugs that can cause immune complex reactions, such as serum sickness or drug-induced lupus syndromes, include:

• hydralazine
• procainamide
• isoniazid
• phenytoin

Serum sickness (a delayed type of drug allergy that may take one to three weeks to develop) can be caused by an allergic reaction to penicillin or related antibiotics. Serum sickness also can be an allergic response to animal proteins present in an injected drug. Serum sickness is characterized by the following:

• fever
• aching joints
• swelling of the lymph nodes
• rash
• general body swelling
• skin lesions
• nephritis (an inflammation of the kidneys)
• hepatitis (an inflammation of the liver)

Some drugs, including penicillins and sulfonamides, can cause delayed dermatologic allergic reactions. These are various types of skin reactions, including eczema, that do not occur immediately upon exposure to the drug. These types of allergies are thought to be caused by metabolites formed from the breakdown or further reaction of the drug.

Drug allergies can result in hypersensitivity reactions, which in turn can result in liver disorders. Such damage can be caused by the following:

• sulfonamides
• phenothiazines
• halothane
• phenytoin
• isoniazid

Pulmonary hypersensitivity allergic reactions that affect the lungs and result in rashes and fever may be caused by nitrofurantoin and sulfasalazine.

Drug sensitivities

Children may have drug sensitivities to aspirin; other NSAIDs; opiates such as morphine and codeine; and some antibiotics, including erythromycin and ampicillin.

Symptoms of drug sensitivities often are very similar to those of drug allergies and include rashes, urticaria, and angioedema.

Anaphylactoid drug reactions are similar to anaphylactic reactions. However, they are caused by a drug sensitivity rather than a drug allergy and can occur upon the first exposure to a drug. Anaphylactoid reactions can occur in response to the following:

• opiates
• radiopaque dyes (radiocontrast media) used in x-ray procedures; 2–3% of patients have immediate generalized reactions to these dyes
• aspirin and other NSAIDs in some people, usually adults
• polymyxin
• pentamidine

When to call the doctor

A physician should be consulted whenever a child has an allergic reaction or sensitivity to a drug. The parent or caregiver should seek emergency assistance if a child has a severe or rapidly worsening allergic reaction to a drug that includes wheezing, difficulty breathing, or other symptoms of anaphylaxis.

Diagnosis

It is important to distinguish between an uncomfortable but mild side effect of a drug and an allergic reaction or sensitivity which could be life-threatening. A drug allergy or sensitivity most often is diagnosed by discontinuing the drug and observing whether the symptoms disappear.

Following a drug reaction the parent should describe the exact course of the reaction; the type of symptoms, when they occurred, and how long they lasted; and whether the child had previously been exposed to the drug. A previous allergic-type reaction to the medication usually is considered diagnostic of a drug allergy. A reaction upon a child's first exposure to the drug is probably a drug sensitivity.

Further diagnosis of a drug allergy may depend on the following:

• a complete medical history, including all drugs taken in the past month, when and how the child received certain drugs, and previous drug reactions
• whether the drug is known to cause allergic reactions
• a family history of drug allergies
• the timing of symptom-onset following drug exposure
• the timing of symptom-disappearance after discontinuing the drug
• the type of rash
• involvement of joints, lymph nodes, or liver
• associated viral infections
• other concurrent medications
• the presence of a chronic disease

Allergy tests

Skin prick tests or intra dermal tests to demonstrate IgE allergies are standardized for very few medications. Penicillin testing is standardized and can be used in extreme situations. Incremental drug challenge tests are also available for several drugs. These tests differ from tests for IgE antibodies but are still useful for demonstrating drug sensitivities. They must be done cautiously as patients are likely to have reactions during the challenge.

The allergist injects a tiny amount of the drug under the skin. If the child is allergic to the drug, swelling and itching occur at the site of injection within 15 to 20 minutes. Skin tests can be used to test for only a few drug allergies, for example, for penicillin and closely related antibiotics. Incremental challenge tests are performed for insulin, streptokinase, chymopapain, and antiserum.

Patch tests may be used to test for allergies to drugs that are applied to the skin such as topical antibiotics . A patch containing a small amount of the drug is applied to the skin to test for a localized reaction.

Desensitization is a test in which the allergist gives the child a tiny dose of the drug—as little as 0.001 or 0.00001 of the usual dose—in its usual form—orally, topically, or by injection. Gradually the dose is increased, and the child's reaction of observed. This procedure is done only in life-threatening situations, however, and only under close observation.

