Approach to Chronic Urticaria From Primary Care and Emergency Services: Case Reports in Spain

Urticaria is a common process. The true incidence is not known; it is believed that between 15 and 25% of the population may suffer at some point in his life. Acute urticaria has a prevalence of 20% and the chronic form 0.5–1%. Urticaria is a disease that affects the skin and mucosa, characterized by the presence of hives. It occurs as a localized intracutaneous edema circled and an area of redness (erythema), which is typically itchy. There are histaminergic foods and drugs that worsen the prognosis of the disease . Foods which rely on aging to taste nice are always presumed to be high in histamine (chocolate, yogurt, seafood, strawberries, etc.) and drugs like nonsteroidal anti-inflammatory drugs. For diagnosis we have several tools (urticarial activity score, chronic urticaria quality-of-life questionnaire (CU-Q2oL), urticaria control test, etc., among which the most useful, simple, and cost-effective is the clinic history). The treatment of choice are antihistamines, from a daily tablet up to four tablets as maximum dose. Corticosteroids are excluded to exacerbations and must be prescribed in short guideline (maximum 10 days) without progressive decrease. Severe forms of urticaria resistant to treatment with antihistamines are treated with biological agents like omalizumab.


Introduction
The interest in making this chapter was to explain the pathology of chronic urticaria as prevalent and its high morbidity.
We often see this problem in our primary care consultations and emergency services, so we consider its important to make a chapter about urticaria.
The current version of the EAACI/GA 2 LEN/EDF/WAO urticaria guideline from 2018 contains new aspects about diagnosis and treatment.
At the end of the chapter, we show a series of cases treated in our practice (observed in a Juan Ramon Jimenez's dermatology room in Huelva, Spain), exposing results obtained with the different forms of treatment (Figure 1).

Epidemiology
Urticaria is a common process. Although the true incidence is not known, it is believed that between 15 and 25% of the population may suffer at some point in his life. Acute urticaria has a prevalence of 20% and the chronic form 0.5-1% [1]. Age, race, sex, occupation, geographical region, and the season of the year may be implicated in urticaria and angioedema. The majority of acute episodes are due to adverse reactions to medications or food or, in children, to viral diseases.
Spontaneous chronic urticaria represents about 70% of all chronic hives and may persist for several years. Patients with chronic urticaria often describe a decrease in the quality of life because of itching and may have alterations of sleep, fatigue, social isolation, or emotional disorders (Figures 2-4).

Physiopathology
Urticaria is a disease that affects the skin and mucosa, characterized by the presence of hives. It is a localized intracutaneous edema that circled an area of redness (erythema), which is typically itchy. Individual hives can persist from 30 minutes to 36 hours and can measure from only 1 millimeter up to 15-20 cm in diameter, named giant hives [3]. Increased dilation and permeability of blood vessels that characterize the hives are present in the superficial dermis and undertake the venous plexus located there ( Figure 5). It is rare and it may occur with concomitant angioedema.
Another similar entity is angioedema, with a similar mechanism as urticaria [4], but the pathology is located in the deep dermis and subcutaneous tissue, and swelling is the main manifestation. The skin may be normal or erythematous. There is less itching, but it can cause pain or burning sensation. The mouth, lips, eyes, throat, feet, and hands are most commonly affected (Figures 6 and 7). When angioedema affects the throat, it can be life-threatening, because there is interference in  breathing. It is caused by an allergic reaction, sometimes by a hereditary condition (hereditary angioedema), but normally we do not know the cause [4].

Food histamine liberator
Foods that require a ripening process to achieve a better taste are presumed to have a high histamine content. In the same way as foods that are made during fermentation. These include de following [5] (Table 1).  The Spanish society of diamine oxidase (DAO) states on their website that the following food histamine liberators: • Alcohol, citrus fruits, strawberries, pineapple, kiwi, tomato sauce, seafood, chocolate, fish, mushrooms, pig, cereals, and egg white.
The department for dermatology in Bonn's paper lists the following foods as being capable of releasing endogenous histamine ( Table 2).

