URTICARIA & ANGIOEDEMA

Please read the initial section on Allergic Respiratory Diseases to review the basic allergic process. Both urticaria (hives) and angioedema (swelling) represent aspects of the same basic problem. Underneath the skin, which is the largest organ in the body, there are a variety of cells and blood vessels. One of the cells is called a mast cell. The mast cell is involved with the acute phase (early phase) allergic reaction. When the mast cell recognizes a substance the person is allergic to (IgE antibodies on the surface of the mast cell identify the specific substance, i.e. penicillin, peanut, etc.) the mast cell releases preformed chemicals(mediators). These preformed chemicals cause leakage of fluid from nearby blood vessels, cause a sensation of itching, and can attract other cells (which can cause the late phase reaction). One of the primary preformed chemicals released is histamine. When the mast cells are located close to the surface of the skin the release of preformed chemicals causes a hive(urticaria). The typical urticarial lesion is raised (a bump), has a pale central area, surrounded by a red area, and is extremely itchy. Urticaria can vary tremendously, from small hives a few mm. in size to huge areas many cm. in size and can take any shape. If the mast cell only releases a slight amount of it's preformed chemicals, sometimes all you get is itching or a faint red rash. When the mast cell is located in deeper areas under the skin and it releases its preformed chemicals, you get a larger type of swelling (usually no redness, itching often less) called angioedema. This is the type of swelling that causes the lip or eyelid to swell several times its normal size. This type of swelling can occur anywhere on the skin (and also anywhere inside the body, but that's beyond this talk).

Now that you understand the basic process causing hives, the question that is useful to ask, is what makes the mast cell leaky (i.e. release it's preformed chemicals/mediators). If you always consider this question " what makes the mast cell leaky?" you will be on your way to sorting out the specific cause of your hives (urticaria) or angioedema (swelling). It always amazes me how everyone assumes hives are caused by a drug or foods. While allergy to drugs and foods certainly can cause hives, there are MANY other causes. This is one of the most important points to remember, that there are a large number of causes of urticaria and angioedema. If allergy is suspected of causing the hives, skin testing can be useful to confirm the diagnosis, as many IgE type 1 allergies can be confirmed usually showing a very positive skin test (the skin testing often produces a clear cut hive). Hives caused by allergy are always highly specific and occur every time an individual contacts the substance they are allergic to. For example if you are allergic to peanut or dog saliva, every single time you eat a peanut or every single time a dog licks your skin you will get hives. Because allergy is so specific, most individuals immediately pick up what they are allergic to within 2 or 3 exposures. For individuals who get hives multiple times who cannot figure it out, allergy is rarely the cause of the hives. However, there are a fairly large number of medication allergies (some type 1, others types 11 or higher) which cannot be confirmed by skin testing (often with medications this occurs because the specific molecule that caused the allergic reaction is a metabolic byproduct of the drug once it is ingested and this byproduct does not exist in the original drug pill-capsule form). That is why it is often very useful to have a person who gets hives or angioedema be seen by an allergist or a physician with experience in this area. If allergy is suspected of causing hives, this should always be proven by skin testing or occasionally challenge testing (keeping in mind that severe reactions often are confirmed by ruling out other suspect causes) if possible.

Medication Allergy – Individuals can become allergic to almost any medication, but keep in mind many reactions to drugs are not truly allergic and represent adverse/idiosyncratic reactions. An example would help. If a person took penicillin and after several days developed hives/itchy rash, skin testing would be useful to confirm this diagnosis. The infection itself can trigger hives so you cannot assume it was the penicillin. If the individual had a clear cut positive skin test to the specific penicillin they took and/or the basic penicillin molecule or a penicillin test material that contained breakdown products of penicillin (this simulates the metabolic byproducts) this confirms type 1, IgE, immediate allergy to penicillin, and this individual should avoid penicillin in the future (and get a Medic AlertTM bracelet). However, penicillin can also cause types 11, 111, and 1V allergy reactions which are not diagnosed by skin testing. These allergies tend to be more delayed types of reactions, often with other features in addition to possible hives, so the history of the reaction is critical. This is important for the individual to understand, because if allergy to penicillin is suspected, all other causes being ruled out, and the person has negative skin testing, they should understand the possibility that these other allergic reactions still exist, and they may have to practice appropriate avoidance measures still. As you can see, this begins to get complicated. The length of time the drug was taken, really doesn't help too much, as initial exposure to any new drug requires several days (often 7 to 10) for the body to produce IgE antibodies and a IgE based reaction. However, the length of time the hives/rash last after starting is very important (how long each separate hive lasts and how long the entire process of getting hives lasts). Once the person is IgE allergic to a drug, subsequent re-exposure results in an immediate allergic reaction. It is estimated that 85% of rashes (not just hives but all rashes) that occur when taking penicillin are due to the infection not true penicillin allergy. Another way of looking at this, is about 85% of individuals who think they are allergic to penicillin are not. Of the 15% where true penicillin allergy is the cause of the hives/rash, about 90% are caused by IgE reactions to penicillin with 10% having delayed penicillin allergy. Many individuals do not remember or know exactly what happened when they took penicillin (often in childhood) and if these individuals have negative skin testing to penicillin I will often say they can take penicillin in the future keeping in mind the 10% risk of delayed penicillin allergy we cannot test for. As most delayed types of allergy take several days of exposure to occur, if this individual develops a skin rash a few days after starting penicillin in the future, delayed allergy is assumed and further avoidance is recommended.

