Help, “hive” got a rash! — Article 1: Practical tips in the assessment of chronic spontaneous urticaria (CSU)

Authors

Kevin KD Lee, MD, FRCPC (biography and disclosures)

Disclosures: Received resident research funding from ImmUnity Canada (previously known as Canadian Immunodeficiencies Patient Organization). Mitigating potential bias: Recommendations are consistent with published European and Canadian guidelines and with current practice patterns. Only published trial data are presented. Treatments or recommendations in this article are unrelated to the research grant from the disclosure statement.

Persia Pourshahnazari, MD, FRCPC (biography and disclosures)

Disclosures: Received honoraria for speaking engagements from Octapharma, Takeda, CSL Behring, Novartis, and Astra Zeneca. Advisory board member for Octapharma, Takeda, CSL Behring, Novartis, Astra Zeneca, Valeo, Sanofi, and Aralez. Mitigating potential bias: Recommendations are consistent with published European and Canadian guidelines and with current practice patterns. Only published trial data are presented.

What frequently asked questions we have noticed

Urticaria are a common condition seen in both primary and specialty care practices. The lifetime prevalence of any type of urticaria is estimated at 15% to 25%. Of these, about 50% will present with only wheals, 40% with wheals and angioedema, and 10% with only angioedema .^1,2 Urticaria is classified by both the duration of the condition (acute if ≤ 6 weeks, chronic if > 6 weeks) and eliciting physical factors (Table 1). The classification is important as it impacts the management and prognosis.

Despite being a fairly common problem, with an estimated prevalence of 0.5–5%,^1,2 chronic spontaneous urticaria (CSU) is often a challenging condition for health-care providers to diagnose and for patients to accept as a diagnosis. This may be due to its variable presentation, fleeting nature, and seeming associations with multitudes of triggers. In our experience, we have often been asked if CSU is associated with an underlying autoimmune disease, if it is related to food ingestions, and if it is caused by COVID-19 vaccinations. This is the first of two articles aimed at providing answers to the above questions, along with a discussion of the differential diagnoses and investigations recommended for CSU.

Data that answers these questions

Is CSU associated with an underlying autoimmune disease (e.g., lupus)? If not, why is it happening?

While the pathophysiology of CSU is thought to be autoimmune in nature, having a diagnosis of CSU does not mean that the patient has systemic lupus erythematosus (SLE) or another systemic autoimmune disease. In one systematic review of 42 studies, the prevalence of CSU in patients with SLE ranged from 0% to 21.9% for adults and 0% to 1.2% for children.³

The exact mechanism of CSU is unclear but is thought to occur due to the release of pre-formed mediators (e.g., histamine) from mast cells and basophils; this process is known as degranulation. Normally, degranulation occurs when IgE molecules that are bound to the cell surfaces of mast cells or basophils recognize and bind to foreign products (known as antigens). However, in CSU, there are two theories as to the cause of increased degranulation of mast cells and basophils.⁴

The first theory, which is the most accepted, is due to presence of autoantibodies. These autoantibodies can bind to parts of the mast cell or basophil (e.g., FcεR1 alpha subunit, Fc region of the IgE molecules) to trigger degranulation. Alternately, the IgE antibody that is bound to mast cells or basophils could be the autoantibody that triggers degranulation by recognizing self. While autoantibodies are also found in patients with autoimmune diseases (e.g., lupus), the diagnosis of CSU does not equate to a diagnosis of a systemic autoimmune disease.

The second (and lesser accepted) theory for the cause of degranulation of mast cells and basophils in CSU involves dysfunction of intracellular signaling that increases spontaneous degranulation. The body of evidence supporting this theory is less robust.

Could CSU be food-related (i.e., allergic)?

True food allergy (IgE-mediated anaphylaxis) is a potentially life-threatening condition characterized by development of systemic symptoms (e.g., cardiac, respiratory, or gastric) with or without urticaria and angioedema each time a person eats a single suspected allergenic food. In comparison, spontaneous urticaria do not present with other systemic symptoms and are not temporally associated with ingestion of food.

