Pediatrics

Urticaria

OVERVIEW: What every practitioner needs to know

Are you sure your patient has urticaria? What are the typical findings for this disease?

Urticaria is a vascular reaction of the skin marked by the transient appearance of smooth, slightly elevated patches (wheals) that are pale or slightly erythematous and that are often attended by severe pruritus or itching. The wheals vary in size and are raised above the surface of the surrounding skin. If you glide over the skin lesions with your hand, you should feel that the lesions are elevated. They are almost always pruritic. Urticaria is very seldom accompanied by pain.

There are three types of urticaria: acute urticaria (onset less than 6 weeks), chronic urticaria (lasting more than 6 weeks from onset), and physical urticaria.

Individual lesions of acute urticaria can appear at different locations, and they fade without scarring, often in a matter of hours. The development of urticaria can be an isolated event without systemic reaction, or it can be a prelude to the development of an anaphylactic reaction. Although urticaria results from transient extravasation of plasma into the dermis, if the swelling extends and results in deep swelling within subcutaneous/submucosal tissues, it is called angioedema. If angioedema develops, patients often complain of pain rather than itching. Urticaria and angioedema may coexist in the same individual.

Skin biopsy is not usually necessary unless the diagnosis is in doubt. If skin biopsy is performed, the histology shows dermal edema without epidermal injury, along with an inflammatory infiltrate. Based on the cell types involved in the inflammatory process, the urticarial lesions may be divided into the following categories: Class 1, which shows a mixture of perivascular dermal lymphocytes and monocytes, along with neutrophils, eosinophils or both; and Class 2, which shows an inflammatory infiltrate chiefly composed of neutrophils. The practical implication of this is that the response to specific treatments could be different.

Pathologically, urticaria results from the release of histamine, bradykinin, leukotriene C4, prostaglandin D2, and other vasoactive substances from the mast cells and basophils in the dermis. Those substances cause extravasation of plasma into the dermis, leading to the urticaria lesions. The intense pruritis of urticaria is a result of histamine released into the dermis.

The common causes of acute urticaria in children are infections (viral infections are most common; mycoplasma, group A beta-hemolytic Streptococcus), sensitivity to drugs or chemical compounds (antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs); or dyes, flavors, and preservatives in suspension; contrast media), sensitivity to foods (milk, soy, eggs, peanuts, tree nuts, fish, shellfish and wheat, etc.), sensitivity to insect venom (honey bees, wasps, yellow jackets, yellow and white faced hornets, fire ants), or sensitivity to latex protein. However, it is important to note that more than 25% of urticaria is of idiopathic origin.

Much less common causes are types of physical urticaria. With physical urticaria, the onset of urticria is related to a specific environmental exposure, such as solar exposure, heat, cold, aquagenic, cholinergic, delayed pressure, vibration urticaria or exercise-induced urticaria.

In patients with chronic urticaria, who have had skin rash for more than 6 weeks from onset, the etiology is frequently unknown. According to some reports, in nearly 40% of cases of chronic urticaria the rash could be reproduced after injection of the skin with the patient's own serum, suggesting an autoimmune etiology. Other sporadic cases were found to be associated with underlying thyroid autoimmunity, intestinal parasites, chronic infections (sinusitis, dental infections), hepatic disorder, sensitivity to lipid transport protein in fruits or with specific autoimmune disorders like systemic lupus erythematosus or juvenile rheumatoid arthritis.

A severe allergic condition, anaphylaxis (characterized by respiratory distress, severe abdominal pain or diarrhea and hypotension), is sometimes preceded by urticaria if a person is severely allergic to certain substances (food, drug, insect venom, or latex protein). Therefore, it is important to remember that urticaria can be an early sign of a severe allergic reaction with anaphylaxis.

Itching

Patients with urticaria universally will complain of severe itching from the onset. It may have started from the very first appearance of skin lesions, then may have spread to a large area or to the entire body. Scratching exacerbates spread of the rash.

Welt or wheal formation

The onset of skin lesions is usually sudden. The lesions will be pruritic and characterized by a pale, slightly red color. (The lesions may turn red if the patient had already begun taking an antihistamine). The size of the lesions ranges from 2 mm to 15 mm, and their appearance is that of flat-topped wheals scattered over the body. If the patient had engaged in frequent scratching, you may see linear-shaped hives clustered in an area or you may observe a large diffused lesion.

What other disease/condition shares some of these symptoms?

Angioedema

Angioedema may coexist with urticaria or as an extension of urticaria. The diffuse and deep swelling of angioedema rarely causes itching. In contrast, angioedema often causes pain. Angioedema most often appears on the face, lips, tongue, neck, and limbs.

Mastocytosis of the skin in childhood or dermatographia

Children proportionally carry more mast cells in their skin than adults. Children with mastocytosis often engage in frequent skin scratching that can create urticaria-like lesions covering the skin wherever the child's hands can reach. The lesions are relatively benign. The skin lesions should recede within two hours.

Urticaria pigmentosa

This is a malignant form of mast cell infiltration that may occur under the skin, in bone marrow, or in the liver. A severe case of mast cell infiltration in bone marrow is called basophil leukemia. It is a generalized disease and has poor prognosis. Urticaria-like skin lesions are frequently present. When the wheals recede, the skin is left with a yellowish or brownish pigmentation.

Atopic dermatitis or eczema

In eczema of new onset, the lesions are often described as erythemic, weeping, oozing, and pruritic. In the chronic stage, the skin is usually thickened with clear markings (lichenification). These skins lesions often migrate as a person ages. For instance, in infants the lesions are commonly seen on the face, cheeks, and extensor surfaces of the arms and legs. As the person grows older, the lesions usually spare the face, but begin to stabilize in creases such as at the neckline, behind the ears, the inner crease of the elbow joints, and behind the knees.

Contact dermatitis

This is an allergic reaction to a substance that comes in contact with the skin. This occurs more often in adults via occupational exposure. In children known to be allergic to certain foods, simple contact with the offending foods may cause erythema or urticaria. A typical contact dermatitis like the reaction after contact with poison ivy or poison sumac usually causes linear weeping lesions, rather than lesions characteristic of urticaria.

