Acute urticaria—what to do?

Acute urticaria (AU) is the most common cause of wheal formation. By definition, it does not persist for more than 6 weeks. It can occur at any age and is more commonly seen in atopic diathesis. Acute spontaneous urticaria is distinguished from inducible forms. This review highlights the clinical presentation, differential diagnosis, possible triggers, and therapeutic strategies. In childhood as in adulthood, viral infections are very frequently associated with acute urticaria, whereas drugs and food are less frequently described as triggers. However, it is not uncommon for multiple triggers to be present simultaneously. Therapeutically, oral nonsedating H1 antihistamines are mainly used. In some patients, concomitant short-term administration of glucocorticosteroids is also necessary.

Mas-related G protein-coupled receptor X2 NSAID Nonsteroidal anti-inflammatory drugs PUPPP Pruritic urticarial papules and plaques of pregnancy Acute spontaneous urticaria is the most common form of urticaria with the typical symptoms of wheals, itching, redness, and/or angioedema.The clinical picture is common, can occur at any age, and more often affects middle-aged women with atopic diathesis and children under 5 years of age [31,35].A recently published study of 284 patients (57% women) with acute urticaria showed a mean age of 43 years [1].By definition, the symptoms of acute spontaneous urticaria do not last longer than 6 weeks [2].The single-cell lesions of the wheals persist less than 24 h in loco, otherwise urticarial vasculitis must be considered.The duration of angioedema may be longer (up to 72 h).
In most cases, the clinical picture resolves after a few hours or days.About 8% of those with acute spontaneous urticaria are reported to develop chronic spontaneous urticaria (CSU) [3].
In a large follow-up study, the following factors were shown to be associated with an increased risk of progression to CSU: Patient age > 10 years, male gender, and underlying autoimmune thyroid disease [4].
If no provoking external stimulus can be considered as a trigger, acute spontaneous urticaria is present.In up to 50% of cases, no trigger can be identified, so that idiopathic urticaria is assumed.
If the symptoms occur as a result of a determinable stimulus, acute inducible urticaria is present.The stimuli can be manifold (Fig. 1).

Possible triggers of acute spontaneous urticaria
In the study by Melikoglu et al. on 284 patients, at least one triggering factor could be identified in 78%, and in 18% several triggering factors were present.Drugs played a role in 55%, and infection in 19%.A combination of infection and drug intake was found in 18%.Acute urticaria occurred rather rarely after food ingestion (3%).Combined food and drug ingestion was found in only one patient.An elevation of C-reactive protein (CRP) was detected in 63% and an elevated antistreptolysin titer in 14% of the patients.The authors concluded that acute spontaneous urticaria or acute angioedema may occur as a result of several triggering factors, some of which act simultaneously [1].

Infections
It is not uncommon for urticaria symptoms to be associated with acute infections (viral, bacterial, parasitic).Viral upper respiratory tract infections are re-ported to be an underlying focus in acute urticaria in 40% of adults and 60% of children [5].In patients with COVID-19, urticaria was one of the most common skin manifestations and preceded classic COVID-19 symptoms in 50% of cases [6,7].
Gastrointestinal infections and urinary tract infections are also associated with acute spontaneous urticaria.In a prospective study of 54 children, infections were the most common cause of acute spontaneous urticaria (49%), followed by medications (5%) and food allergies (3%) [8].
In childhood, herpesviruses (cytomegalovirus, Epstein-Barr virus, herpesvirus type 6) play a major role in acute spontaneous urticaria [9].Other viruses (adenovirus, rotavirus, respiratory syncitial virus, parvo virus B19) and bacteria (Mycoplasma pneumoniae and Streptococcus spp.but less so Chlamydia) have also been described as trigger factors [5].Otitis media, urinary tract infections, and skin infections were shown to be other childhood triggers in a study among pediatric patients in a Thai emergency department.Medications played only a minor role in this cohort (approximately 4%).In 34%, the causative infection could not be detected [10].If eosinophilia is present, parasites should also be considered.
The incidence of infectious causes of acute urticaria is reported to decrease with age.

Medication, food and other triggers
With regard to medications, antibiotics and nonsteroidal anti-inflammatory drugs trigger acute urticaria 304 Acute urticaria-what to do?K review in children, while "nonsteroidal anti-inflammatory drugs" (NSAID), ACE inhibitors, and neuromuscular blockers have been described more frequently in adults [11].Acute urticaria after food ingestion must be distinguished from true IgE-mediated allergy, which typically occurs after consumption of cow's milk, hen's eggs, peanuts, tree nuts, wheat flour, and seafood [8,[12][13][14].Acute contact urticaria (stages 1-3 according to von Krogh and Maibach), for example to latex, tomatoes, potatoes, wheat flour, animal proteins (saliva, meat, etc.) must be distinguished from this.After vaccines, acute urticaria may be due to an IgE-mediated or non-IgE-mediated reaction [13].

