Twenty percent of individuals (one in every five), of all ages, races, and/or gender have experienced at least one episode of “hives”, welts or urticaria in their lifetime, lasting from minutes to years. These, usually very itchy (“pruritic”), reddened (erythematous), lesions (“hives”, welts, or urticaria), can vary in size from a small mosquito-bite (papular urticaria) to plaques, which cover the entire body (“giant hives”). In some, the hives occur with swelling (angioedema) of the lips, eyelids, and/or other “soft” tissues. (See below.) Fortunately, these hives, (welts, urticaria), and swellings will disappear with or without treatment (spontaneously) in time. Unfortunately, like a “fever”, “cough”, and “aches”, there is no single cause for their occurrence, it is not a disease (like acne, psoriasis or melanoma), and relief of its’ intolerable itch is more attainable than the identification of its suspected cause. Conventional wisdom decrees taking Benadryl (the “best known”, least effective of the over-the-counter available antihistamines), and/or prednisone (a most effective symptom-relieving medication, which can be potentially harmful, with long-term use), then start the frustrating search for a mysterious “allergen” that is causing the hives. Eventually, one realizes, that there is no magical “cure” for chronic, or persistent (idiopathic) hives/urticaria, only some welcomed relief!
How hives occur
Hives are, almost exclusively the skin’s reaction to histamine, a chemical alarm released by mast cells, one of the many key players of our immune (protection) system. Mast cells are found in every organ of the body, and those in the skin are its major source of histamine.
When mast cells are triggered to release histamine into the skin, a characteristic reaction recognized as (1) itch (pruritus) at the site, felt within seconds; (2) redness (erythema) at the same site within minutes; and shortly thereafter (3) a raised wheal (urticaria). Immunologists and dermatologists know this reaction (when histamineis in the skin), as the Triple Response of Lewis. Figure 2 demonstrates this response to a test injection of histamine just under the skin of a subject’s forearm. The raised wheal and surrounding redness are visible, and the subject will experience severe itching. The response will then disappear within 20-30 minutes, because the body promptly breaks down (metabolizes) histamine to an inactive chemical.
Acute urticaria indicates the release of histamine from a patient’s mast cells with their first bout of hives, or when the cause for that histamine release is readily identifiable, i.e. within the first15-20 minutes after taking a medication (usually a penicillin), or a food acting as an “allergen”. A foreign “allergen” (a specific amino acid) in these agents trigger the sensitized patients’ (those having the ability to produce IgE antibodies to the specific amino acid) mast cells to release the preformed histamine contained, producing the hive (welt, urticaria). Once the “antigen” is metabolized (“broken down”), and/or passes through the gastrointestinal tract, the mast cells are no longer activated and the hives dissipate (fade away), within 20-30 minutes after its onset, as the final step of the “Triple Response” (see above). These patients rarely require treatment, since the lesions disappear within a short time, and they quickly perceive that avoidance of the “allergen” prevents the recurrence of hives, and every-time that “allergen” is administered, the hives recur. Unfortunately, every IgE-induced urticaria has the potential of heralding (progressing to) an anaphylactic reaction. Anaphylaxis can be a most severe allergic reaction (with hives, sneezing, wheezing and shock) and occasionally may be fatal.
Chronic urticaria indicates that, the patient’s hives have lasted for longer periods of time (from weeks to months). The hyper-reactive (“twitchy”) mast cells of patients with chronic hives are usually, for some unknown reason easily activated, releasing increased amounts of histamine. Eventually the unidentifiable “trigger” will disappear just as inexplicably as it appeared (within minutes to years). These usually non-IgE (chemicals not belonging to the IgE family) reactions can only cause anaphylactoid reactions, and not anaphylaxis, therefore having a rare lethal potential.