Pathogenesis
The mast cell is the main effector cell in urticaria and angioedema. Cutaneous mast cells attach to fibronectin and laminin through the integrin beta1 of Very Late   Antigen (VLA), VLA-3, VLA-4, and VLA-5 activation and vitronectin through alfa1 and beta3 integrin [6].
Histamine is an amine vasoactive located in granules of mast cells [6], basophils, and platelets. Its effects on the skin are mediated through histamine H1 and H2 receptors. H1 receptors mediate urticaria vasodilation, increased vascular permeability, and sensory nerve stimulation. Sensory nerve stimulation determines the release of neuropeptides such as substance P, peptide vasoactive intestinal (VIP), and somatostatin, which in turn induce the mast cell activation and increase in histamine.

Yogurt
Soured cream Buttermilk Quark

Histamine liberator food.
The vascular endothelium expressed a significant number of H2 receptors, so the vascular response in the UC is an immunomodulatory effect, to increase the synthesis of pro-inflammatory cytokines such as IL-1 and IL-6 of monocytes and IL-6 and IL-8 cell endothelial. In addition to histamine, other soluble factors synthesized by mast cells contribute to the increase of vascular dilation and permeability; favor chemotaxis, cell activation of leukocyte, and endothelial cells; and induce stimulation sensory. These are the cytokines, chemokines, and neuropeptides and arachidonic acid metabolites.
The degranulation is attributed to immunological causes (autoimmune, IgEdependent, immune complexes, complement-dependent), not immune (pseudoallergies, agents release by mast cells) and idiopathic. The path of the synthesis of prostaglandins and leukotrienes, hours later the mast cell activation, occurs in the synthesis of leukotrienes and prostaglandins from arachidonic acid via two-way enzymatic metabolism: the cyclooxygenase path and the lipoxygenase pathways.
Studies have shown that LTB4 has a potent chemotactic activity, which is produced by mast cells in the early and selective recruitment of leukocytes. At chronic urticaria (CU), these mediators appear to be the most important in the chronicity of the disease. There are no immune reactions (pseudoallergics); the mechanisms are not clear but may compromise the metabolism of arachidonic acid, prostaglandins, and leukotrienes [3] (Figure 8).

Classification
According to the time evolution, urticaria can be divided into: • Acute urticaria: less than 6 weeks.
Recurrent urticaria: outbreaks recur over time, but its duration is limited. Episodes of hives last less than asymptomatic intervals. * Chronic urticaria is divided into two: Spontaneous chronic urticaria: spontaneous emergence of hives, angioedema, or both for longer than 6 weeks, due to a known or unknown cause.
Inducible urticaria: physical urticarial (This hives occur at the site of the stimulation)l, cholinergic, aquagenic and contact urticarias (Figure 9).

Diagnosis
For diagnosis we have several tools, among which the most useful, simple, and cost-effective is the clinical history, but we can ask for additional tests in the case of diagnostic doubt or suspicion of systemic disease [2].

Clinical history
A detailed clinical history and a good physical examination of the patient are necessary to make the diagnosis. Thanks to its history, we can classify chronic urticaria as spontaneous or inducible. For this, we must focus on the following aspects: • A family history of atopy or urticaria.
• Commonly used drugs and relation with the hives.    • A history of allergies, infections, or any other cause that has been able to trigger hives.
• Work performed and hobbies.
• Induction of urticaria due to exercise or exposure to physical agents.
• How the body reacts to insect bites.
• If the patient has been on holidays or trip recently.
• If it has relationship with the menstrual cycle or stress.
• If the quality of life is affected.
• Duration of the disease.
• Frequency and duration of the hives, size, shape, and distribution.
• If associated symptoms are subjective such as pain, burning, etc.
• If the patient has nocturnal or diurnal variation.
• How the response was to the treatments used.

Complementary tests
Complementary tests serve as support to the diagnosis, to detect associated systemic diseases or for differential diagnosis.
Basic laboratory tests, as blood count and biochemical reaction (determination of C-reactive protein, glomerular sedimentation rate), can help us rule out there is a systemic disease. The baseline of tryptase, antithyroid antibodies, and thyroid profile and study of complement and specific IgE where allergy is suspected, could also be useful. If an infection cause is suspected, hepatitis B and C virus or Helicobacter Pylori could be detected.
New guidelines recommend not to perform additional exploration in a systematic way in acute urticaria and just a complete blood count with ESR and a suspension of nonsteroidal anti-inflammatory drugs (NSAIDs) in the CU (Figure 16).