Juvenile idiopathic (rheumatoid) arthritis (JIA, or JRA)

In the acute, febrile stage of systemic onset of JIA, patients may have salmon pink-colored, spindle shaped or lacey skin rashes that appear on the trunk. The major difference between a JIA rash and urticaria is that the former is seldom itchy or pruritic. The rash is evanescent, receding when the fever resolves.

Pityriasis rosea

The benign herald patches of pityriasis rosea vary from 1 cm to 10 cm in diameter, and may be accompanied by a syndrome of fever, malaise, arthralgia, and pharyngitis. The lesions typically have raised borders with fine, adherent scales, appearing in a symmetrical fashion involving primarily the trunk and proximal limbs. A "Christmas tree pattern" is often present, which is characterized by long axes of lesions aligned with cutaneous cleavage lines.

Serum sickness

Serum sickness is a side effect of infusion with foreign proteins. More commonly, serum sickness occurs as a reaction to drugs, and may present as a skin rash similar to that of acute urticaria. The lesions may not be as pruritic as those of urticaria. More importantly, many patients will present with arthralgia or arthritis characterized by joint swelling. Serum sickness is often accompanied by fever.

Vasculitis or thrombophlebitis

In these instances, the urticaria-like skin lesions are more stationary and are seldom fleeting or mobile. The rash will not be as pruritic as that of urticaria. There will be skin color changes, such as near purplish discolorations. Usually, vasculitis or thrombophlebitis are accompanied by an underlying vascular pathology that would need a biopsy to confirm it. The lesions can also be seen in systemic lupus erythematosus.

What caused this disease to develop at this time?

  • Epidemiology

    • 15-25% of the population at some point in life will experience urticara. In children, the incidence of acute urticaria is near 7%. Stratified by age: infant 15%, preschool-aged 24%, school-aged 23%, and adolescent 4% in a large study comprised of 953 patients who visited the Emergency Department. The incidence of chronic urticaria is from 0.1% to 3%, while the incidence of physical urticaria is less than 1.0% in children.

  • Causes of acute urticaria

    • Infections(48%). This includes viral infections such as caused by cytomegalovirus, herpes simplex 1, influenza A, enterovirus, parvovirus B19, Epstein-Barr virus, hepatitis A or B, and mycoplasma infection. The most documented bacterial infection that causes urticaria is group A beta-hemolytic streptococci.

    • Foods(24%). The most common are shrimp and other seafoods including fish and shellfish, milk, eggs, peanuts, and tree nuts.

    • Medications (12%). Among them, antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common. A word of caution is that these patients may not have true drug allergy. Most young patients develop the rash while on the suspension form of drugs. It raises a strong possibility that the children may be reactive against chemical excipients (dyes, flavors or preservatives) in the drug suspension instead of the drug itself. The same may be true for other drugs in liquid form.

    • Inhalants (2.0%). These are typically seasonal pollens of grasses, trees or weeds. Other indoor factors, such as saliva and dander from cats, dogs, or other animals, may cause urticarial rash at exposure.

    • Insect venom (2.0%). Patients may have developed sensitivity against insect venom. The important insects include fire ants and flying insects (honey bees, wasps, yellow jackets, yellow hornets, white faced hornets, mosquitos, and others).

    • Contact allergy.This includes contact with latex protein, metals such as nickel, or contact with offending foods.

    • Idiopathic (13%). No cause can be found even after an extensive work-up.

  • Causes of chronic urticaria (Incidence of underlying cause unknown). Reports have listed the following:

    1. Chronic infections (sinus infection, dental infection, urinary tract infection (UTI) or chronic hepatitis)

    2. Parasites (Few cases of intestinal parasites or Helicobacter pylori have been reported)

    3. Food allergies

    4. Collagen vascular or autoimmune diseases

    5. Autoimmune process: 30%-50% of patients test positive with the autologous serum skin test (ASST). However, there is debate on whether the test confirms autoreactivity, rather than functioning as a specific test for autoimmune urticaria. Thyroid autoimmunity has been suggested in 10% of adolescent girls with chronic urticaria.

Physical urticaria

The list under this category includes solar urticaria, heat urticaria, cold urticaria, aquagenic urticaria, cholinergic urticaria, delayed pressure urticaria, vibration urticaria, and exercise-induced urticaria.

Diagnosis of Urticaria

Diagnostic considerations:

In nearly 50% of patients with acute urticaria, a specific etiology can be identified. Brief episodes of urticaria can be associated with temporarily identifiable causes, as listed above. The method of exposure (i.e., direct contact, oral, or IV route) is usually known.

Urticaria may be confused with a variety of other dermatologic diseases that may look similar in appearance and are pruritic, including atopic dermatitis (eczema), maculopapular drug reactions, contact dermatitis, insect bites, erythema multiforme, pityriasis rosea, and others. Usually, clinicians can distinguish these conditions from urticaria because the latter has a distinctive appearance and intense pruritus or itch, and because urticarial lesions blanch completely with pressure.

Clinical approach to the work-up of urticaria:

All forms of urticaria are generally diagnosed based on a detailed patient history and physical findings.

First, urticaria should be quickly classified as either acute (duration <6 wks), or chronic (>6 wks).

Second, allergic urticaria and non-allergic urticaria need to be separated. For allergic urticaria, if the patient's history is very suggestive, a skin test or radioallergosorbent test (RAST) for the IgE antibody against the potential allergens can be performed to confirm the correct diagnosis and identify a specific cause. For chronic urticaria, if the history and physical findings are suggestive of an underlying cause, additional tests for autoantibodies, searching for parasites or H. pylori could be ordered in selective cases. The causes of physical urticaria should be identified by the history.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory testing for acute urticaria may be useful if the patient has allergenic urticaria. The patient's history would direct the search for potential offending foods or drugs. Usually, urticaria likely occurs within two hours after ingestion or contact.

For possible food allergy, IgE allergic antibody tests for the list of foods that are well known to cause allergic reaction may be useful. Common causes include milk, eggs, peanuts, tree nuts (almonds, Brazil nuts, cashews, hazel nuts, pistachio nuts, pecans, walnuts and others, as well as wheat, soy, sesame, fish, and shellfish (crab, clams, oysters, shrimp, lobster, and scallops).