Treatment

Mild allergies/sensitivities

Drug allergies and sensitivities most often are treated by discontinuing the medication and replacing it with an alternative one. Mild symptoms usually disappear within a few days after discontinuation of the drug. Hives usually disappear within a few hours. Itchy rashes and hives may be treated with over-the-counter products such as oral antihistamines . Occasionally topical corticosteroid drugs are applied to the skin. Angioedema can take hours or days to subside; however, the swelling can be reduced with a corticosteroid or antihistamine.

Severe reactions

Severe immediate reactions occurring within one hour of drug administration, accelerated reactions occurring one to 72 hours after drug exposure, and late reactions (including rash, serum sickness, or fever) that develop more than 72 hours after drug exposure are all treated as follows:

• discontinuation of all nonessential suspect drugs
• antihistamines for hives and rashes
• oral corticosteroids for inflammation

Severe angioedema requires an immediate injection of epinephrine (a form of adrenaline) and further observation in a hospital.

Anaphylaxis requires an immediate injection of epinephrine into a thigh muscle. Epinephrine opens the air passageways and improves blood circulation. Intravenous fluids and injections of antihistamines or corticosteroids such as hydrocortisone also are administered. Cardiopulmonary resuscitation (CPR) and intubation may be necessary.

An asthma attack that is triggered by aspirin or other medications can be relieved by quick-relief or rescue medications. These include:

• epinephrine
• short-acting bronchodilators such as albuterol, proventil, ventolin, or xopenex
• prednisone for all moderate to severe reactions

Desensitization

Desensitization or immunotherapy sometimes is used by an allergy/immunology specialist to treat drug allergies to insulin, penicillin, or other antibiotics. Small amounts of the drug are injected or swallowed over a period of hours or a few days or in slowly increasing doses, to reduce sensitivity. Once antibiotic desensitization has been achieved, the full course of antibiotic treatment is followed. The procedure must be repeated if the drug has been discontinued for more than 72 hours.

Sometimes desensitization is used for non-IgE-mediated drug reactions. Desensitization may take up to a month for the following:

• aspirin
• alloprinol
• gold
• sulfamethoxazole
• sulfasalazine

Prognosis

Mild symptoms of a drug allergy usually disappear without treatment within a few days of discontinuing the drug. Although children may lose their sensitivity to penicillin, if the reaction was urticarial or anaphylaxis, they are not re-challenged with the drug for safety reasons (i.e. it is not possible to predict who has lost sensitivity). In rare cases drug allergies may cause severe asthma attacks, anaphylaxis, or death.

Prevention

Drug allergies are unpredictable because they occur after a child has been exposed to the drug one or more times. The major prevention for known drug allergies and sensitivities is to avoid those drugs and to inform all physicians, hospital personnel, and dentists of the allergies or sensitivities before treatment. In the case of a serious drug allergy, the child should wear a medical alert necklace or bracelet or carry a card (Medic-Alert and others) at all times to alert emergency medical personnel.

KEY TERMS

Allergen —A foreign substance that provokes an immune reaction or allergic response in some sensitive people but not in most others.

Anaphylactoid —A non-allergic sensitivity response resembling anaphylaxis.

Anaphylaxis —Also called anaphylactic shock; a severe allergic reaction characterized by airway constriction, tissue swelling, and lowered blood pressure.

Angioedema —Patches of circumscribed swelling involving the skin and its subcutaneous layers, the mucous membranes, and sometimes the organs frequently caused by an allergic reaction to drugs or food. Also called angioneurotic edema, giant urticaria, Quincke's disease, or Quincke's edema.

Antibody —A special protein made by the body's immune system as a defense against foreign material (bacteria, viruses, etc.) that enters the body. It is uniquely designed to attack and neutralize the specific antigen that triggered the immune response.

Antihistamine —A drug used to treat allergic conditions that blocks the effects of histamine, a substance in the body that causes itching, vascular changes, and mucus secretion when released by cells.

Antiserum —Human or animal blood serum containing specific antibodies.

Corticosteroids —A group of hormones produced naturally by the adrenal gland or manufactured synthetically. They are often used to treat inflammation. Examples include cortisone and prednisone.

Cytotoxic —The characteristic of being destructive to cells.

Epinephrine —A hormone produced by the adrenal medulla. It is important in the response to stress and partially regulates heart rate and metabolism. It is also called adrenaline.

