Anaphylaxis

Allergic Reactions

What is an allergic reaction? 

An allergic reaction is an overactive or misdirected immune response that results in local tissue injury or changes throughout the body in response to a foreign substance. These reactions can be caused by many factors, including chemo treatments. Immune response to a foreign substance is potentially a "two-edged sword" it can either protect or harm the host. It protects us from foreign substances such as viruses or bacteria, but it can also bring about an exaggerated (hypersensitive) response when previously sensitized individuals are exposed to the same foreign substance. Food allergies, including allergy to peanuts and tree nuts, are said to account for the majority of fatal or near fatal anaphylactic reactions in the US.

What are other terms can be used for allergic reactions?

A mild to moderate reaction to anti-cancer therapy, such as chemotherapy or monoclonal antibodies, may also be known as a hypersensitivity reaction or an infusion reaction. A more severe type of allergic reaction is known as anaphylaxis, which can be fatal in some cases. Symptoms may overlap between infusion reactions and anaphylaxis. Quick identification and intervention of symptoms related to an infusion or anaphylactic reaction are important. 

What drugs are known to cause allergic reactions? 

Infusion reactions can range in severity from mild to severe or life threatening, although most are mild and occur within one hour of drug administration. Reactions can occur at time during therapy, although there may be specific time points when they are more likely to occur with each individual drug. 

Infusion reactions have been reported with most chemotherapy drugs. Anaphylactic reactions are rare, but can occur more commonly with platinum drugs (like carboplatin and oxaliplatin), taxanes (paclitaxel and docetaxel), and less often with other drugs including L-asparaginase, cyclophosphamide, ifosfamide, ixabepilone, procarbazine, and cytarabine. 

Infusion reactions to monoclonal antibodies typically develop within 30 minutes to two hours after the start of the infusion, although can be delayed for up to 24 hours. Most reactions occur after the first or second exposure to the drug. Infusion reactions are more common with certain monoclonal antibodies, including rituximab, cetuximab, alemtuzumab, traztuzumab and daratumumab, and less commonly with others including blinatumomab, elotuzumab, gemtuzumab ozogamicin, isatuximab, moxetumomab, ofatutumab, olaratumab, pertuzumab, polatuzumab, ramucirumab, and scaituzumab govitecan. Some monoclonal antibodies, particularly cetuxmiab, rituximab and trastzumab can also cause anaphylaxis. 

Infusion reactions have also been reported with immunotherapy drugs that target PD-1 and PD-L1. Most reactions tend to be mild, and have been observed with nivolumab, durvalumab, atezolizumab, avelumab, pembrolizumab and cemiplimab. Severe or life-threatening reactions are rare. 

What precautions are taken to prevent allergic reactions? 

Care is taken when working with anti-cancer drugs that are known to cause infusion reactions, which can prevent or lessen the severity of reactions by using pre-medications. Healthcare providers and nurses are trained to promptly recognize signs and symptoms of allergic reactions. For some drugs, the rate of administration is started slow and gradually increased based on tolerance to minimize the incidence of infusion reaction. Other drugs have low rates of infusion reactions when certain pre-medications are used. Anaphylactic reactions cannot be prevented by premedications, although the severity may be reduced. Quick identification of symptoms of an anaphylactic reaction is important to survival.

Things you can do to minimize the effects of cancer therapy related reactions:

• Notify your healthcare provider of any allergies you may have, including food and drugs. Also let your healthcare provider know if you have had an allergic reaction to any drugs - specifically chemo treatments - in the past. If you are unsure if it was an allergic reaction or a side effect of the drug it is better to bring it up for discussion.
• Be aware of what caused the reaction. Notify your healthcare provider that this substance causes reactions. Medication may have to be given before the drug is given again, or a different drug may have to be substituted.
• Take prescribed pre-medications prior to chemotherapy as directed. If you forget let your healthcare provider know.
• If you develop a rash that is not causing you discomfort make sure your health care provider is aware of the rash so it can be evaluated. Not all rashes require treatment.

What are common symptoms of infusion and/or allergic reactions?

Symptoms of infusion and/or allergic reactions can vary widely by patient and medication. Healthcare providers and nurses are trained to promptly recognize signs and symptoms of allergic reactions. 