Although many patients may have tried various food elimination diets prior to seeing a clinician about their symptoms, there is no clear association between food ingestion and urticaria. While a study reported symptom improvement in about a third of patients who were following a “pseudoallergen-free” diet, this was a non-blinded study and its interpretation and clinical application should be made with caution.⁵ If any special dietary modifications are trialed, they should be time-limited with attempted reintroduction of avoided foods after 2 to 3 weeks.¹

It is important to consider the risks of prolonged food avoidance, including the potential to develop a true food allergy and nutritional deficiency. This is particularly important in children. As such, we do not routinely recommend any specific food avoidance unless the food in question is diagnosed as a true food allergy. One exception to this rule is alcohol, which is a known cofactor for mast cell destabilization. Patients with CSU are routinely advised to limit alcohol ingestion if possible.

Could CSU be due to COVID-19 vaccinations?

Vaccinations in general can act as an immunologic trigger for onset of chronic urticaria. There have been many case reports of new-onset urticaria or exacerbations of pre-existing urticaria that have been published since the start of the COVID-19 vaccination campaign. For example, de Montjoye et al⁶ reported 8 cases of CSU after COVID-19 vaccination, of which 7 were de novo and 4 had further exacerbations after their subsequent vaccine dose.⁶ Another study reported that 4 of 60 adults with a history of CSU (in remission for at least 4 weeks on antihistamines and omalizumab) had a flare of their urticaria after receiving a COVID-19 vaccine.⁷

However, this finding is not restricted to COVID-19 vaccinations but is also seen with COVID-19 infections. Lascialfari et al⁸ reported that in 26 pediatric patients with CSU and COVID-19 infection, 5 (19.2%) had a relapse or worsening of their CSU.⁸ In comparison, 2 of 26 (7.7%) pediatric patients with CSU had relapse or worsening of their CSU symptoms following COVID-19 vaccination. Further, flares of CSU are often seen with other vaccines, likely due to general stimulation of the immune system.⁹

In this context, CSU is not a contraindication to any vaccinations (including COVID-19 vaccines) and vaccination schedules need not be interrupted in patients with CSU. We do advise patients with CSU to take a higher dose of antihistamines prior to vaccinations to minimize the risk of symptom flares. If urticaria do develop after vaccination, then it is important that health-care providers take an appropriate history to differentiate between spontaneous urticaria versus urticaria associated with anaphylaxis. Subsequent management would differ significantly in cases where anaphylaxis was thought to have been precipitated by a vaccine.

What else could this be (differential diagnoses)?

It is important to ensure that the “hives” reported by patients are true urticaria. Non-urticarial rashes should also be considered.^1.2 There are several key historical features that can be useful in differentiating urticaria from other cutaneous eruptions. Urticaria are highly pruritic and migratory and do not scar or bruise upon resolution. Insect bites (a common urticarial mimic) will typically persist for days and may affect multiple household members. Other rashes that may mimic urticaria (e.g., urticarial vasculitis, bullous pemphigoid, erythema multiforme, Still’s disease) are usually reported as being painful and individual lesions will typically last for longer than 48 hours. Persistent skin changes may remain after resolution of the initial rash. Other features of inflammation (e.g., fever, chills, arthritis) may be present if the patient’s rash is secondary to a systemic process. This would not be expected with typical urticaria.

Anaphylaxis should also be considered in the differential diagnosis of any patient presenting with urticaria. Temporal onset of urticaria following exposure to a suspected trigger (such as medications, foods, or venoms) in association with other organ system involvement should trigger prompt treatment with epinephrine. In comparison, symptoms should be limited to the skin only for CSU.

Table 1: Classification of urticaria and their eliciting factors

What testing is needed for diagnosing CSU?

The majority of urticaria can be diagnosed by history and physical examination alone. It’s important to inform patients of the nonallergic nature of chronic hives as they may request panel testing (e.g., skin prick tests or specific IgE levels) for allergic evaluation. This is unnecessary and uninformative in chronic urticaria.