The clinician has the choice of using RAST (blood test) or skin test for IgE against the offending foods.

RAST is best performed with the immunocap assay that will give the units of antibody present (i.e., KU/L.) The negative value cut-off is at <0.34 KU/L. Therefore, any value greater than 0.34 KU/L indicates that the patient is likely sensitized. The higher the value of RAST, the higher the degree of sensitivity.

The only RAST available now for any drug is for penicillin. If the patient has a suspicious sensitivity to penicillin or drugs in the cephalosporin family, RAST followed by a skin test with PRE-PEN® and penicillin G is highly recommended. The PRE-PEN® is for the major determinant and Penicillin G is for the minor determinant of the penicillin molecule. Both tests need to be done to rule out penicillin sensitivity.

For testing for other drugs, it is recommended that the patient be referred to a specialist.

For detection of latex allergy, only the RAST is currently available.

Immediate hypersensitivity skin tests, if necessary, should be done in a specialist's clinic or office. A positive test will show a large wheal and erythema at the site where the allergen is placed. However, if the patient is still taking antihistamines or has extensive skin lesions, skin testing can result in false negatives.

Again, any positive result of RAST or skin testing needs to be matched with a positive history. Therefore, random use of either test for the work-up of urticaria should be discouraged.

Although infection is the most common cause of acute urticaria in children, only two tests are practically useful: the Streptococcal antigen assay for group A beta-hemolytic streptococci, and the serological test (or cold agglutinin test) for mycoplasma infection. The reason for doing these tests is that these two conditions can be treated with appropriate antibiotics to shorten the course of urticaria.

For the work-up of chronic urticaria, selective testing can be useful for exploring possible underlying medical conditions. For teenage girls with a family history of thyroid disease, a work-up for autoimmune thyroid disease would be helpful. If a child has arthropathy, an autoimmunity work-up including CBC, ESR, and autoantibody screening such as antinuclear antibody and rheumatoid factor (RF) may be useful. For those with a history of gastrointestinal symptoms, checking for antibodies against H.pylori or ova and parasites in stool may be useful.

For most forms of physical urticaria, no particular test is useful. The history will provide the best clues to the cause of the urticaria.

Would imaging studies be helpful? If so, which ones?

  • No imaging studies are found to be useful in managing acute, chronic, or physical urticaria.

  • Imaging studies are recommended only when the patient has an associated or underlying medical condition.

Confirming the diagnosis

  • When urticaria is identified, the immediate step is to classify it as acute (duration < 6 weeks), chronic (duration > 6 weeks) and physical urticaria (by history).

  • The first step of history-taking should include a review of any potential exposure that might have caused allergenic urticaria within 48 hours prior to the onset of the urticaria. This will allow for prevention of further exposure and help prevent the risk of allergy symptoms escalating to anaphylaxis.

  • The list of items of possible allergic exposure should include categories of: foods, drugs, insect sting or bite, and latex

    • Food category should include: eggs, milk or dairy products, peanuts, tree nuts, fish, shellfish, wheat, soy, sesame, or other foods mentioned. The allergic cause could be determined by either RAST or skin test.

    • Drug category should include: antibiotics, NSAIDs, and others. It is important to consider a reaction to dye, flavorings, or preservatives if the patient took any liquid medicine. Refer to an allergy specialist for work-up.

    • Insect sting category should include: history of flying insect sting or fire ant bite (this would show classic white pustules on sites). Refer to allergy specialist for a long-term solution like immunotherapy.

    • Contact allergic reaction: should question history of exposure to metal, chemical substance, or latex.

    • Inhalant category: should question seasonal fluctuation of symptoms.

  • Infection category: should question possibility of upper respiratory tract infection (URI), urinary tract infection (UTI), or gastrointestinal complaint. It is not mandatory to use isolation or serology to investigate the cause of infection, especially a viral infection. But, identifying the antigen for group A beta-hemolytic streptococcal infection or using the cold agglutinin test for mycoplasma infection would allow the clinician to give proper antibiotics to the patient to abate the skin rash.

  • Idiopathic category. Nearly 40% of patients do not have an identifiable cause of urticaria. The goal is to initiate management of those patients.

  • Chronic urticaria. In chronic urticaria, there is much less chance of finding the cause. Selective laboratory testing is only required for those who have an underlying medical disease or associated medical condition.

  • Physical urticaria. The patient's history will provide clues to the cause of the skin rash. No laboratory test is generally recommended except for patients with heat, cold and pressure urticaria. In those circumstances, the clinician may arrange exposure to ice, hot water, or physical stroking on the arm to confirm the diagnosis.

If you are able to confirm that the patient has urticaria, what treatment should be initiated?

  • The first step is to differentiate between acute urticaria (duration < 6 weeks), chronic urticaria (duration > 6 weeks), and physical urticaria.

  • The second step is to carefully obtain a good history. Suspected offending factors should be removed immediately. It may help relieve the urticaria quickly if the cause is found.

  • The third step is to work quickly to rule out food allergy, drug sensitivity, insect sting allergy, latex allergy, or contact allergy by requesting appropriate testing like RAST or the skin test for IgE antibody. If infection-induced urticaria is suspected, detection of group A beta-hemolytic streptococci and identification of mycoplasma infection by the cold agglutinin test or an antigen assay would offer the opportunity for antibiotic treatment.

For the treatment of acute urticaria, make sure that the urticaria is not the prelude to the development of anaphylaxis. In that case, epinephrine IM (0.01 cc /Kg, max of 0.3 cc) should be given immediately, followed by corticosteroid treatment and a short-acting antihistamine.

First-Line Treatment (Single drug): H1 antagonists (first-generation antihistamines)

  • For simple acute urticaria, a short-acting antihistamine should be given immediately for the first three to five days.

