Anaphylaxis is a severe and potentially life-threatening reaction that usually occurs within seconds or minutes of exposure to an allergen. Several distinguishing characteristics can aid in the differentiation between anaphylaxis and urticaria. Anaphylaxis typically manifests with a sudden onset, occurring within minutes to hours after exposure to an allergen, whereas urticaria tends to develop more gradually and can persist for longer. Anaphylaxis often co-exists with urticaria, but is characterized by the presence of additional systemic symptoms. These symptoms can affect various organ systems, including the gastrointestinal, respiratory, cardiovascular, and neurological systems. Urticaria typically resolves within a few hours to several days, whereas anaphylaxis can have a shorter duration but may persist for longer if not promptly treated (5).

Anaphylaxis affects multiple systems in the body and can progress rapidly if left untreated. The signs and symptoms of anaphylaxis can vary, but mostly (>80%) include skin reactions, such as urticaria, angioedema, pruritis, flushing, or pallor. Gastrointestinal symptoms include nausea, vomiting, abdominal pain, or diarrhea. Morbidity and mortality are high if there is respiratory or cardiovascular system involvement (6). Respiratory symptoms include dyspnea, wheezing, stridor, cough, and chest or throat tightness. Cardiovascular symptoms are characterized by tachycardia, hypotension, light-headedness, dizziness, or fainting (7). A feeling of impending doom or anxiety may also accompany these symptoms. In childhood, anaphylaxis is most commonly triggered by food allergens such as cows'milk, hens’ eggs, peanuts, tree nuts, sesame, and shellfish, followed by medications (e.g., penicillin, NSAID), and insect stings (e.g., honey bees, wasps), or latex. Prompt treatment is critical for the prevention of mortality, and the primary treatment involves the administration of intramuscular epinephrine (adrenaline) (6, 7).

Exercise-induced anaphylaxis is characterized by the development of anaphylaxis, including hives, dyspnea, hypotension, and systemic reactions, triggered explicitly by physical activity or exercise. Many patients notice a tingling, itching, or burning sensation on the skin 10–25 min after exercise before hives appear. The macules may coalesce to form large areas of erythema (8). It is considered a rare but potentially severe condition. The exact cause of exercise-induced anaphylaxis is not fully understood but is believed to involve a combination of factors, including physical exertion, specific foods or medications consumed before exercise, and sometimes other environmental factors (9).

In exercise-induced anaphylaxis, the appearance of urticaria usually coincides with or shortly follows the onset of physical activity. Urticarial lesions are often widespread, affecting various areas of the body. They can occur on the skin surface exposed to friction during exercise, such as the thighs, trunk, arms, and neck. Urticaria in exercise-induced anaphylaxis is accompanied by intense itching, which may be a notable symptom during physical activity. The individual hives are typically larger in size (often >1 cm in diameter) and may coalesce to form larger areas of swollen and red skin. The hives may persist for variable durations, ranging from minutes to hours after the exercise has ceased (10).

It is important to consider the sudden onset of other systemic symptoms, such as respiratory distress, gastrointestinal symptoms, and cardiovascular changes, as these can help differentiate this condition from isolated urticaria.

In some cases, exercise alone can trigger anaphylaxis, whereas in others, the combination of exercise and specific triggers, such as certain foods or medications, is necessary. Food-dependent exercise-induced anaphylaxis (FDEIA) is an exercise-related allergy after food intake. The most commonly reported triggering foods are wheat, celery, grapes, nuts, peaches, eggs, rice, tomatoes, seafood, and cheese (11). Cholinergic urticaria (CholU), FDEIA, and heat urticaria can be differentiated according to whether this condition develops secondary to exercise and/or heat stimulation (12). CholU is another entity characterized by small 1–3 mm punctate papules, usually surrounded by an erythematous halo (Figure 2). It typically starts on the upper chest and neck but can spread over the whole body. A single lesion typically resolves within 15 to 20 min. Exercise, emotional stress, and a sudden increase in body temperature are frequent etiologies (13). There appears to be an increase in plasma histamine levels in patients with symptoms. As the exposure to triggering factor continues, hives may coalesce and resemble angioedema, but vascular collapse is rare (13).

Urticaria is the most prevalent form of pediatric urticaria, affecting up to 25% of the pediatric population (14). It can manifest either sporadically, with individual episodes lasting from a few hours to several days, or it may recur in response to various triggers. While it can affect children of all ages, it is more frequently observed in younger children. Interestingly, there is no significant gender predominance, as it affects both boys and girls equally. Approximately 40% of cases of acute urticaria may present with concomitant angioedema (15) (Figure 3). Infections, such as viral and bacterial infections, are the most common triggers (48%) for acute urticaria (4, 15). For example, urticaria accounts for approximately 10%–20% of cutaneous manifestations in pediatric patients with COVID-19 (16, 17). Although infectious causes primarily trigger acute urticaria, it is not uncommon to blame antibiotics used in treating infection for its etiology (15).

A study evaluating urticaria ICD codes suggested that the most common causes of urticaria after infection are drugs, foods, insect bites, pollen, blood products, and vaccination (18). The rates of urticaria cases attributed to food and drug hypersensitivity are 2.7% and 5.4%, respectively, among all cases of acute urticaria (15).