Angioedema is erroneously, frequently regarded as a “deep” hive, however it is a non-erythematous (not red), non-pruritic (not itchy) swelling of any “soft” tissue of the body i.e. eyelids, lips, tongue, genitals, joints, etc.). It cannot be reproduced by injecting histamine under the skin, and does not respond to the administration of antihistamines. (They usually resolve spontaneously – with or without any treatment, within 96 hours.) The few biopsies studied do not show the same microscopic changes that are seen with hives (urticaria).
The confusion arises from the observation that angioedema does occur at times with hives (welts, urticaria), especially when the hives are caused by aspirin, ibuprofen [and other NSAIDs], and IgE-allergens. More often AE occurs without hives, especially when triggered by the blood pressure medications known as ACE-inhibitors, or as part of a rare hereditary disease (Hereditary AngioEdema (HAE). When no trigger is identifiable, the angioedema is considered idiopathic
The Work-up/Looking for a possible cause of hives:
“Acute” hives (urticaria) is the label given with the first episode of hives, or when the “trigger” for the appearance of the hives is readily identifiable from the history.
Drugs (medications) are the most common identifiable cause of acute urticaria. (See Figure 3,) These hives appear within 36 hours of a dose, and they may be seen over the entire body (generalized). Some of the hives will fade, while new ones continue to appear elsewhere. It is unusual for drug-induced hives to appear days or weeks after discontinuing the medication. This pattern is the typical “allergic” (IgE-induced) reaction, and occurs only after one has been sensitized to the drug earlier in their life! IgE-reactions require prior sensitization, whereas, non-IgE reactions, such as aspirin/NSAID hypersensitivity reactions (the second most common cause of drug-induced hives, usually with skin swellings [angioedema] –see above), can occur after a first dose. Any drug has the potential to cause an IgE-type hive on re-exposure – some medications more often than others. Therefore, it is essential to obtain a complete “drug history” – including, alternative remedies, vitamins, eye drops, douches, etc. (Late reactions to drugs), which usually occur after 72 hours, often 5-10 days into the course of therapy – are not urticarial (hives), but more measle-like, and often, predominantly on the arms and legs – never causing anaphylaxis.
Foods – a less frequent cause of hives. When foods are the cause, they are frequently accompanied with nausea, cramps, diarrhea, and/or vomiting. Seven foods cause 85%-90% of the “allergic” (IgE) food reactions! Peanuts, shellfish, tree nuts, milk, egg, wheat, and soy are the major culprits. Other adverse food-induced, non-allergic (not IgE) reactions with or without hives, welts or urticaria do occur. “Non-allergic” (not IgE-induced) reactions are usually dose-related, meaning a small amount (dose) may not cause a reaction, but larger amounts result in a response (this is frequently noted with eating strawberries – a non-allergic (not caused by IgE). Most individuals get no hives if they eat a few strawberries, but develop generalized itching and/or hives when they eat many strawberries).
Our immune (protection) system’s memory remains remarkable, and is most active in younger, healthy individuals – it rarely, if ever forgets one is allergic (IgE sensitive) to a drug or a particular food, and suspecting, or blaming “something new” as the cause of one’s hives is always disappointing. Thus, if one can ingest a drug or a food without a reaction sometimes, and react to it at other times, then it is not allergic (IgE-induced). (Geriatric patients [senior citizens], however, often believe they have “outgrown” their allergies, but – as one ages, the immune system becomes less efficient, producing less immunoglobulins and surveillence cells, and is less likely to react adversely to a formerly allergenic substance, this is recognized as “immuno-senescence”).
When the cause of the hives is clear to both the patient and the healthcare provider, a complete history and physical examination is less pressing. Avoidance of that allergen is the treatment of choice. Since, patients with episodes of “acute” urticaria, are always at risk of having an anaphylactic type reaction, these patients with episodic bouts of hives, and no identifiable trigger, it becomes imperative to search for the cause, enabling them to avoid it. Skin prick testing or RAST (blood) testing for the seven common allergenic foods can be vital, while “at random” food allergy test results must always be interpreted in the context of the medical history, because many positive results do not equate with clinical symptoms – these are considered biologically false positive results. There is no need to stop eating a positive food test result, if that food is ingested without having hives, or any other “allergic” symptom. Atopic patients (those having a genetic tendency of producing increased amounts of IgE antibodies, and having a history of eczema, asthma and/or allergic rhinitis [hay fever]) often have many false positive food RAST results.