    • Effect: reduces the lesions and pruritis. Because first generation antihistamines cause drowsiness (the anticholinergic effect) some clinicians have recommended that they be preferentially be given at bedtime. The use of this class of medications is reserved for acute cases. Recommendations are to give an initial trial for two weeks. If not improved, try the following steps:

      • Diphenhydramine (Benadryl)

        • 12.5 mg - 25 mg PO q 6-8h prn, or 5 mg/kg/d PO divided q 6-8h prn, or 150 mg divided q 6-8 h prn; not to exceed 300 mg/d

        • Adult dose: 25-50 mg/IV/IM q 4-6h.

      • Hydroxyzine (Atarax, Vistaril).

        • 0.6 mg/kg/dose PO q 6 h; 0.5-1 mg/kg/dose IM q 4-6 h; 2-4 mg/kg/d PO divided tid/qid;

        • >6 years: 50 mg/d PO/IM in divided doses q 6 h prn.

      • Chlorpheniramine (Chlor-Trimeton)

        • < 2 years: Not established; 2-6 years: 1 mg PO q 4-6 h; not to exceed 4 mg/d

        • 6-12 years: 2 mg PO q 4-6 h; not to exceed 12 mg/d. >12 years: 4 mg PO q 4-6 h; 10-20 mg per dose IV/IM/SC; not to exceed 40 mg/d.

      • Cyproheptadine (Periactin)

        • <2 years: Not established. 2-6 years: 2 mg q 8-12 h prn

        • 7-14 years: 4 mg q 8-12 h prn; not to exceed 16 mg/d

        • >14 years: 2-4 mg PO tid; 4 mg PO q 8 h initial dose, increase by 2 mg q 8 h to effect; 32 mg/d maximum.

    • H1 Antagonists (second generation antihistamines)

      Effect: This group of antihistamines is non-sedating and long-acting. Therefore, these are highly recommended for chronic cases. After two to four weeks, if symptoms remain unchanged, it is recommended that the dose could be doubled.

      • Cetirizine (Zyrtec)

        • <6 months: Not established.

        • 6-12 months: 2.5 mg PO qd; 12-24 months: 2.5 mg PO qd/bid

        • 2-6 years: 2.5-5 mg PO qd; not to exceed 5 mg PO qd or divided bid.

        • > 6 years: 5-10 mg PO qd.

      • Levocetirizine (Xyzal)

        • < 6 years: Not established.

        • 6-12 years: 2.5 mg (half tab) PO qd in evening.

        • >12 years: 5 mg PO qd in evening.

      • Fexofenadine (Allegra)

        • < 6 years: Not established.

        • 6-12 years: 30 mg PO bid.

        • >12 years: 60 mg PO bid; or 180 mg SR PO qd.

      • Loratadine (Claritin, Alavert)

        • <2 year: Not established.

        • 2-6 years: 5 mg/d PO qd;

        • >6 years: 10 mg PO qd

      • Desloratadine (Clarinex)

        • <6 months: Not established

        • 6-11 months: 1 mg PO qd;

        • 12 months to 5 years: 1.25 mg PO qd.

        • 6-11 years: 2.5 mg PO qd;

        • >12 years: 5 mg PO qd.

Second-Line Treatment (combined with H1)

(A). H2 antagonists (antihistamines)

Effect: Block the vasodilatation mediated by H2 receptors in blood vessels leading to less edema in urticaria. The combination of H1 antagonist with H2 antagonist is found more effective for the treatment of urticaria.

1. Famotidine (Pepcid)

0.5 mg/kg/d (may use qd or bid) PO; not to exceed 40 mg/d total dose;

Adult: 40 mg PO qd or 20 mg PO bid; 20 mg IV plus 25 mg diphenhydramine IV for acute urticaria.

2. Cimetidine (Tagamet)

Infants: 10-20 mg/kg/d PO q 6 h;

Children: 20-40 mg/kg/d PO in divided doses separated by at least 6 hr.

>12 years: 20-40 mg/kg/d PO.

Adults: 300-800 mg PO q 6-8 h; 300 mg IV/IM q 8 h; 300 mg IV with diphenhydramine 25 mg IV for acute urticaria.

3. Ranitidine (Zantac)

<12 years: Not established.

>12 years: 1.25-2.5 mg/kg/dose PO q 12 h; not to exceed 300 mg/d;

0.75-1.5 mg/kg/dose IV/IM q 6-8 h; not to exceed 400 mg/d.

Adult dose: 150 mg PO bid; not to exceed 600 mg/d. 50 mg/dose IV/IM q 6-8 h; not to exceed 400 mg/d; 50 mg IV with 25 mg diphenhydramine IV for acute urticaria.

(B). Corticosteroids

Effect: In instances of acute or chronic urticaria in which antihistamine may fail even at higher doses. corticosteroids stabilize mast cell membranes and inhibit further histamine release as well as reduce the inflammatory effect of histamine and other mediators.

In fact, if other mediators are involved, corticosteroids can be effective. Corticosteroids are also effective in patients with urticaria vasculitis. However, long-term use of systemic steroids should be avoided.

A short course of an oral corticosteroid, administered daily for 5-7 days, with or without taper, or a single dose of a long-acting injectable steroid is not usually associated with long-term sequelae when used for an acute episode of urticaria that was nonresponsive to antihistamines. The effect has been proven.

1. Prednisolone (Pediapred, Prelone, Delta-Cortef)

Pediatric dose: 0.5-2 mg/kg/d PO divided bid/qid.

Adult dose: 40-60 mg/d PO or divided bid.

2. Methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol)

Pediatric dose: 0.16-0.8 mg/kg/d PO divided bid/qid.

Sodium succinate/Solu-Medrol: 0.5-2 mg/kg per dose IV/IM, repeated at intervals depending on clinical response; this drug is most often used for acute urticaria associated with an allergic emergency and is not used for chronic urticaria.

Adult dose: 4-48 mg PO. Sodium succinate/Solu-Medrol: 0.5-2 mg/kr per dose IV/IM.

3. Prednisone (Deltasone, Orasone, Meticorten)

Pediatric dose: up to 1 mg/kg/d PO qd or divided bid/qid for 5 d. For persistent symptoms, administer for 2-3 weeks while gradually tapering the dose downward,

Adult dose: 40-60 mg/d PO divided 1-2 doses/d; or 5-60 mg/d PO qd or divided bid/qid 40 mg PO qd burst over 4 d in combination with antihistamine; when used alone, taper over 2 wk.

