Last revised: 06/2020 Questions or suggestions? Email: ______Next expected review: 12/2020 Urticaria Goal: Provide PCPs with initial workup algorithm for urticaria, including when to refer. Diagnostic Workup

Inclusion Consider these alternative conditions Criteria Does the that may be mistaken for urticaria. patient truly have Non pruritic: Raised, red, itchy, urticaria? This includes 3 Non-puritic: pruritic, fleeting • - AuriculotemporalViral exanthem syndrome components: • Sweet syndrome plaques 1) Area of central swelling, usually with - Auriculotemporal syndrome surrounding erythema - Sweet syndrome No Pruritic: 2) Itchiness • Eczema ! Pruritic: 3) Fleeting/migrating individual • Contact dermatitis All - Eczema wheals (usually lasting • Drug eruptions urticaria - Contact dermatitis 30 mins-24 hrs) • Insect bites is caused by - Drug eruptions • Bullous pemphigoid release of - Insect bites • Erythema multiforme minor histamine, but - Bullous pemphigoid • Plant-induced reactions (e.g. histamine release is not - Erythema multiforme minor poison ivy, poison oak) always IgE-mediated (type I Yes - Plant-induced reactions (e.g. • Viral exanthem allergic reaction). poison ivy, poison oak) * Consider the following categories of potential culprits of IgE-mediated allergic reactions: - Medications Signs/symptoms Administer epinephrine, send to ER. Use - Foods & food additives concerning for ASAP score to guide decision making if Yes - Insect bites and stings anaphylaxis (involvement diagnosis of anaphylaxis is unclear. After - Latex of at least 2 organ ER visit, refer to allergist. - Blood products systems)?

Consider the following categories of potential culprits of direct mast cell activation (non-IgE mediated): No - Narcotics (including codeine and dextromethorphan) - Anesthetic muscle relaxants Urticaria - Vancomycin preceded by Refer to allergist for workup of - Radiocontrast medium exposure to potential IgE-mediated allergic reaction or non-IgE Yes - Foods (tomatoes and strawberries especially) identifiable trigger* mediated mechanism (through direct mast - Stinging nettle plant within 2 hours of cell activation). onset? NSAIDS (e.g. aspirin, naproxen, ibuprofen) can cause urticaria due to IgE-medicated allergic reactions or due to non-allergic mechanism (due to Diagnostic workup for infections targeted to underlying abnormalities in arachidonic acid No current symptoms, treat accordingly. metabolism). - Infections are associated with over 60% of pediatric acute urticaria cases. Mechanism is through autoimmune Symptoms response to the infection, in which IgG develops against mast cells and Acute urticaria: present <6 weeks. of acute viral or triggers degranulation.5 Chronic urticaria: present most days of the week bacterial infection? (e.g. Yes for >6 weeks. respiratory illness, - If urticaria develops multiple days into UTI, otitis antibiotic course, it is very unlikely an 5 In many patients, no specific etiology for urticaria media) IgE-mediated drug allergy. Do not can be identified. Acute urticaria is more likely to label the patient with an allergy to the have an identifiable etiology than chronic urticaria. drug! When child is well, either adminster an observed dose in the No office and watch for 1 hour, or refer to allergist for definitive allergy testing.

Travel to Order stool O&P. endemic area - Infections with Ancylostoma, Continue to next for parasitic infections, Strongyloides, Filaria, Echinococcus, No Yes page or found to have peripheral Trichinella, Toxocara, Fasciola, blood eosinophilia? Schistosoma mansoni, and Blastocystis hominis have all been associated with urticaria. Diagnostic Workup Cont. (Less Common Causes)