Keeping these points in mind, it is useful to look at the common causes of urticaria and angioedema, to see if you fit into one of these categories.

Occasional Single/Isolated Hives - often occurs in people who have multiple allergies, they will often note a single small hive or a few small hives will appear and then disappear on its own, they have noticed this for years, and there has been no change in the severity or frequency of the hives. The treatment is not to scratch the hive (scratching puts pressure on the leaky mast cells, causing them to release more chemicals, causing a larger hive).

Dermatographism - this is often a lifelong problem, these individuals develop a welt along any line where they have scratched themselves, they often say they have " sensitive skin", the welt is usually itchy, and a scratch anywhere on the body will result in a welt forming exactly where the scratch occurred. This is never serious. In essence, when the scratch occurs, the mast cells directly under the scratch are pressed on, leak a small amount of chemicals, resulting in a welt appearing – the mast cells are inherently leaky compared to a normal individual. 2 important points should be remembered. Dermatographic individuals have a higher risk of developing chronic urticaria (discussed below) or hives from any other cause. These individuals when skin tested (especially with the scratch method) are sometimes told they are allergic to "everything" because each scratch causes a welt. Needless to say this is poor testing. These individuals can be skin tested, but their testing requires extra care, multiple control scratches, requires several readings, and a longer time to interpret properly.

Physical Urticarias - this distinct group of individuals have specific physical triggers which cause hives. This is often a lifelong problem once it develops, although it can wax and wane, and again is not usually serious. In these people, a specific physical stimulus causes the mast cell to release it's preformed chemicals. The common physical triggers are : heat, pressure, and cold. If heat causes hives any activity that warms the skin will result in hives. These hives are often quite small and multiple. Examples include heating the skin up when exercising, having a hot bath or shower, pulling extra covers over yourself at night, etc. Two important points should be made : 1) if you are developing hives for any reason, heating the skin up will always make the hives worse, in this specific physical urticaria, only heating the skin up causes hives. 2) you only develop hives with no other symptoms (i.e. if you go running and develop hives along with difficulty breathing and tummy cramps, you may have exercise induced anaphylaxis). If exercise alone causes hives with no other symptoms, this is exercise induced urticaria ( although slightly different, the difference is beyond this discussion). Pressure urticaria requires extended pressure on a specific area for several minutes prior to the urticaria appearing. An example would be of a woman carrying a heavy purse with the strap over her shoulder while shopping. After shopping she notices a hive/swelling develop where the strap was pressing on her shoulder. In cold induced urticaria, the most common form occurs when a skin surface has been cooled sufficiently (any exposed skin area during our type of winter) and when subsequently rewarmed that area develops hives (often angioedema also). Some of these individuals develop hives immediately on cold exposure. This physical urticaria can be dangerous. If someone with cold urticaria has a major whole body cooling exposure (the worst is usually accidental emersion in ice cold water) they can develop such severe generalized urticaria and angioedema that it can be life threatening (in essence, so much fluid moves out of the blood vessels to cause generalized swelling that there is not sufficient fluid left in the blood stream to support adequate blood pressure). These individuals have to take extreme care in avoiding major cooling episodes, and often require an EPI-PENTM and regular treatment with antihistamines during the winter. The treatment of all physical urticaria is primary avoidance of the specific physical trigger often along with pre treatment with antihistamines. Antihistamines are much more effective taken prior to exposure (no matter what the cause), as the antihistamine blocks the histamine receptor prior to the mast cell leaking out histamine, and therefore blocking much of the histamine effect. If you take an antihistamine after getting hives or angioedema, the antihistamine will block further released histamine, but does not initially treat the areas where histamine has already had its effect. Fortunately, histamine wears off rapidly and taking an antihistamine helps within an hour in the affected areas also. Important point to remember, antihistamines are more effective taken prior to exposure-reaction.