Pathogenesis
Mast cells play a crucial pathogenetic role in acute urticaria.Activation of mast cells with subsequent mediator release (e.g., histamine, leukotrienes, plateletactivating factor) can occur via various surface receptors.
Overall, IgE-mediated reactions appear to play a minor role in triggering acute spontaneous urticaria [15].In the case of acute IgE-mediated urticaria in the setting of anaphylaxis, determination of tryptase within 1-4 h after reaction and compared to baseline tryptase (in the course after more than 48 h) may be helpful [5].
The exact pathogenesis of the triggering of acute spontaneous urticaria by infections is not known.Recently, an analysis was performed in 18 patients with regard to the cytokine spectrum before and after therapy.Thus, in infection-associated urticaria, serum levels of CRP, D-dimers, interleukin 6 (IL-6), and chemokine ligand 8 (CCL8) were found to be elevated and decreased after steroid administration.CCL8 and IL-6 correlated with serum neutrophil granulocyte count [6].A retrospective study of 106 children hospitalized for severe acute urticaria, without adequate response to antihistamines, also showed elevated D-dimers in 51% of patients [16].
Here, attention must be paid to possible accompanying symptoms and, if necessary, specific diagnostics, for example, a skin biopsy, must also be performed.

Diagnostics
Acute spontaneous urticaria, since it is self-limiting, usually does not require any special diagnostic workup besides a history for possible trigger factors.However, a targeted history is important and can lead to useful diagnostic measures.
The history should include the following questions: Signs and symptoms: itching, wheals, angioedema including localization, Duration of the individual skin changes in loco, Time of occurrence, Possible accompanying symptoms/signs: fever, fatigue, joint problems, shortness of breath, circulatory problems, gastrointestinal problems, Accompanying circumstances/illnesses: pregnancy, infection, psychosocial stress, Food intake including timing and quantity, Insect bite including time and location, and Medication intake including time, dose, method of administration and reason for medication.
An allergic cause can be suspected if the patient has been in contact with potential allergens shortly before the onset of symptoms (30-120 min for oral intake, much faster for intravenous administration).
In such cases, allergological diagnostics such as prick testing or intradermal testing (especially for drugs available in sterile solution) should be performed.In addition, allergy testing should include determination of specific IgE, in vitro tests (e.g., cellular antigen stimulation test [CAST], basophil activation test [BAT]), and/or exposure testing, if possible and appropriate.

Therapy
Initial treatment of acute spontaneous urticaria is aimed at symptom control, improvement of itching and reduction of the number and size of wheals.Antihistamines are typically used, and glucocorticosteroids may be administered for a few days [22].
There is no generally valid recommendation as to the period over which H1 antihistamines should be given in acute spontaneous urticaria.As a rule, treatment over several days is recommended until  symptoms resolve safely.Some patients will require a higher than standard dose even in acute spontaneous urticaria [22].
If antihistamines, also as up to fourfold updosing ("off-label use"), are not sufficient, systemic glucocorticosteroids can be used in the short term.Usually, these will not be needed for more than 10 days.The dose should not exceed 1 mg prednisolone equivalent per kilogram of body weight per day.H1 antihistamine therapy should be continued in parallel.If symptoms do not recur after discontinuation of glucocorticosteroids, antihistamines can also be discontinued after a few days [3].
In refractory situations, intravenous administration of glucocorticosteroids may be necessary or older H1 antihistamines available for parenteral administration, such as diphenhydramine, may be used (Fig. 2).It must be remembered that these first-generation antihistamines can cross the blood-brain barrier and are thus centrally active.Due to the sedative effect, a reduction in vigilance and impaired driving ability may occur, which requires special education of the patient.Anticholinergic effects with dry mouth, constipation, micturition difficulties, and potential provocation of narrow-angle glaucoma may also occur.
In summary, nonsedating, second-generation oral antihistamines are recommended for mild symptoms and several days of therapy.Simultaneous administration of different antihistamines is not recommended.H2 blockers or leukotriene receptor antagonists also play no role in the therapy of acute urticaria [3].