(C). Sympathomimetic Agents

Effect: Cause vasoconstriction and reduction of vascular dilation that contribute to urticaria formation. Drug of choice for the treatment of severe or generalized urticaria as part of an anaphylactic reaction. It could restore systemic hypotension and bronchodilatation. The injectable epinephrine is now available in portable form, EpiPen®. Effect is confirmed.

Epinephrine (Adrenalin, Sus-Phrine, EpiPen®, Ana-Guard, Twinject).

Pediatric dose: 0.01 mg/kg, up to 0.5 mg, IM single dose; can be repeated in 15- to 20 min intervals prn.

IM administration has been associated with a faster time of onset than SC when studied in pediatric and adult populations.

(D). Leukotriene Receptor Antagonist

Effect: It prevents or reverses some of the pathologic features associated with the inflammatory process mediated by leukotriene C4, D4, and E4. The effect is confirmed when it is used with H1 antihistamine.

1. Montelukast (Singulair®)

Pediatric doses: <2 years: Not established.

2-5 years: 4 mg PO qhs.

6-14 years: 5 mg PO qhs.

>14 years: 10 mg PO qhs.

2. Zafirlukast

5 yr to 11 years, 10 mg PO bid;

>12 years, 20 mg PO bid.

(E). Tricyclic Antidepressants

Effect: Use of tricyclic antidepressants takes advantage of their antihistamine effects, blocking both the H1 and H2 receptors. Tricyclic antidepressants have been used in the treatment of allergic reactions, especially urticaria. Evidence is weak compared to others but may be most useful if urticaria caused significant discomfort. Evidence is somewhat weak.

Doxepin (Sinequan, Adapin, Zonalon)

<12 years: Not recommended.

>12 years:25-50 mg/d PO hs or bid/tid; increase gradually to 100 mg/d.

Immunomodulatory and anti-inflammatory therapy (Combined with Tier 1)

(1). Cyclosporine

It has been shown to be effective in 2 double-blind placebo-controlled studies. Effect on children remains unknown.

(2). IV gammaglobulin and plasmapheresis

These have been tried in a limited number of case studies involving adult patients. These therapies can be considered in severe cases, particularly for the autoimmune type of urticaria that is unresponsive to conventional medications. Such treatment is usually only initiated by specialists with considerable expertise in urticaria because the treatments carry adverse effects.

(3). Colchicine and Dapsone

Both are known to modulate the function of polymorphonuclear cells. Therefore, it seems most helpful if the lesions are mixed with inflammatory cells consisting of polymorphonuclear cells. The treatment is reserved for severe or refractory cases that failed to respond to antihistamine treatment. The experience in children is unknown.

(4). Omalizumab (Xolair®)

This monoclonal antibody to IgE has been used in chronic urticaria, and its results appeared promising. More studies are needed, and its indication for children needs more study.

Biofeedback control to manage scratching (Combined with Tier 1 or Tier 1/Tier 2)

Urticaria is the result of inflammatory lesions where mast cells are activated and mediators are released. Histamine is the primary mediator that causes vascular reaction of the skin. Other mediators like cytokine and chemotactic factors may attract more inflammatory cells such as eosinophils and lymphocytes to the site to sustain the inflammation.

The skin lesions are very vulnerable to pressure. Therefore, if patients continue to scratch, it causes more inflammation under the urticarial lesions. For this reason, any supportive measure to discourage scratching should be incorporated into the general treatment scheme.

(A). Biofeedback Control

In our clinic, all children above age 4 are taught to squeeze their hands when feeling the urge to scratch. A parent will help count 15 seconds to wait for the itch sensation to subside. This a very effective educational tool to help eliminate habitual scratching. Parents are also encouraged to help their children engage in educational activities such as art or playing musical instruments to offer a positve distraction from scratching. In older children, a sport activity is highly recommended with chronic urticaria.

(B). Conventional Alternative Medicine (CAM)

Acupuncture, martial arts, massage therapy, or yoga are frequently recommended for patients with chronic or refractory urticaria. It also serves as a means of positive distraction from scratching. At least, these approaches will help relieve patients' anxiety. The greatest advantage is that there are virtually no side effects to cause concern.

Long-Term Treatment

It is recommended that for acute urticaria, the patient will benefit by combining treatment with and . Any allergic cause needs to be removed and infection treated.

For chronic urticaria, treatment with , 2 and 3 should be combined.

For physical urticaria, use and avoid offending factor(s).

What are the adverse effects associated with each treatment option?

H1 antihistamines, especially the short-acting drugs such as Atarax, Benadryl, chlorpheniramine, or cyproheptadine, all have a significant sedating effect. If used for a long time, these drugs may begin to affect quality of life. School children would be most likely affected in the classroom. Therefore, the length of treatment should be kept within four weeks.

If a patient does not respond to the medications above, it is recommended to switch to a long-acting, non-sedating antihistamine such as cetirizine, levocetirizine, fexofenadine, loratadine, or desloratadine. These drugs are more tolerable for the student population.

After two months, if the frequency or severity of the patient's urticaria does not change, clinicians have the option of either doubling the dose of a long-acting, non-sedating antihistamine, or combining the long-acting, non-sedating antihistamine with a montelukast like Singulair®. The FDA has issued warnings about the potential of Singulair® to cause suicidal ideation or attempts, which have been noted in some teenagers.

If after four weeks of treatment, a patient's acute urticaria is still having a debilitating effect on the patient's life, the patient would then be ready for treatment with anti-inflammatory drugs like oral corticosteroids. Steroids are notoriously known for their side effects of weight gain, high blood glucose, change of bone density, or stunted growth in children. Steroids also produce a risk for stomach ulcer or increased susceptibility to infection. It is advised that after the positive effect of a steroid is seen, the patient should be gradually tapered off the steroid at the rate of one quarter of the total dose every 7 days or week. An antacid should be considered if the patient begins complaining of stomach aches.