Allergic Urticaria - this type of urticaria has been discussed above. The essential ingredient is exposure to a substance that you are allergic to with the subsequent development of hives or angioedema. It is completely specific upon exposure to a substance you are allergic to and does not occur without exposure. Usually these episodes of allergic urticaria will last minutes to hours in a given spot, and very rarely last more than a day (unless you are repeatedly getting re-exposed). This type of allergic reaction should be proven by appropriate testing if at all possible and appropriate avoidance measures taken subsequently. The allergic reaction that causes hives alone is not as serious as the reaction that causes anaphylaxis (where the skin and other systems are involved in the reaction). See the Anaphylaxis subsection for further details. Hives that last for more than 24 hours in a specific spot are rarely caused by IgE mediated allergy. Certain specific drug allergies and other immune system reactions have hives that last longer than a few hours. Virtually any substance that involves contact or ingestion can cause urticaria. All too often the diagnosis of allergic urticaria is assumed incorrectly, with subsequent unnecessary avoidance of a particular drug, food, or substance. A pretty good rule of thumb is the longer the urticaria lasts in a specific spot and the longer duration in days, the less likely it is that IgE mediated allergy is the cause.

Post Infection Urticaria- hives start after an infection sets in or up to a couple of weeks after an infection has cleared. This is very common in childhood and often occurs in individuals who are dermatographic. These hives usually appear and disappear over several hours in a specific area and last from 2 days to several weeks before stopping completely.

Vasculitic Urticaria - the hallmark of this urticaria is the area where the hive occurs often stays for days in the same place (whereas most types of urticaria come and go within minutes to hours) and this area develops or leaves a bruised appearance. This is an important entity to identify as it signifies an allergic or immune reaction going on in the body that is damaging small blood vessels (i.e. causing the bruise). This can be associated with several significant diseases, and can accompany similar damage to small blood vessels in other organs (the kidneys, etc.). This type of urticaria requires immediate assessment by a physician and appropriate investigations.

Chronic Urticaria - while all the above types of urticaria can last for minutes to days to several weeks, they rarely extend beyond a month's duration. By definition, chronic urticaria is a continuing (daily or almost daily) occurrence of hives that lasts at least six weeks or more in duration. The hives come and go with nothing that can be clearly identified as a trigger (they occur anywhere, anytime). This is why the history is so critical as to when the hives actually started. The vast majority of these cases are not similar to any of the kinds of urticaria discussed above. The majority of cases of chronic urticaria are caused by problems in the immune system. Although there are subtypes, a simple way of looking at this type of urticaria, is that the immune system directly affects the mast cells and makes them leaky. This type of urticaria tends to wax and wane over months to years, and usually is not serious. The major problem is the itching and distraction and lack of sleep that these chronic hives cause. The itching can be extraordinarily severe. In chronic urticaria we often don’t know what causes the immune system to initiate the hives, but then anything that stimulates the immune system can trigger hives or keep the hives occurring. There are a huge number of things that can stimulate the immune system including: hormones, stress, infection, allergies, medication, etc. Chronic urticaria is often associated with laboratory evidence of an overactive immune system (the common findings are thyroid antibodies, mild thyroid function abnormalities, and a mild positive ANA). It is important to know this, as these abnormal lab tests usually do not imply any major disease process going on. I always tell patients with chronic urticaria and thyroid antibodies present, that long term they have a greater chance of developing thyroid problems, whether it's overactive (hyperthyroidism) or underactive (hypothyroidism), but that this is very treatable. While it is extremely uncommon, chronic urticaria can occasionally be caused by some chronic diseases, parasitic infection, and very very rarely food allergy. Because the hives occur frequently and we cannot anticipate when the mast cells will leak, the treatment is to take high dose nonsedating antihistamines regularly (to completely block histamine receptors) so when mast cell mediator release occurs the individual stays comfortable. This treatment is very safe and continued until the immune system settles down on it’s own. If there is no evidence of any urticaria for 2 weeks on this regimen, the patient simply stops their antihistamine to see if it is still required.