In most cases, investigations are not needed for CSU.^1,2 However, in persistent or uncontrolled cases, or as guided by history, limited investigations for potential comorbidities can be considered. Some patients with CSU can have concomitant autoimmune thyroid disease and screening for anti-thyroid peroxidase autoantibodies is appropriate if there is clinical suspicion. If urticarial vasculitis is suspected, then a complete blood count, C-reactive protein, and skin biopsy should be obtained. If any other differential diagnoses are being considered, then this would direct further workup as appropriate. For those patients who are suspected to have chronic inducible urticaria, targeted provocation testing may be performed to confirm triggers (e.g., delayed pressure, ice cube test). These investigations are typically completed at an allergist’s office.

What we recommend (practice tips)

We summarize the above discussion as follows:

1. A diagnosis of CSU does not automatically equate to a diagnosis of lupus or another systemic autoimmune disease.
2. The current proposed pathophysiology of CSU includes either the presence of autoantibodies or dysfunction of intracellular signaling mechanisms that leads to increased degranulation of mast cells and basophils.
3. With the exception of alcohol (which can destabilize mast cells), we do not routinely recommend dietary modification for CSU. CSU is not related to food allergy and food avoidance may increase the risk of developing a true food allergy and/or nutritional deficiency.
4. CSU onset and exacerbation have been associated with both COVID-19 vaccinations and COVID-19 infections. CSU is not a contraindication to receiving vaccinations. We advise patients with CSU to take a higher dose of antihistamines prior to receiving vaccinations to try and minimize the risk of symptom flares.
5. In most cases, investigations are not needed when making a diagnosis of CSU. Allergy panel testing (serum-specific IgE and skin testing) are unnecessary and uninformative in CSU.

References

1. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-1414. doi:10.1111/all.13397 (View)
2. Kanani A, Betschel SD, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):59. Published 2018 Sep 12. doi:10.1186/s13223-018-0288-z (View)
3. Kolkhir P, Pogorelov D, Olisova O, Maurer M. Comorbidity and pathogenic links of chronic spontaneous urticaria and systemic lupus erythematosus–a systematic review. Clin Exp Allergy. 2016;46(2):275-287. doi:10.1111/cea.12673 (View with CPSBC or UBC)
4. Bracken SJ, Abraham S, MacLeod AS. Autoimmune Theories of Chronic Spontaneous Urticaria. Front Immunol. 2019;10:627. Published 2019 Mar 29. doi:10.3389/fimmu.2019.00627 (View)
5. Magerl M, Pisarevskaja D, Scheufele R, Zuberbier T, Maurer M. Effects of a pseudoallergen-free diet on chronic spontaneous urticaria: a prospective trial. Allergy. 2010;65(1):78-83. doi:10.1111/j.1398-9995.2009.02130.x (Request with CPSBC or view with UBC)
6. de Montjoye L, Herman A, Baeck M. Chronic spontaneous urticaria following COVID-19 vaccination. JAAD Case Rep. 2022;25:35-38. doi:10.1016/j.jdcr.2022.05.011 (View)
7. Picone V, Napolitano M, Martora F, Guerriero L, Fabbrocini G, Patruno C. Urticaria relapse after mRNA COVID-19 vaccines in patients affected by chronic spontaneous urticaria and treated with antihistamines plus omalizumab: A single-center experience. Dermatol Ther. 2022;35(11):e15838. doi:10.1111/dth.15838 (View)
8. Lascialfari G, Sarti L, Barni S, et al. Relapse or worsening of chronic spontaneous urticaria during SARS-CoV-2 infection and vaccination in children: A telemedicine follow-up. Allergol Immunopathol (Madr). 2022;50(S Pt 2):1-7. Published 2022 Sep 22. doi:10.15586/aei.v50iSP2.722 (View)
9. Magen E, Shalom G, Waitman D, Kahan N. Chronic spontaneous urticaria following vaccination. Int J Adv Res. 2018;6(2):1434-9. doi:10.21474/IJAR01/6574 (View)

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