Physical urticaria occur in response to a (usually obvious) physical stimulus. They appear within minutes of direct stimulation of the skin by stroking, pressure, sunlight (ultraviolet light), heat, cold, or water.
Dermatographia (literally writing on the skin), occurs with stroking, or scratching the skin, and a wheal reproduces the path of the stroking or scratching (see figures above ). This reaction occurs in 3-5% of the population, especially while being treated with aspirin, penicillin, or have an upper respiratory infection, or scabies. Most physical urticaria fade within 30 minutes of onset, and rarely require treatment, but there are some very sensitive individuals that will react with the slightest physical contact, and these patients then require treatment for comfort.
Pressure urticaria appear when pressure of a belt on the skin, or prolonged sitting on the backside, or standing on the soles of the feet. In women, they are frequently seen under bra straps. This is the most common type of physical urticaria, and is noted in almost everyone that is having hives.
A drop (cold) or rise (heat) of temperature of the skin can cause hives in susceptible individuals. The source of the heat can be external or internal body heat. Since physical exertion can raise the core body temperature, exercise sometimes causes hives, known as cholinergic urticaria. The ability of (cold) temperature to cause histamine release can also be demonstrated by touching a patient’s skin with an ice cube (producing cold urticaria – see figure 1). Fatal, sudden fall of core temperature has been observed in patients with cold urticaria, diving into a cold stream or pool.
Solar urticaria are produced with exposure to different rays of ultra violet light (sun). Figure to the right illustrates this reaction in a subject whose back was covered with a stencil during exposure to a sun lamp.
Aquagenic urticaria may occur, in sensitized individuals, with direct contact with water of any temperature. The cause of a patient’s mast cell activation, by such common stimuli is unknown.
There is a rare disorder, resulting from an increased number of mast cells in the skin, and other organs, known as mastocytosis. Patients with mastocytosis are recognized because stroking of their skin readily produces dermatographia. Their management is similar to other patients with that skin finding. Rarely patients with mastocytosis can develop systemic symptoms by unrecognized activation of their mast cells in their internal organs releasing mediators, and may require more aggressive treatment.
Contact urticaria- refers to the hive, wheal and redness resulting upon contact of a skin site with a triggering substance, appearing in 15-60 minutes after contact. Contact urticaria is not considered an “allergic” (not IgE) reaction. Common examples of contact urticaria (resulting on touching) include jellyfish, nettles, and one of several chemicals – eugenol, formaldehyde, etc.), and require no prior exposure (sensitization). Absolute avoidance prevents contact urticaria.
Urticaria are rarely, the presenting (first) symptom of an underlying systemic disease – except for Hepatitis B infections. Hives may occur concurrently in patients who have certain underlying problems, such as hypo- or hyper- thyroidism, Systemic Lupus Erythematosis, Rheumatoid arthritis, (“vasculitis” See Figure 5) and some very rare diseases such as Still’s Disease, Muckle-Wells Syndrome, Combined Immuno-deficiencies, or Schnitzler’s disease. Unless the history suggests documentation to support a “trigger” or mechanism, “random” tests are rarely, if ever clinically indicated. Tests merely confirm a clinical impression, but are unlikely to identify a hidden “trigger” (cause).