Special features during pregnancy
Acute spontaneous urticaria is thought to have similar overall patterns and causes in pregnancy as in nonpregnant patients [23][24][25].
For both acute and chronic urticaria, higher incidences have been described in women than in men, so the influence of sex hormones in urticaria has been repeatedly discussed [24,26,27].
Numerous hormonal changes occur during pregnancy, including increased secretion of estrogens and progesterone, with both hormones also having immunomodulatory effects [23].In animal models, it has also been shown that estrogens can increase histamine release, so a possible pathogenetic effect on chronic urticaria has been suggested [28,29].Data regarding the influence of sex hormones on acute urticaria, for example in terms of increased susceptibility, do not exist, but two clinical pictures have been described that may be associated with hormone-associated urticarial changes and should also be considered differentially in patients who are pregnant.On the one hand, patients with autoimmune progesterone dermatitis may react to cycle-dependent endogenously increased progesterone as well as to exogenously applied progesterone [30].In a study with 89 affected individuals, 14.61% had a first manifestation of this condition during pregnancy [31].However, it may also be pre-existing and exacerbate during pregnancy [32].
Furthermore, a similar clinical picture with urticarial changes as a hypersensitivity reaction to endogenous estrogen has been described with estrogen dermatitis, which can be aggravated by pregnancy [33].
Although acute spontaneous urticaria is not a typical disease in pregnancy, urticarial changes can occur in different pregnancy dermatoses, for example in the urticarial stage of pemphigoid gestationis or PUPPP (pruritic urticarial papules and plaques of pregnancy).Erythema exsudativum multiforme may also have urticarial aspects, and lastly, the differential diagnosis should also consider the initial manifestation of anaphylaxis in the presence of wheals and/or angioedema [20,25].
Although no incidence data exist on anaphylaxis events in pregnancy, a thorough history and investigation of possible involved organ systems is essential when acute urticaria occurs, as anaphylaxis can lead to severe damage to both mother and fetus and, in the latter, may cause hypoxic-ischemic encephalopathy via a negative effect on fetal oxygenation, among other effects [34].
Overall, however, the symptomatology of nonanaphylactic acute urticaria is not associated with a negative impact on maternal fertility, teratogenicity, fetal development, or overall perinatal outcome [25,27].
For the treatment of symptomatology in pregnancy and lactation, loratadine and cetirizine, although not approved, are treatment options that are considered safe and have shown no associations with congenital malformations in studies [19,27].First-generation an-306 Acute urticaria-what to do?K review tihistamines are not recommended during breastfeeding because of their secretion into milk [35].

Special features in childhood
The prevalence of acute spontaneous urticaria in childhood has been reported in prospective studies to be 13.9-16.2%[36,37].In both adults and children, acute spontaneous urticaria is a frequent reason for presentation to the emergency department [33].
In the pediatric study population, the simultaneous presence of angioedema has been described in 10-50% [38,39].Compared with adults, AU in childhood usually shows no gender-specific clustering and in some studies even a slight male predominance [40,41].In an older paper, in children between 1 and 36 months of age hospitalized for acute urticaria, it was found that 20-30% of children may have recurrent urticarial episodes that may progress to chronic urticaria [42].
Numerous studies place infections as the leading trigger for acute spontaneous urticaria in childhood [5,8,43].Clinically, an association of underlying infections in children with acute urticaria can also be observed.Thus, it was observed that 30-50% of children with acute urticaria showed fever, 40-60% respiratory symptoms, and 12-17% gastrointestinal symptoms [40,44].
Interestingly, a seasonal clustering of acute spontaneous urticaria and colds was observed in one study, suggesting a possible association between the two conditions as well [45].
With regard to a drug-induced cause of acute urticaria in childhood, some studies describe the interpretation of a causal relationship as uncertain.Although more frequent antibiotic use has been observed in children with acute urticaria than in control patients without urticarial symptoms, many prescribed medications are taken because of an underlying infection, and subsequent allergy testing is often negative [8,40,44,46,47].Similarly, food is a suspected cause; for example, in a retrospective study of 250 children, food allergy was suspected in 12% but confirmed in only 2.4% (of 250) [39].Finally, the age group should be taken into account when acute urticaria occurs, since the prevalence of infectious causes is highest in infants and preschool children, but decreases with age, whereas the prevalence of medications (26.8%) and food (36.6%) increases significantly in adolescents [41].

Conclusion
In childhood as in adulthood, viral infections are very frequently associated with acute spontaneous urticaria, whereas drugs and food are less frequently described as triggers.It is not uncommon for multiple triggers to be present simultaneously.Especially in pregnancy and childhood, important differential diagnoses associated with urticarial skin changes must be delineated.Therapeutically, oral, nonsedating H1 antihistamines are primarily used.In some patients, short-term administration of glucocorticosteroids is also necessary.Further diagnostic testing is usually not indicated.If a drug or IgE-mediated food allergy can be identified as the trigger, an allergy passport should be issued after appropriate allergic diagnosis.The affected person should also be shown strategies for avoiding the triggers.If the triggers are difficult to avoid, the prescription of emergency medication may be considered.

Fig. 1
Fig. 1 Possible classification of acute urticaria with differentiation of the spontaneous from the inducible form.ASS Acetylic salicylic acid duration of treatment depends on signs and symptoms (days to weeks)

Fig. 2
Fig. 2 Therapeutic approach to acute spontaneous urticaria.BW body weight