Mild forms of urticaria
• The treatment of choice are antihistamines, from a daily tablet up to four tablets as maximum dose.
• Corticosteroids are excluded for exacerbations and must be prescribed in short guideline (maximum 10 days) without progressive decrease.

Severe forms of urticaria or exacerbations and associated angioedema
• Nonsedative H1-antihistamines to full dose (four tablets in a day) [11].
*Omalizumab is a recombinant humanized monoclonal antibody, which blocks the high-affinity Fc receptor of IgE (Figure 18). It has been approved for treatment in cases of moderate-to-severe asthma, but it has promising results in the management also of chronic urticaria [12]. The dose is 150 or 300 mg by subcutaneous injection every 4 weeks. Dosing is not dependent on body weight or serum IgE level. The appropriate duration for CIU has not been evaluated yet. It's necessary to periodically reassess the need for continued therapy with omalizumab [13].

Clinical guidelines
The European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) and the American Academy of Allergy, Asthma, and Immunology (AAAAI) have some differences in their recommendations for urticaria treatment, but the core recommendations remain similar.
A brief summary of AAAAI guidelines are as follows [14]: As first-line treatment, second-generation nonsedating H1 antihistamines. Remain in the treatment algorithm first-generation H 1 antihistamines (differs from EAACI/GA 2LEN/EDF/WAO guidelines).
Second-line options to consider: adding other second-generation H 1 antihistamines, up-dosing second-generation H 1 antihistamines, leukotriene receptor antagonists, adding H 2 antagonists or first-generation H 1 antihistamines at bedtime.
Omalizumab as third-line treatment. Corticosteroids considered only for short treatment. Cyclosporine A* is used in refractory chronic urticaria not responsive to other treatments.
A brief summary of EAACI/GA2LEN/EDF/WAO guidelines are as follows: First-line treatment, second-generation H 1 antihistamines. Up-dosing second-generation H1 antihistamines are the second-line therapy.
Omalizumab is the third-line treatment, which is recommended because it is less toxic than cyclosporine A.  (Figure 19).  Not included in algorithm H2 antihistamines (used only on an individual case). Avoid first-generation H1 antihistamines based on benefit to risk ratio. Corticosteroids may be considered only for the short-term intervention. Cyclosporine A for refractory chronic urticaria not responsive to other treatments.
*Cyclosporin A is an immunosuppressive agent, widely used in organ transplantation to prevent rejection.
The current version of the EAACI/GA 2 LEN/EDF/WAO urticaria guideline recommends: When chronic inducible urticaria is suspected, differential diagnoses should be ruled out. The diagnosis should be confirmed by provocation test disease. The activity should be measured by determining the trigger threshold disease burden and control should be measured.
Second-generation H1 antihistamines remain the treatment of first choice. If continuous treatment for 2-4 weeks does not lead to adequate control of symptoms, the guidelines recommend up-dosing (up to four times the standard dose).
If there is no improvement with high-dose antihistamines, it is recommended to add omalizumab to the regimen in patients with chronic spontaneous urticaria. If there is no success after 6 months of omalizumab therapy, off-label treatment with cyclosporine is recommended.

Assessment scales
Assessment scales serve to evaluate the treatment, as well as this pathological entity affects the quality of life of the patient. We have the urticarial activity score (UAS) [15] or angioedema activity score (AAS) [16], chronic urticaria quality-oflife questionnaire, and urticaria control test (UCT). The current guideline endorses the urticaria activity score and/or the angioedema activity score to assess the disease activity in CSU patients [17] (Figure 20).
The urticaria control test should be used in all CSU patients. The UCT is a retrospective tool used to rapidly and reliably assess disease control with four simple questions (Figure 21). Patients answer each of the four UCT questions, and the corresponding points (0-4 per answer) are added up to yield a total score of 0-16. The cutoff for controlled urticaria is 12 points. A score of 11 or less indicates insufficient disease control, whereas a score of 12 or more suggests adequate disease control [18].

Conflict of interest
None.