Histamine —A substance released by immune system cells in response to the presence of an allergen. It stimulates widening of blood vessels and increased porousness of blood vessel walls so that fluid and protein leak out from the blood into the surrounding tissue, causing localised inflammation of the tissue.

Immunoglobulin E (IgE) —A type of protein in blood plasma that acts as an antibody to activate allergic reactions. About 50% of patients with allergic disorders have increased IgE levels in their blood serum.

Radiopaque dyes, radiocontrast media —Injected substances that are used to outline tissues and organs in some x-ray and other radiation procedures.

Urticaria —An itchy rash usually associated with an allergic reaction. Also known as hives.

Children with allergies or sensitivities to aspirin should avoid all aspirin-containing drugs. Such children usually can tolerate acetaminophen and non-acetylated salicylates such as sodium salicylate and salsalate.

If a child is allergic to a drug for which there is no substitute, sometimes the dosage can be reduced to prevent an allergic reaction. If the allergy is mild and the drug cannot be discontinued, the physician may decide to pretreat the allergy, with an antihistamine such as diphenhydramine or a corticosteroid such as prednisone, before the drug is administered to reduce or eliminate the allergic reaction. The physician also may "treat through" the allergy by prescribing antihistamines and corticosteroids during drug administration.

Some disorders cannot be diagnosed without the use of radiopaque dyes. Special dyes that reduce the risk of an anaphylactoid reaction can be used. Children at risk for reaction to such dyes may be premedicated with anti-histamines and corticosteroids alone or in combination with beta-adrenergic agents before the dye is injected. Premedications include the following:

• prednisone
• diphenhydramine
• ephedrine

Parental concerns

When a child is given a new medication or starts a new course of treatment with a previous medication, parents should watch closely for symptoms of a drug allergy or sensitivity.

If a child suffers a mild to moderate allergic reaction or sensitivity to a drug, the parent should take the following steps:

• stay calm and reassure the child; anxiety can worsen the symptoms
• apply calamine lotion and cold cloths for an itchy rash; do not use medicated lotions
• observe the child for signs of increasing distress

If a child shows signs of a severe allergic reaction or sensitivity, the parent or caregiver should:

• inject allergy medication if it is available
• check the child's air passage, breathing, and circulation
• call 911 or other emergency assistance if the child is having difficulty breathing, becomes very weak, or loses consciousness
• begin rescue breathing or CPR if necessary
• calm and reassure the child
• inject emergency allergy medicine if available; do not give oral medication if the child is having difficulty breathing
• prevent shock by laying the child flat, elevating the feet, and covering the child with a coat or blanket

In the case of a severe allergic reaction, a parent should not:

• assume that any pretreatment with allergy medication will protect the child
• place a pillow under the child's head if the child is having trouble breathing since this could block the air passage
• give the child anything by mouth

Resources

BOOKS

Honsinger, Richard W., and George R. Green. Handbook of Drug Allergy. Philadelphia: Lippincott Williams & Wilkins, 2004.

PERIODICALS

Honsinger, Richard W. "Drug Allergy." Annals of Allergy, Asthma, and Immunology 93, no. 2 (August 2004): 111.

Roberts, Shauna S. "Drug Allergy FAQ." Diabetes Forecast 57, no. 4 (April 2004): 21–2.

ORGANIZATIONS

American Academy of Allergy, Asthma, & Immunology. 555 East Wells Street, Suite 1100, Milwaukee, WI 53202–3823. Web site: <www.aaaai.org>.

American College of Allergy, Asthma & Immunology. 85 West Algonquin Road, Suite 550, Arlington Heights, IL 60005. Web site: <www.acaai.org>.

Asthma and Allergy Foundation of America. 1233 20th Street NW, Suite 402, Washington, D.C. 20036. Web site: <www.aafa.org>.

National Institute of Allergy and Infectious Diseases. 6610 Rockledge Drive, MSC 6612, Bethesda, MD 20892–6612. Web site: <www.niaid.nih.gov>.

WEB SITES

"Drug Reactions." The Allergy Report. Available online at <www.aaaai.org/ar/working_vol3/051.asp> (accessed December 27, 2004).

Shepherd, Gillian. "Allergic Reactions to Drugs." Allergy & Asthma Advocate, Spring 2001. Available online at <www.aaaai.org/patients/advocate/2001/spring/reactions.stm> (accessed December 27, 2004).

Margaret Alic, Ph.D.