Chronic Idiopathic Urticaria
When no cause is recognized, the hives, welts of urticaria are labeled “idiopathic”. Forty percent of patients with Chronic Idiopathic Urticaria, have been found to produce an antibody to their own mast cells – and are recognized as having an “auto-immune” mechanism (“trigger”) type of hive. “Auto-immunity” is a mechanism whereby the body, for unknown reasons, attempts to reject one of its own natural tissues or cells. (Examples are – Hashimoto’s thyroiditis, Alopecia areata, vitiligo, Crohn’s disease, etc..) The autoimmune-mechanized hive patients are less responsive to “standard” treatments. They present a special challenge to most health providers. See “treatment” below. Another mechanism, which could be just as challenging to treat is recognized as urticarial vasculitis (a mechanism, not a cause) – this type of hive usually presents differently, it is often “purpuric” (fine lines of bleeding, blood vessels in the skin), and are frequently accompanied by potentially serious systemic symptoms, i.e. hematuria (blood in the urine), joint pains, headaches, etc., and is best confirmed with a biopsy. (See Figure 6.)
A “biopsy’ is a most valuable test to support the diagnosis of “idiopathic” urticaria. The latter remains a diagnosis of exclusion, thus when the history does not suggest a specific “trigger”, and “aggressive” standardized courses of treatment are not relieving the symptoms – more information may help in the management of the patient. Urticarial vasculitis can only be confirmed with a biopsy. When the biopsy reveals a particular white blood cell (i.e neutrophil), as the predominant inflammatory cell – it suggests a course of other treatments (i.e. “sulfones”, hydroxyquinone, colchicine). Elderly patient with hives (usually not responding to standard anti-histamine treatment) should be biopsied to identify bullous pemphigoid, another type of autoimmune problem, which often present as persisting, scaly hives, occurring almost exclusively in the elderly, and usually require long-term prednisone (a “steroid”) for effective management.
Appropriate laboratory (blood) tests are helpful when the obtained history indicates signs and/or symptoms of a possible cause for the urticaria. Random testing (laboratory, blood, and/or “allergy” tests) are almost always disappointingly “normal”, but may be required to support the absence of an underlying medical problems. Provocative challenges with suspicious allergens are extremely reliable, however, due to the high risk of anaphylaxis, should be done in a monitored location – a clinic or hospital. Most essential for finding a cause, to recommend an effective course of management for a patient with persistent, or episodic hives, is obtaining a very careful, reliable history, from the onset of the hives, and the progression till the present status, including the effect of all prescribed treatments.
Treatment of hives (welts. Urticaria)
Avoidance of a recognized “trigger” is essential. Persistence of hives suggests the “trigger” is still present, whether it is a drug, food, physical agent, or unidentifiable agent or mechanism.
Antihistamines remain the primary medicinal treatment for all types hives, welts, urticaria. The challenge for their use is appreciating the subtle differences between each available antihistamine, amount and frequency of administration, and whether supplementary medications deserve to be added.
Diphenhydramine (Benadryl) was discovered in 1940, and promptly noted to effectively block the Triple Response of Lewis (see above), when administered 15-60 minutes prior to introducing the histamine. It was then successfully utilized for reducing (and/or eliminating) clinical symptoms caused by histamine (i.e. urticaria, “hay fever”, etc).
Unfortunately, 4-8 hours after the administration of this antihistamine, the histamine reaction (i.e hiving, sneezing, etc.) was noted to recur! That was due to the Benadryl “half-life” (i.e. its natural break down to an inactive compound which no longer “blocks” the histamine reaction). An antihistamine does not “cure” the cause of the symptom (hive), it merely effectively “blocks” the released histamine from producing the symptom (the itch, redness and welt). Therefore, the doses of diphenhydramine must be administered every 4-8 hours to control the symptoms for longer periods of time.