In case of chronic urticaria, the patient should be treated with an H1 long-acting, non-sedating antihistamine. The dose may be doubled, with the option of adding an H2 antihistamine or leukotriene receptor antagonist like Singulair®. In many cases, the use of a corticosteroid PO will become unavoidable if the condition becomes refractory. It is always advisable to keep the dose of the corticosteroid as low as possible or use an every-other-day regimen. The purpose is to find the lowest, most tolerable, and yet effective dose for the individual patient. Patients should be watched carefully for the side effects of corticosteroids such as weight gain, stomach ulcer, low bone density, hypertension, or stunting of growth.

It is advisable that when treatment with medication is considered, the patient should be referred to a specialist because those drugs carry more side effects.

During treatment with , or Tiers 1 and 2, it is recommended that the patient be taught Biofeedback control to manage habitual scratching. All patients should be educated that scratching when urticaria is active will only worsen and prolong the clinical course. Biofeedback control does not carry any adverse effects. Likewise, positive feedback control activities, such as art, playing a musical instrument, working at a computer, tai chi, and yoga, benefit overall health without producing any adverse effects.

What are the possible outcomes of urticaria?

The prognosis of acute urticaria is generally benign. If the urticaria is caused by infection, the clinical course should be brief, especially if the patient is treated adequately with an antibiotic in response to Streptococci or Mycoplasma. In acute urticaria, If the offending allergens are found and removed, the rash should resolve very quickly. The patient should be taught to avoid the offending factors until a specialist has the opportunity to evaluate the nature of the patient's sensitivity.

The prognosis of chronic urticaria is more difficult to predict. Although cases in children are relatively few compared with adults, urticaria still carries a significant morbidity for a child and may affect the child's quality of life.

If the etiology remains unknown, as happens with many patients, or / pharmacotherapy combined with supportive treatment should remain the mainstay of management.

If the patient has an underlying pathology, such as urticarial vasculitis in lupus erythematosus, the prognosis would be determined by how the underlying medical condition is managed.

Risk/Benefit (R/B) ratio of available treatment options

If the cause of urticaria can be determined, especially in the case of acute urticaria, avoidance of the offending factor(s) will have the best R/B ratio and may help shorten the course of drug therapy. However, finding the cause is missed in about 25% of cases. The cause of chronic urticaria is usually largely unknown. Therefore, most patients would benefit by drug therapy even when the cause cannot be found.

Overall, however, the R/B ratio is very small if the patient is on therapy. Drowsiness is the major side effect of concern. If the treatment is escalated to , many immunomodulators or anti-inflammatory agents will carry more side effects if the treatment is prolonged. In that sense, the R/B ratio is higher. Close follow-up would be important. treatment is virtually risk-free. Therefore, the addition of treatment with is highly recommended for easing anxiety and for control of scratching.

What causes this disease and how frequent is it?

  • Detailed epidemiology:

    • At some point, 15% to 25% of the population will experience urticaria.

    • It is estimated 7% of children will develop acute urticaria.

    • The incidence of urticaria according to age, as found in a large study, is: Infant (14.5%), Preschool-aged (58%), School-aged (23.2%), and Adolescent 4.3%.

    • Chronic urticaria occurs in 0.3%~3.5% of children and physical urticaria in <1% of children.

    • If infectious, the mode of transmission is: Only group A beta-hemolytic streptococci and mycoplasma are known to cause acute urticaria. These are both respiratory pathogens. There are many viral exanthems that could be associated with acute urticaria. They are primarily respiratory or gastrointestinal viruses (Epstein-Barr virus, hepatitis virus A, B, and C, herpes simplex virus, and parvoviruses)

    • Predisposing exposures (zoonoses, environmental factors, toxins, activities)

    • Food allergy (peanuts, tree nuts, shellfish and fish) may explain nearly 25% of acute urticaria in children.

    • Inset venom (flying insects and fire ants) may cause urticaria in susceptible individuals.

    • Parasitic infestation, H. pylori, and malaria are a few known causes of chronic urticaria.

    • The following types of environmental exposure may cause urticaria: exposure to sun, cold temperature, heat, aquagenic rash, vibration and pressure-related delayed reaction. Exercise-induced urticaria may occur in teenagers.

    • In children, exposure to drugs, especially in suspension form, could cause urticaria. The offending factors may be drug or chemical excipients (dyes, flavors, or preservatives).

  • Genetics

    • No genetic predisposition is known for acute, chronic, or physical urticaria.

How do these pathogens/genes/exposures cause the disease?

  • The exact pathogenic mechanisms of the infectious agents that lead to mediator release from mast cells, that in turn lead to urticaria, are not well understood. Most pathogens are not known to cause IgE development in the host. We could speculate that either the pathogen or its toxin might directly trigger the mast cells for histamine release.

  • The only known toxin to cause IgE formation is exotoxin B of Staphylococcus aureus. This organism is a frequent cause of skin infection. It may not result in urticaria, but could cause significant pruritis.

Other clinical manifestations that might help with diagnosis and management

A patient with a sudden onset of bright erythematous skin rash, possibly generalized and with significant pruritus, having features similar to urticaria, may be seen in the Emergency Room. The patient may present with abdominal discomfort with complaints of severe nausea, vomiting, abdominal pain, and diarrhea. The patient usually has a history of very recent ingestion of fish (dark meat like tuna) but has no history of food allergy. The cause of the clinical symptoms is primarily due to the ingestion of spoiled fish meat (scombroidosis) that contains a large amount of histamine. Only symptomatic treatment is needed for such a patient. The treatment includes hydration and a short course of antihistamine.

In severe cases of urticaria, the swelling may reach the base of the dermis. The condition is called angioedema. Angioedema will not cause itching, but it causes pain due to significant swelling in deep tissue. The treatment of angioedema is the same as for urticaria.

In rare cases of angioedema, patients may have a family history of similar swelling. Some family members may have died of airway closure. This may raise a red flag for hereditary angioedema (HAE). With further questioning, the patients often have complaints of frequent abdominal pain due to diffuse swelling in the gut. They rarely have complaints of itching or the presence of urticaria. It is important to refer these patients to a specialist for further evaluation because the treatment of HAE is quite different from ordinary angioedema. If HAE is suspected in a patient, the clinician may first request a plasma level of complement 4 or C4. If the level is low, the patient should be referred to a specialist for further confirmation and for advanced treatment.