If you think you may be having a reaction, notify your healthcare team immediately

• Hives (urticaria): May develop quickly or up to 36 hours later. These lesions tend to be raised, red and itchy
• Facial swelling (angioedema): May occur with or without hives, but tends to happen much less often than hives alone. The tongue, lips, or eyelids are generally affected. Swelling of the airways can result in difficulty breathing, closing off of the airway and death. If facial swelling with or without difficulty or speaking, seek help immediately.
• Breathing Difficulty (Hypoxia): May occur with or without shortness of breath, wheezing, throat tightness, cough or repetitive cough. Seek help immediately if you notice any new-onset breathing difficulty. 
• Itching (pruritis): May or may not be associated with a rash
• Flushing: May temporarily occur on the face and neck and can feel warm
• Rash (Maculopapular rash): May look like a combination of small, distinct, flat reddened areas and small, raised bumps, and is the most common type of drug-induced allergic skin reactions. 
• Usually, it starts on the chest, neck, arms, and legs, while the face may be spared. The rash is usually bright red in color and the skin may feel hot, burning or itchy. 
• A severe form of an allergic rash can be a wide spread, red rash that blends together. Often associated with peeling of the skin, and desquamation (areas of wet or dry open sores (also known as Stevens-Johnson syndrome). There may be other symptoms such as fever, lymph node enlargement, and loss of appetite.
• Back pain or abdominal pain: May be more common with infusion reactions than anaphylaxis 
• Fever and/or shaking chills: May be more common with infusion reactions, may be associated with flushing and/or blood pressure changes. 
• Blood Pressure changes: Low (Hypotension) or High (Hypertension): Associated symptoms may include Dizziness, Fainting, Loss of Consciousness, Heart Rate changes: Fast (Tachycardia) or Slow (Bradycardia) or Seizure. It is important to notify your health care team or seek care immediately if you notice any of these symptoms. These symptoms can be associated with both infusion reactions and anaphylaxis

If you feel you are having allergic reactions brought on by cancer treatments, seek emergency help immediately and notify your health care provider, it you experience the following symptoms:

• Shortness of breath
• Wheezing
• Difficulty breathing 
• Tightening or closing up of the throat
• Facial swelling
• Hives 
• Dizziness, feeling faint or a loss of consciousness

Contact your health care provider within 24 hours of noticing any of the following allergic reactions so the following can be evaluated:

• Skin rash
• Itching
• Hives
• Fever

How are reactions managed?

Many mild to moderate infusion reactions are managed by temporary interruption of the infusion, the treatment of any symptoms, additional premedication and possibly restarting the infusion at a reduced rate.

Anaphylaxis is a more severe type of allergic reaction, which can cause shortness of breath, low blood pressure, shock and occasionally death. Quick identification and treatment of an anaphylactic reaction is important to survival. 

If a drug causes a severe infusion reaction or anaphylactic reaction, treatment with epinephrine, antihistamines, steroids, supplemental oxygen and/or intravenous fluids may be required. It may be necessary to stay in the hospital for observation. Re-challenge is typically discouraged. It is important to report any allergies or allergic reactions to drugs taken in the past to your health care provider. 

General drug classes used in treatment of cancer-related allergic reactions include:

• Antihistamines: These drugs block histamine receptors, which are commonly released in allergic reactions. There are 2 types of histamine receptors that have differing actions, H1 and H2 receptors. 
• Examples of antihistamines are: diphenhydramine, hydroxyzine, loratidine, cetirizine famotidine and cimetidine.
• Corticosteroids: Steroids work by decreasing inflammation and swelling. People may benefit from steroids, either inhaled, by pill form, or in the vein (IV)
• Steroids are most often are given by IV or by pill as premedication. 
• Steroids can also be used to help quickly relieve symptoms of an infusion or anaphylactic reaction with severe shortness of breath and airway inflammation either by pill, IV or inhalation (aerosol).
• Examples of corticosteroids include dexamethasone, prednisone, solumedrol, hydrocortisone and budesonide.  
• Bronchodilators: These drugs work by opening (or dilating) the lung passages, and offering relief of symptoms, including shortness of breath. These drugs, typically given by inhalation (aerosol).
• Examples of bronchodilators include albuterol, ipratropium or terbutaline. 
• Epinephrine, is used in an emergency situation and works to dilate airways while constricting blood flow to increase heart rate and blood pressure
• Antipyretic: Acetaminophen can be used both as a premedication and treatment for mild infusion reactions. It is sometimes used in combination with antihistamines and/or corticosteroids. 

If you feel you are having allergic reactions brought on by cancer treatments, the following guidelines suggest when to notify your doctor or health care provider:

Seek emergency help immediately and notify your health care provider, if you experience the following symptoms:

• Shortness of breath

• Wheezing

• Difficulty breathing

• Tightening or closing up of the throat

• Swelling of facial features

• Hives 

Contact your health care provider within 24 hours of noticing any of the following allergic reactions so the following can be evaluated:

• Skin rash

• Itching

• Hives

What is a desensitization or a desensitization protocol?

Desensitization is the process of reintroducing a medication to which a person previously had a severe infusion reaction or anaphylactic reaction. Typically this is done when there is ongoing benefit of further treatment with a specific drug and no other reasonable alternatives exist. This is done in a highly controlled and monitored environment using a series of sequential steps and additional pre-medications. Desensitization should only be carried out in a setting that is comfortable with the emergency management of anaphylaxis and by trained medical personnel. Desensitization induces a state of temporary tolerance to a medication, but that tolerance is lost after completing the infusion and must be repeated each time the drug is given. Referral to an allergy specialist, with experience in drug desensitization is recommended.