In those patients who do not respond completely, or only partially to the administered antihistamine indicate that histamine may not be the sole chemical (mediator) from the mast, or other inflammatory cells that is producing the “hive” or urticaria – and these “other” mediators contribute variable features to the classic histamine-induced hive. The non-histamine-induced hives may not fade within 30 minutes, and more often can persist for hours. These hives may itch less, or more, and sometimes the itch feels “burning” and/or painful. Antihistamines are only effective for the histamine-induced effect of the urticaria, and antagonists that block the effect of the other pro-inflammatory mediators may be required. The more the hive behaves like the Triple Response of Lewis, the more likely it would respond to antihistamines. A reason for failure of response to “recommended” doses of antihistamines is that since, antihistamines are competitive inhibitors, i.e they compete with histamine for a (receptor) site on a blood vessel or cell, and when the histamine occupies a histamine receptor site, firstly it does not displace histamine in the receptor, and secondly there may be too many activated receptor sites for the amount of available antihistamine that was administered, and more antihistamine may be required to block more hives (urticaria) to form. Newer antihistamines (i.e hydroxyzine, cetirizine, loratadine, fexofenadine) have been developed, which are more effective in blocking many more histamine receptors than Benadryl, and can be administered in higher doses yet cause fewer bothersome side effects (i.e. drowsiness, headaches, etc). (See below.)
Treatment of Acute hives (urticaria)
1. Avoid the recognized “trigger” – The shorter the period between administration or exposure of the “trigger” (allergen) i.e. food, medication, insect sting, latex, and the appearance of hives, with rapid spreading, especially if accompanied with itchy scalp, soft palate, genitals, palms and soles, swelling of the throat, shortness of breath, wheezing, or tightness in the chest, the greater the signal of impending anaphylaxis. These potentially dangerous signs and symptoms should not be taken lightly, and demands:
a) Epinephrine/EpiPen (adrenalin) 0.1-0.5 mgm, 1:1000 solution, subcutaneously or intramuscularly every 5-15 minutes, or must proceed immediately to an Emergency Facility for its administration. (Intravenous fluids may be required.)
b) Antihistamines, H1 and H2 types orally (i.e. H1 type – diphenhydramine 50 mgms [Benadryl], loratidine 10 mgms [Claritin], fexofenadine 180 mgms [Allegra], cetirizine 10mgms [Zyrtec]; H2 type – cimetidine [Tagamet]; doxepin and amitriptyline 10-25mgm [contain most potent both H1 and H2 antagonists;) should be administered immediately. Should the signs of anaphylaxis (see above) start to appear after taking the antihistamines, epinephrine may be indicated.
c) Antileucotrienes (montelukast) Singulair 10 mgms, every 24 hours especially for patients with a history of dermatographia, and/or angioedema.
d) “Steroids” i.e. prednisone, methylprednisilone, is never a “rescue” medication, the healthcare provider must decide whether it should be given for control of a potential “late phase” reaction, and added as a supplement to the standard antihistamine regimen. Gradually weaning from steroids is only indicated if the medication has been administered for longer than 2-3 weeks. It is not unusual for the hives to recur when the steroid is discontinued. There will be patients who will require a low dose of steroids for maintenance, until no hives are noted for 96 hours while taking the steroid. (Steroids are not a “cure”.)
For an initial episode of hives, or recurrent episode (non-“allergic”) with no progression to anaphylaxis, the management is as above omitting the urgency for the administration of epinephrine (adrenalin). Most often the hives (urticaria) are well managed with an appropriate “cocktail” of antihistamines.
Diphenhydramine (Benadryl) 50 mgms, which is the most recognized of all the antihistamines, but the least effective and has the most “side-effects”. Histamine in our brain maintains alertness, therefore when it is blocked in the brain, by an antihistamine, drowsiness can occur. More importantly, in approximately 40% of individuals that take diphenhydramine, experience impaired cognitive function, which has the same effect on driving as DWI levels of alcohol. The older antihistamines (i.e hydroxyzine [Atarax]; chlortrimeton; cyproheptadine [Periactin]) also have other bothersome side-effects, especially anticholinergic – resulting in dryness of the mouth, nose and eyes, and Periactin can increase ones appetite.