What complications might you expect from the disease or treatment of the disease?

Acute urticaria or acute onset of physical urticaria itself rarely results in a life-threatening condition. However, if aucte urticaria is a prelude to the further development of anaphylaxis, the most severe form of allergic reaction, the urticaria must be managed as quickly as possible. Anaphylaxis is a life-threatening condition. It is estimated that nearly 100 to 120 persons in this country alone have died because of delayed or poor management of anaphylaxis.

To recognize whether urticaria is a prelude to anaphylaxis, an appropriate and timely clinical history must be obtained to see whether that possibility exists. The focus of the questions should be directed toward the possibility of the patient having any allergic cause that led to the urticaria.

The clinician should carefully inquire about the ingestion offending foods (especially peanuts, tree nuts, shellfish or fish), history of insect stings (flying insects or fire ants), drug ingestion, or latex exposure. If there is a past history of a similar event, aggressive treatment is necessary because the symptoms may continue to escalate. The use of sympathomimetics (epinephrine injection) and corticosteroids should be the first treatment of choice in that instance.

The history should also inquire about the possibility of exercise-induced urticaria.

Complications of treatment usually occur when a patient receives a large amount or a prolonged course of treatment. H1 antihistamines produce significant anti-cholinergic activity, especially for older patients. The patient should be monitored for excessive sedation, which may interfere with driving, or cause CNS depression, hypotension, urinary retention, or cardiac arrhythmia.

Prolonged treatment with a leukotriene antagonist should take into account the FDA warning on neuropsychiatric events, especially anxiety reactions and hallucinations.

Patients receiving epinephrine should be monitored for adverse effects of palpitation, jitteriness, or blood pressure elevation.

Regarding corticosteroids, the adverse effects of long-term use in children include weight gain, stunting of growth, hypertension, hair growth, or acne. Children receiving corticosteroids should have frequent physical examinations, including growth rate assessment. When administering corticosteroids to children, caution should be taken with respect to hyperthyroidism, non-specific ulcerative colitis, peptic ulcer, diabetes mellitus, and myasthenia gravis.

For patients having chronic urticaria with underlying medical conditions, treatment should be aimed at management of the primary diseases.

Are additional laboratory studies available; even some that are not widely available?

In patients with chronic urticaria, an autologous serum skin test (ASST) has been reported to be useful. In one series, it was reported nearly 40% of children may show a positive result for the ASST. However, the test itself has been regarded as a test of autoreactivity, rather than a test for autoimmune urticaria. It has a high negative predictive value. The result would not change the treatment strategy.

The basophil histamine release test (BHRT) has also been reported in the evaluation of chronic urticaria. However, it has not been popular in clinical practice.

Stool testing for parasite ova is reserved for selected cases. In females with chronic urticaria, a thyroid autoantibody test, such as the peroxidase test or the thyroglobulin antibody test, may detect positive results in perhaps 10% of the population. It is uncertain whether aggressive thyroid hormone supplementation actually helps reduce urticaria.

Although infection may be suspected in as high as 50% of patients with acute urticaria, it is not very practical to use serology testing to confirm certain viral infections in the clinical setting.

How can urticaria be prevented?

Prevention of acute urticaria can be done only for patients with allergic causes. Avoiding offending foods, drugs, insect stings or bites and latex exposure will help. For exercise-induced urticaria, solar urticaria, heat or cold urticaria, pressure urticaria, aquagenic urticaria, cholinergic urticaria (primarily exercise) or vibration urticaria, the patient should be educated to avoid those factors.

Behavioral factors will not prevent urticaria, acute or chronic. However, biofeedback control, yoga, and tai chi will help control the itching.

No genetic counseling is useful for any form of urticaria.

The only nutritional factors that affect the course of acute urticaria are to avoid the offending foods.

People who are malnourished have physical stress that does not help relieve the severity of urticaria, especially in the case of chronic urticaria. Thus, maintaining general health is important.

What is the evidence?

Zuberbier, T, Asero, R, Bindslev-Jensen, C. "EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria". Allergy. vol. 64. 2009. pp. 1417-26.

(The summary of the 3rd International Consensus Meeting on Urticaria, with the joint initiatives of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GALEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO). The guideline covers recent progress in identifying the causes, clarifying the factors, and understanding the pathomechanisms. In addition, the guideline provides evidence-based approaches for the different subtypes of urticaria. The guideline is accepted by the European Union of Medical Specialties (UEMS). This position paper is very comprehensive and updated. The one regret is that only small sections are devoted to pediatric cases.)

Zuberbier, T, Asero, R, Bindslev-Jensen, C. "EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria". Allergy. vol. 64. 2009. pp. 1427-43.

(A continuation of the consensus summary in the reference listed above. The suggestions here were discussed by more than 200 international specialists at the meeting to achieve a consensus. The summary emphasizes that urticaria has a profound impact on quality of life; therefore, effective treatments are required. The recommended first-line treatment is the new generation of non-sedating H1 antihistamines. If not effective, increasing the dose by four-fold is recommended in adults, two-fold in pediatric patients. It is recommended that second-line therapies should be added if a high-dose H1 antihistamine is not effective. In the choice of second-line treatment, both cost and risk/benefit profile are important to consider. Corticosteroids are not recommended for long-term treatment due to their unavoidable severe adverse effects. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Again, limited space is given to pediatric patients.)

Liu, TH, Lin, YR, Yang, KC. "First attack of acute urticaria in pediatric emergency department". Pediatr Neonatol. vol. 49. 2008. pp. 58-64.

(Detailed etiologies of the first attack on urticaria in children were analyzed. An Important finding is that there is a decrease in the prevalence of various infections as causative factors as a child's age increases. The etiologies of foods and medications are more prevalent in adolescents than in younger children. This is by far the largest collection of pediatric cases, 953 in total, of acute urticaria. This article has much useful information for pediatricians.)