Direct Drug Induced Urticaria – this type of reaction is not fully understood, but in essence these medications directly affect the mast cell causing it to leak it’s mediators with resulting hives/itching/angioedema. Because this is a direct effect, this reaction is dose dependent (whereas true allergic reactions can result from encountering very small amounts of allergen). This is critical to understand as any individual with this problem with one medication, if taking another medication in the same general drug group/class, would start with a very small amount of that drug and gradually increase the dose until reaching full dose or hives appear. Individuals vary considerably in the severity of reaction and the triggering dose. Individuals with a history of a severe reaction usually avoid the entire drug class and can only be tested under monitored/hospital conditions. There are two common classes of drugs that can cause this type of reaction. The first are the narcotics (codeine, morphine, oxycodone, Demerol, etc.). The second are the nonsteroidal anti-inflammatories (NSAIs) including : ASA(aspirinTM,etc.), Ibuprofen(AdvilTM,etc.), NaprosynTM, Naproxen(AleeveTM,etc), Indomethacin(IndocidTM), Celecoxib(CelebrexTM),etc. For further details read the subsection on NSAI Sensitivity.

TREATMENT

There are other rare types of urticaria, but the above types cover the majority of cases. The treatment of urticaria is very straightforward. If a specific substance or physical exposure caused the urticaria, avoidance is the treatment of choice. Keeping the skin cool helps as excessive heating of the skin always makes the mast cell more unstable. If hives occur the area must not be scratched as scratching causes the mast cell to leak more and makes the hives/itching worse. H1 antihistamines are the mainstay of drug treatment. Remember, taking an antihistamine prior to developing hives is more effective. If you are getting hives more frequently than twice a week consider taking antihistamines regularly. The antihistamines of choice are the nonsedating newer agents (ReactineTM (ceterizine), ClaritinTM (loratadine), AllegraTM (fexofenadine) or AeriusTM (desloratadine). These antihistamines are safe and have no significant drug interactions. Ceterizine is slightly more effective for hives but also is associated with a slight increased incidence of sedation that the other three antihistamines do not have. Often individuals will find one antihistamine that seems to suit them better. Older antihistamines should be avoided, as they have been shown to cause significant sedation and adversely affect motor performance and memory, even though the individual taking the antihistamine says they feel fine. There is some use for older antihistamines (BenadrylTM (diphenhydramine), AtaraxTM (hydroxyzine) at bedtime, to promote sleep and to be used as additional medication for breakthrough hives while on a regular nonsedating antihistamines. Older antihistamines have additional effects in addition to blocking the histamine receptor which is why they cause impairment of motor function and memory with the patient often not aware of this impairment (which is why they can be dangerous as the individual feels they are OK while taking them). Doxepin, an antidepressant, has extremely potent antihistamine properties, but is very sedating, and should be used cautiously because of this. Occasionally the H2 antihistamines (used to reduce acid in the stomach), such as ranitidine etc., can be added on top of your standard H1 antihistamines to provide better control, particularly in chronic urticaria. If the above treatments do not control urticaria, other medications can be tried to block other chemical mediators that are released by the mast cell. This is where a physician experienced in this area can help. These other medications range from Singulair, to hormone preparations, to drugs affecting the immune system, and generally carry a much higher risk of adverse reaction. A special mention should be made about prednisone. While prednisone is almost always effective in treating hives, there are only very specific situations where this should be used (when you want a major anti-inflammatory or anti-immune system effect). Using prednisone for standard types of urticaria is not appropriate, and should be the drug of last choice in chronic urticaria as these patients always rebound (urticaria comes immediately back) when the prednisone is stopped. Long term prednisone use has many adverse effects.

Angioedema - I will not go into this area in any significant detail. People who suffer from recurrent pure angioedema (without hives/itching) should always be assessed by a physician experienced in this area. In essence, there are two basic types of pure angioedema that occur. The first type is hereditary angioedema, where there is a family history usually, and specific lab tests should be carried out to prove this diagnosis with other family members also being tested if this diagnosis is made. The other type is secondary angioedema - which includes all other causes. Angioedema that occurs with hives and itching usually is part of the urticaria group as reviewed above. Angioedema (remember, this is the larger swelling that can occur that has no accompanying hives and no itching) requires assessment and investigation. Virtually all the causes of angioedema are created by problems within the immune system, whether it be a hereditary immune system problem or a secondary (acquired) immune system problem (i.e. a immune system problem caused by a specific disease, etc.). The immune system is extremely complicated and is based on a huge number of different cells interacting in complex ways with an unbelievable number of chemicals(mediators) involved in these interactions (and we are discovering more every day). A special mention should be made about a class of medications called ACE inhibitors. These medications (captopril, enalapril, ramipril, cilazapril, fosinopril, lisinopril, quinapril, others) are used to treat high blood pressure, heart failure, and diabetics. They can occasionally cause angioedema which usually affects the head, neck and throat. This is sporadic, can occur after being on the drug for years, and is an idiosyncratic reaction (not a true allergic reaction). If these drugs cause an episode of angioedema this class of medications should be avoided if at all possible as fatalities have occurred.

End - Dr. Bruce Sweet 2013