Diagnostic testing (challenge procedure) is Urticaria not required, but can be helpful for associated wtih physical stimuli (e.g. confirming the trigger. Refer to allergy or cold exposure, sudden dermatology if considering confirmatory diagnostic testing or if symptoms are changes in body temperature, Yes pressure or vibration against refractory to exposure avoidance and the skin, exercise, Physical (inducible) forms of antihistamines. (See "Physical urticarias" exposure to urticaria probably result from page for table of diagnostic tests and sunlight)? heightened sensitivity by the mast treatment suggestions for refractory cell to environmental conditions, symptoms.) although the exact pathogenesis is unknown. No Consider serum sickness if patient has fever, along with joint pain or swelling. FacialConsider swelling serum and sickness lymph node if patient has a enlargementfever. Another may potential also be seen. clue: Thisindividual is a Urticaria urticarialtype III hypersensitivity lesions are typically and occurs longer after lasting began 2-3 Yes exposure(days to weeks)to foreign in proteinsserum sickness such as than in weeks after exposure antivenoms,other anti-toxins, etiologies anti-thymocyteof urticaria. to a new globulin and chimeric monoclonal medication? antibodies. Consult allergy and nephrology for further evaluation. Urticaria onset correlates with starting a There are rare reports of progesterone-based progesterone-associated urticaria. Consider No Yes medications, or occurs switch to a different contraceptive (if cyclically during latter applicable), or treat symptomatically. half of menstrual cycle?

No Call dermatology through SCH provider line to discuss potential biopsy; this could be urticarial vasculitis*.7 - Urticarial vasculitis can be may be a cutaneous or systemic disease, and it Are individual lesions may occur in the setting of another painful, long-lasting (longer rheumatologic disorder or rarely, a than 24 to 36 hours), appear Yes malignancy. It always requires biopsy purpuric or ecchymotic, or leave residual for diagnosis (looking for ecchymosis or hyperpigmentation upon leukocytoclastic vasculitis). resolution (in the absence of trauma from scratching)? OR * Urticarial vasculitis is extremely rare in children Is urticaria acompanied by fever (outside of acute infection), arthralgias, arthritis, weight changes, bone pain, or Positive lymphadenopathy? Darier's sign This could be mastocytosis.8 Do NOT (development of vigorously rub the affected area/lesion, as Urticaria localized urticaria and this could trigger hypotension. Refer to associated with erythema within ~5 mins following Yes dermatology. systemic disorders rubbing, scratching, or stroking - In children, 80% of cases appear during skin) by patient history? is usually No 1st year of life. Most resolve by recurrent, (Do not attempt to adolescence. persistent, and reproduce this in clinic.) relatively difficult to No treat. Order diagnostic labs for systemic condition Preceding of concern. Consider calling SCH provider signs/symptoms line (206-987-7777) to discuss case with suggestive of systemic Yes rheumatologist or dermatologist on call prior illness, such as lupus, rheumatoid to ordering labs. arthritis, celiac disease, thyroid disease, or other If urticaria present <6 wks, treat autoimmune symptomatically (see Treatment page). disease? Two-thirds of cases of acute urticaria will resolve. If persistent or recurrent over >6 wks, continue to next page. No No

Diagnostic Workup Cont. (Chronic Urticaria)

Urticaria present or recurrent over a period of >6 weeks?

Yes

Routine lab tests are unlikely to be revealing when the clinical history does not suggest an underlying allergic etiology or the presence of systemic disease. Guidelines suggest initially obtaining a limited set of laboratories to screen for the systemic disorders that may involve urticaria3: 1. CBC with diff - Eosinophilia should prompt evaluation for an atopic disorder or parasitic infection. 2. ESR or CRP - Significant elevations in ESR or CRP should prompt further investigation for systemic diseases, such as autoimmune, rheumatologic, infectious, or neoplastic diseases. Such an evaluation may include measurement of antinuclear antibodies, cryoglobulins, hepatitis B and C serologies, total hemolytic complement, and a serum protein electrophoresis. If high ESR or CRP, refer to rheumatology or dermatology rather than ordering these subsequent labs in the primary care setting. 3. Consider TSH +/- antithyroglobulin and antimicrosomal antibodies - Autoimmiune thyroid disease is uncommon in children with chronic urticaria, and thyroid testing is not recommended by international guidelines as part of workup. However, urticaria can rarely be associated with autoimmune thyroid disease, so some clinicans choose to check these labs as part of the workup. Symptomatic Treatment

Start here:

1) Avoidance of trigger, if identified. 2) Long-acting, non-sedating H1 antihistamine (certirizine, levocetirizine, loratidine, or fexofenadine are all appropriate choices).

