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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease."

The 2021 evidence-based international on urticaria, updated and revised by 64 experts from 31 countries, provides a detailed roadmap for physicians based on increased understanding about this "frequent, mast cell-driven disease that presents with wheals, angioedema, or both." The recommendations outline consensus-based diagnostic and therapeutic approaches for the different subtypes of urticaria, underscoring their heterogeneity, the broad range of clinical manifestations, and the potential for two or more subtypes to show up in the same patient.

In spite of this growing knowledge base, the cause of urticaria remains unknown in more than 80% of patients. Urticaria is a clinical diagnosis, and the guideline strongly recommends against the use of a routine diagnostic workup in acute urticaria, which is defined by a duration of 6 weeks or less.

"It is important to remember that not all possible causative factors need to be investigated in all patients," the guidelines team wrote. "Intensive and costly general screening programs for causes of urticaria are strongly advised against."

Wheals and angioedema can be a symptom of anaphylaxis, and in rare cases indicate significant underlying disease. However, the course of urticaria is usually benign and self-limited. Most cases of acute urticaria, which is thought to be caused by a type I hypersensitivity or an immediate immunoglobulin E (IgE)-mediated reaction to foods, drugs, and other allergens, are spontaneous and resolve within a week.

The availability of safe and effective therapies -- and the promise of more to come -- has created a subtle shift away from expensive diagnostic work-ups and towards better symptom control and long-term management, noted Jonathan Silverberg, MD, PhD, of George Washington University School of Medicine and Health Sciences in Washington, D.C.

"We have to realize that when doing these [expensive] work-ups for autoimmune disease -- and many still are -- the clinically relevant yield is extremely low in the overall patient population," he told MedPage Today. "It's become clear over the years of research that for the vast majority of patients, this is a chronic autoimmune disease and needs to be treated as such."

As with all clinical diagnoses, a detailed patient history and thorough physical examination is recommended. In the case of urticaria, this is to identify potential triggers and exacerbating factors, and to exclude other diseases, conditions, and syndromes that feature wheals and/or angioedema. Given the transient nature of urticaria, physicians are urged to include a review of patient photos of wheals and angioedema in the evaluation.

The exception to the "no diagnostic work-up in acute urticaria" recommendation would be the patient suspected of having a type I food allergy reaction or drug hypersensitivity -- especially to non-steroidal anti-inflammatory drugs. "In this case, allergy tests and patient education may be useful to allow patients to avoid re-exposure to relevant causative factors," the guideline authors said.

"The combination of physical exam and history are going to guide you in terms of what kinds of work-up you need to do," said Alison Ehrlich, MD, MHS, of Foxhall Dermatology and Research Center in Washington, D.C., and the former founding chair and director of clinical research in the Department of Dermatology at George Washington University. "Certainly, for the person in their 80s coming in with urticaria, I might also do a malignancy work-up. Before I start ordering labs, I want to know about all of that patient's medication, whether any are new, and how long the patient's been on them."

For patients with chronic urticaria, which is classified by the presence or absence of definite triggering factors, the guideline-recommended third step is a basic diagnostic work-up. Chronic spontaneous urticaria (CSU) accounts for 60-90% of chronic urticaria but has no definite triggers, while chronic inducible urticaria has definite, subgroup-specific triggers, such as cold, heat, and pressure.

In patients with CSU, the guideline recommends a differential blood count and C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR), with a total IgE with IgG-anti-thyroid peroxidase in those under the care of a specialist. Based on the results, further diagnostic testing may be indicated, especially in patients with long-standing and/or uncontrolled disease. The goal of any diagnostic test should be clear to both physician and patient, the guideline authors emphasized.

The value of these tests is debatable, said Silverberg, adding that the test results are unlikely to impact either the choice of therapy or its effectiveness. "Xolair [omalizumab] will work one way or another, so why are we wasting time and money with these tests? What's the point?"

Aside from testing for standard markers such as ESR and CRP, the most important test is thyroid function, Silverberg emphasized. "At the very least, you'll find out if the patient has underlying thyroid disease that is clinically relevant."

He said he has found that testing for different IgE antibodies to food allergens or other potential triggers "is generally low yield and often fraught with false positives."

"Chronic spontaneous urticaria is more of a lab work-up," Ehrlich noted. "If the patient is coming in after having hives for 8 weeks, we really have to go through medications to see if there's a trigger there."

Ehrlich said that although she checks thyroid function, she also tests for anti-nuclear antibodies, since these are considered a possible sign of autoimmune disease such as lupus, scleroderma, Sjögren's syndrome, juvenile arthritis, and polymyositis. "If the patient is in the age category to have pre-bulbous pemphigoid, and has lesions that are actually sitting there for a few days at a time, you may want to do a skin biopsy and also rule out urticarial vasculitis," she advised.

The diagnostic work-up should be symptom-based, particularly when it indicates chronic infection, said Jenny Murase, MD, of the University of California, San Francisco. "If the patient doesn't have symptoms of infection, it's been shown that labs are pretty much worthless."

Gall bladder infection, prostatitis, and yeast infection have all been linked to urticaria, she pointed out. "So asking about a recent infection or symptoms related to these kinds of infection is important and a reasonable thing to do."

Murase said she routinely asks patients if they have tooth pain, pain on urination, a cheesy vaginal discharge, chest pain, or burping after eating or other symptoms of reflux disease, and so on. "If the patient doesn't have tooth pain, there's no need to look for a dental abscess," she explained. On the other hand, if the patient has symptoms of a sinus infection, she orders an anti-streptolysin O titer.

Having patients keep a food log can be helpful for pinpointing urticaria triggers, Murase said. "This really comes back to history, and finding out when the patient is having flares and what their diet is like. Do you do serum tryptase testing on everybody? No. You do this in the patient you suspect may have mastocytosis."

Dietary sources of red and yellow food dyes contained in red licorice, maraschino cherries, orange soda, and orange vitamin drinks have been linked to urticaria, as have salicylates found in spices and herbs, such as curry and hot paprika powder, she noted. "It's really like finding the needle in a haystack, but sometimes we find the most random things are the cause, like a protein supplement drink, for example."

More recently, several cases have been reported of allergic reactions to annatto, a pigmented seed used as a less expensive substitute for saffron that gives Spanish, Jamaican, and Filipino dishes their characteristic yellow-orange color. "You can have cross reactions with one thing and then something else can trigger that reaction," said Murase. "This is also important to remember."

The guideline recommends that patients with chronic urticaria be assessed for disease activity, impact, and control at every visit. In those with CSU, the urticaria activity score and/or the angioedema activity score are recommended for the assessment of disease activity. The use of the urticaria control test or the angioedema control test can be used to assess disease control.

In patients with chronic inducible urticaria, it is recommended that the routine diagnostic work-up exclude differential diagnoses, identify the subtype, and determine trigger thresholds to assess response to treatment. Provocation testing with validated tools for cold and heat urticaria, symptomatic dermographism urticaria, delayed pressure urticaria, cholinergic urticaria, contact urticaria, and aquagenic urticaria is advised.

Read Part 1 of this series: Urticaria/Hives: The Search Continues for Causes