Huang, SW. "Acute urticaria in children". Pediatr Neonatol. vol. 50. 2009. pp. 85-87.

(This paper discusses the causes of urticaria with respect to infection. Urticaria could be the result of infection per se, or could be secondary to antibiotic treatment. The author emphasizes the necessity of pursuing the cause of a drug-related rash, because this has often been mislabeled as drug allergy. True drug allergies in children are actually very few. The clinician should not hesitate to prescribe a useful antibiotic for a child if that drug is proven to be non-allergic in that child.)

Lin, YR, Liu, TH, Wu, TK. "Predictive factors of the duration of a first-attack acute urticaria in children". Amer J Emer Med. vol. 29. 2011. pp. 883-9.

(Another large collection of pediatric patients, 1075 in total. This study surveyed age, various etiologies, clinical manifestations, occasional pyrexia or angioedema and personal allergy factors. The authors concluded that etiology and personal allergy history may be the most important predictors of the duration of a first attack of acute urticaria. The information is very useful for pediatricians.)

Lara-Corrales, L, Balma-Mena, A, Pope, E. "Chronic urticaria in children". Clin Pedia(Phila). vol. 48. 2009. pp. 351-5.

(A quick review and commentary on chronic unticaria in children. The included flow sheet may be useful for clinicians.)

Sahiner, UM, Civelek, E, Tuncer, A. "Chronic urticaria: etiology and natural course in children". Int Arch Allergy Immunol. vol. 156. 2011. pp. 224-30.

(The authors conclude that the etiology of chronic urticaria in children is related mainly to an autoreactive background, as in adults. Chronic urticaria has overall a favorable prognosis, and resolution is seen in half of children within 5 years. Girls older than 10 years may have an unfavorable prognosis).

Church, M, Weller, K, Stock, P, Maurer, M. "Chronic spontaneous urticaria in children". Pediatr Allergy Immunol. vol. 22. 2011. pp. 1-8.

(This is a review article. The authors point out that current information on urticaria in children is largely lacking. The authors propose that future studies should focus on determining the prevalence, possible presence of biomarkers, comorbidities, and effectiveness of treatment of chronic urticaria.)

Kilic, G, Guler, N, Suleyman, A, Tamay, Z. "Chronic urticaria and autoimmunity in children". Pediatr Allergy Immunol. vol. 21. 2010. pp. 837-42.

(A detailed analysis of 40 children with chronic urticaria. The authors categorized the patients according to chronic autoimmune urticaria (CAU) and chronic idiopathic urticaria (CIU), and analyzed in depth the possible etiologies. Between the two groups, there were overlapping clinical manifestations, but the etiologies were diverse. No treatment was fully discussed.)

Herguner, S, Kiliç, G, Karakoç, S. "Levels of depression, anxiety and behavioural problems and frequency of psychiatric disorders in children with chronic idiopathic urticaria". Br J Dermatol. vol. 164. 2011. pp. 1342-7.

(This study found a high prevalence of psychiatric disorders in affected children. The authors recommend combining dermatologic and psychiatric evaluations as necessary for the management of chronic idiopathic urticaria.)

Spadoni, M, Jacob, C, Aikawa, N. "Chronic autoimmune urticaria as the first manifestation of juvenile systemic lupus erythematosus". Lupus. vol. 20. 2011. pp. 763-6.

(Among 271 juvenile patients with SLE, two (0.7%) patients had chronic autoimmune urticaria as the first manifestation of SLE. Rigorous follow-up is advised for children suffering from autoimmune urticaria, due to the possibility of the development of connective tissue disorders such as pediatric lupus.)

Doshi, DR, Weinberger, MM. "Experience with cyclosporine in children with chronic idiopathic urticaria". Pediatr Dermatol. vol. 26. 2009. pp. 409-13.

(Among 54 children with chronic urticaria, seven failed to respond to high-dose antihistamines. The patients were given cyclosporine 3 mg/kg/day divided bid. In six of seven patients, cessation of hives occurred in 1-4 weeks, one in 8 weeks. Treatment should be reserved for selected cases, and the cyclosporine serum concentration needs to be closely monitored. The authors claimed that relapse was seldom, but the long-term outcome is unclear.)

Singh-Franco, D, Ghin, HL, Robles, GI. "Levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria in adults and children". Clin Ther. vol. 31. 2009. pp. 1664-87.

(This is a combined analysis of multiple studies in adults and children. After 6 weeks of therapy, improvement of hives was significant compared with controls. There is concern on the possibility of febrile seizures in infants treated with LCZ. The authors recommended a comparison study with other drugs. This is by far the best study that confirms the effectiveness of long-acting, non-sedating H1 antihistamines in urticaria.)

Huang, SW, Borum, PR. "Study of skin rashes after antibiotic use in young children". Clin Pediatr (Phila). vol. 37. 1998. pp. 601-8.

(The authors confirmed that true drug sensitivity is rare in children. The common cause of skin rashes, including urticaria, after antibiotic use is likely due to infectious agents or an adverse reaction to dyes, flavors, or preservatives).

Ongoing controversies regarding etiology, diagnosis, treatment

In nearly 25% of patients with acute urticaria and 70% of chronic urticaria, we may never know the exact cause.

The controversies on the treatment of urticaria have two aspects. The first is that the definitions of acute and chronic urticaria are arbitrary. If the skin lesions last for less than six weeks, the condition is called acute, while if the lesions last for more than six weeks, the condition is termed chronic. Undoubtedly, there will be overlap in treatment between the two conditions when using similar drugs.

The other aspect of the controversy is when to decide to move from Tier 1 treatment (also, first-line to second-line) to Tier 2 treatment. The decision is strictly at the discretion of the clinician who takes care of the patient. However, it is reasonable to change the treatment strategy if there is no improvement in the clinical manifestations, intensity, or extent of the rash within two to three weeks. A long wait may begin to significantly affect the patient's quality of life. Regrettably, there has been no large scale, prospective study conducted in children of varying ages with either acute or chronic urticaria. It is often necessary to apply experience from adult studies to pediatric patients.

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