The newer antihistamines (loratidine [Claritin]; fexofenadine [Allegra]; cetirizine [Zyrtec,Xyzol] are more effective histamine antagonists, and are less likely to affect the brain causing less, to no drowsiness, and most importantly, impairing cognitive function minimally. The newer antihistamines also can be administered less often (every eight to twenty-four hours). Interestingly, it has been noted that combining the newer antihistamines, can be more effective than increasing the dose of each one, individually. Small doses of selected tricyclic antidepressant medications (i.e doxepin 10-25mgms, amitryptaline 10 mgms) are the most effective antihistamines available. However, the latter drugs can be very hypnotic (sleep-inducing), and is best given at bedtime.
Management of Chronic Idiopathic Urticaria (CIU)
Review of the last fifty years of literature regarding the natural history of chronic idiopathic urticaria (CIU) indicates, with or without treatment:
50% of patients with CIU resolve within 3-12 months
20% of patients with CIU resolve within 12-36 months
20% of patients with CIU resolve within 36-60 months
2% of patients with CIU may continue (especially episodically) to hive for many years.
However, more than half all patients with CIU will experience recurrent episodes!
Since there is no identifiable cause for “idiopathic” hives, there is no need to avoid any imaginary cause! Antihistamines remain the primary medication, for the management of CIU. The dosage for these patients may require frequent adjustments of the dose (titration) with each flare-up (exacerbation) and remission. (Just as for patients with diabetes, who must adjust their dose of insulin by measuring the amount of sugar in their blood, or urine. Unfortunately, the only sign of increased need for antihistamines for patients with CIU, is the visible increase of the hives, or “itch”.) Combining the second generation of antihistamines (loratidine, fexofenadine, the cetirizines) is often more rewarding than increasing one type alone.
The second medication for CIU is the antileucotriene (Singulair 10 mgm every 24 hours), especially if the patient also reports having had, or has dermatographism, and/or angioedema. Response to the primary and secondary medication should be noted within 48 hours, and if the symptoms (itching, hiving) are still intolerable, the health care provider will decide if the patient requires a tertiary drug: sulfone, an anti-malarial, or immunosuppressant (i.e glucocorticosteroids, cyclosporine). The decision to use the tertiary medications are added to the “cocktail” of primary drugs, and determined from special testing, namely biopsy, and/or the presence of autoimmune antibodies. Each of the tertiary medications requires careful, regular examinations (for blood pressure, eye examinations) and blood tests. Properly monitored, the use of these drugs is less a risk than driving to the doctor’s office.
The success of all treatments depends on the compliance of the patient. It is common for patients who are required to take medications for long periods of time, to become less compliant (skipping and/or discontinue their medication without a health care providers instructions!). The health care provider should explain the realistic objectives of the treatment. There are but a few disorders that can truly be “cured”, while relief of discomfort is usually achievable.
Urticaria and Angioedema (Textbook) – ed Greaves MW, Kaplan AP. Marcel Dekker, In c. 2004;New York.
AAAAIA & ACAAI. Diagnosis and Management of Urticaria: A Practice Parameter. Ann Allergy Asthma Immunol. 2000;85:S521-544.
Brodell LA, Beck LA, Saini SS. Pathophysiology of Chronic Urticaria. Ann Allergy Asthma Immunol 2008;100:291-298.
Castenado-Tardan MP, Jacob SE, Baumann LS. Contact Urticaria to Cosmetics and toiletry Ingredients. Cosmetic Dermatology 2008;21:339-346.
Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence-based review, part 1.Ann Allergy Asthma Immunol 2008;100:403-412.
Beltrani, VS. Angioedema: Some “New” Thoughts Regarding Idiopathic Angioedema – Chapter 19. In Urticaria and Angioedema, eds Greaves MW, Kaplan AP. Marcel Dekker, Inc 2004;421-441.
Morgan M, Khan DA. Therapeutic alternatives for chronic urticaria: an evidence-based review, part 2. Ann Allergy Asthma Immunol 2008;100:517-526.
Vincent S. Beltrani, MD, FAAAAI
Associate Clinical Professor
Department of Dermatology, Columbia University New York, New York
Associate Clinical Professor
Department of Allergy, UMDNJ
Newark, New Jersey