Dosing of non-sedating H1 antihistamine can be escalated to BID, TID, or even QID. Some pediatric patients with chronic urticaria may need doses up to 4 times Continue treament for the duration of time the standard effective dose to be that symptoms had been present prior to Symptoms effective. This dosing is not approved by achieving improvement. No improved? the FDA and risks (mild increase in (E.g. if urticaria had been present for 3 incidence of somnolence and greater risk days, continue current effective treatment of adverse effects such as dry mouth and x3 days before trialing off. If urticaria had Yes constipation) and benefits (improved been present 1 month or longer, wait 1 control of urticaria) should be reviewed month before trialing off. The exception is with caregivers.4 prednisone, which should only be given for 3-5 days regardless of preceding symptom duration.) If urticaria resumes upon trial off of antihistamines and/or leukotriene modifiers, resume these medications and wait the Symptoms same amount of time before trialing off Yes improved? again.

No ! Patients with history Trial one or more of the following of anaphylaxis interventions (no head-to-head studies should be exist comparing these)9 while continuing prescribed an EpiPen. the H1 antihistamine: Patients with urticaria - Prednisone burst (1 mg/kg/day) for without an identifiable trigger 3-5 days. No taper needed.5 and without anaphylaxis should - H2 antihistamine (weak evidence) not be prescribed an EpiPen. - Leukotriene modifiers (e.g. montelukast; weak evidence, be aware of black box warning for suicidality) Yes

Symptoms improved?

No

Referral to allergist or dermatologist for consideration of Omalizumab, a monoclonal antibody that targets IgE, approved for age 12 years+ for chronic urticaria. Dosing is 150-300mg Q 4 wks.4 ASAP Score

The algorithm below is copied from Seattle Children's Anaphylaxis clinical standard work pathway: https://www.seattlechildrens.org/pdf/anaphylaxis-pathway.pdf Physical Urticarias

This information is taken from the UpToDate article on "Physical (inducible) forms of urticaria".

Diagnostic considerations It's generally best to defer administration of these tests to allergists or Treatment of refractory symptoms dermatologists: "During these challenges, physical stimuli are applied to "Patients who fail to respond to avoidance of the triggering stimulus the skin for a specified amount of time (usually a few minutes) and then combined with safe and practical doses of a second-generation removed. Urticaria typically develops after removal of the stimulus. antihistamine should be considered candidates for chronic therapy with Leaving the stimulus in contact with the skin until urticaria or angioedema omalizumab. Other therapies for refractory disease, depending upon the actually appear can result in excessive exposure and systemic specific disorder, include phototherapy, physical desensitization protocols, symptoms. Similarly, exposure time may need to be reduced in patients and immunomodulatory agents." who describe unusual levels of sensitivity." References 1. Asero R. New-onset urticaria. UpToDate. Topic last updated 4/2/20. Accessed 6/10/20. 2. Dice J, Gonzale-Reyes E. Physical (inducible) urticaria. UpToDate. Topic last updated 4/16/20. Accessed 6/10/20. 3. Saini S. Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history. UpToDate. Topic last updated 4/7/20. Accessed 6/10/20. 4. Pier J, Bingemann TA. Urticaria, angioedema, and anaphylaxis. Pediatrics in Review. Jun 2020;41(6):283-290. 5. Behar S, Claudius I, Kelso J. "Urticaria." PedsRAP podcast, HIPPO Education. Nov 2016. 6. Anaphylaxis: Seattle Children's Clinical Standard Work Pathway. Last updated May 2020. https://www.seattlechildrens.org/pdf/anaphylaxis-pathway.pdf 7. Brewer J, Davis M. Urticarial vasculitis. UpToDate. Topic last updated 3/17/20. Accessed 6/10/20. 8. Castells M. Mastocytosis (cutaneous and systemic): Epidemiology, pathogenesis, and clinical manifestations. UpToDate. Topic last updated 6/12/18. Accessed 6/10/20. 9. Khan DA. Chronic spontaneous urticaria: Standard management and patient education. Topic last updated 4/3/20. Accessed 6/10/20.