(Table 2).

Contact urticaria and urticarial contact dermatitis are two distinct skin conditions, which although sharing some similarities, exhibit differences in their characteristics.

Contact urticaria typically manifests as the development of hives and itching at the point of contact with an allergenic or irritating substance. These symptoms arise swiftly, often within minutes of exposure to the triggering agent. Common culprits encompass foods, latex, specific chemicals, plants, and insect bites. The manifestations of contact urticaria typically subside within a few hours once the triggering substance is removed (47).

Urticarial Contact Dermatitis also presents with hives and itching at the site of contact with an allergen or irritant. The visual appearance of the rash resembles that of contact urticaria. However, in urticarial contact dermatitis, the rash emerges relatively rapidly, akin to contact urticaria, but can also occur several hours to a day following exposure. Urticarial contact dermatitis stems from allergic or irritant reactions upon skin contact with particular substances, including certain chemicals, plants (such as poison ivy or poison oak), or metals (e.g., nickel) (48, 49). Unlike contact urticaria, urticarial contact dermatitis can persist for days or even weeks, especially with continued exposure to the triggering agent.

In children, the most frequent causes of contact urticaria are foods, which are particularly prevalent in children with atopic dermatitis. Food-associated contact urticaria typically results from immunological reactions (50). Nevertheless, instances of non-immunological contact urticaria related to foods do exist, often linked to items such as tomatoes, ripe cheese, pineapple, red wine, contaminated tuna, and yeast (51). Furthermore, additives and preservatives, such as benzoic acid, sorbic acid, cinnamic acid, and cinamic aldehyde, incorporated into foods, can also induce contact urticaria through the same mechanisms.

Mast Cell Activation Syndrome (MCAS) is a condition characterized by the abnormal activation and release of mast cell mediators throughout the body. It is considered a subset of mastocytosis, but unlike mastocytosis, MCAS does not involve a significant increase in mast cell numbers (52). The symptoms of MCAS can vary widely and affect multiple organ systems. Common symptoms include skin and gastrointestinal manifestations. Skin symptoms include flushing, itching, urticaria, angioedema, and dermatographism. Gastrointestinal symptoms are abdominal colic, bloating, diarrhea, nausea, and vomiting. Respiratory symptoms (wheezing, dyspnea, nasal congestion, and throat tightness) and cardiovascular symptoms (tachycardia, dysrhythmia, hypotension, and fainting) may accompany them. Patients may experience idiopathic and allergic anaphylactic shock. Abnormalities in laboratory tests are common and varied. Biomarkers such as urinary histamine metabolites, tryptase, urinary PGD2 metabolites, and urinary leukotriene 4 metabolites can be used to diagnose the disease (53).

Unlike urticaria, MCAS has a wide range of systemic symptoms that go beyond just skin manifestations. In addition, the diagnosis of MCAS includes evaluation of the levels of mast cell mediators such as tryptase during both asymptomatic and symptomatic episodes (54).

Serum sickness-like reaction, also known as drug-induced SSLR, is a type III hypersensitivity reaction that can occur in response to certain medications. It resembles serum sickness, but the term “serum sickness-like” is used because it typically occurs without the exposure of serum or its components (55). In SSLR, the immune response leads to the formation of immune complexes, which deposit in various tissues. These immune complexes trigger an inflammatory response, causing skin rash, fever, fatigue/malaise, lymph node enlargement, and gastrointestinal symptoms (56).

Serum sickness-like reaction can occur in a broad age range from infancy to adolescence. In the study of Magana et al. (55), which included 83 patients aged 11 months to 12 years, the mean time between exposure to the drug and the development of symptoms was recorded as 8 days in 80% of the patients with amoxicillin. Urticaria and similar rashes were present in 35% and erythema multiforme in 38.5% of the cases. Furthermore, hand and foot arthritis was present in 60% of the study cohort (55). Itching, lip/eye swelling, and fever have been reported in approximately 30%–45% of patients. Erythematous, annular, edematous, urticaria-like plaques evolving to ecchymotic patches may occur together or separately. Echymotic-colored erythematous urticarial plaques of variable size often appear one to three weeks after drug exposure with swelling of the hands and feet (Figure 6). It is frequently seen on the face, trunk, and extremities and has no mucosal involvement (57). It may be accompanied by fever, weakness, irritability, and difficulty in walking. Most patients recover without complications. Systemic corticosteroids and antihistamines facilitate recovery (57).

Kawasaki disease primarily affects children under the age of five and is characterized by the involvement of medium-sized blood vessels, including the coronary arteries (58, 59). The exact cause of Kawasaki disease is unknown, but it is believed to involve an abnormal immune response, possibly triggered by an infection. The characteristic symptoms of Kawasaki disease include prolonged fever (lasting for at least five days), and rash (on the trunk, extremities, or genital area), which is often described as erythematous and may be accompanied by peeling of the skin, particularly on the hands and feet, red eyes, strawberry tongue, enlarged lymph nodes (particularly in the neck area) and edema on the hands and feet (59). Skin lesions include a diffuse, tender, erythematous plaque and eruptions with morbilliform, urticarial, and scarlatiniform morphologies that take several days to settle (60). Prompt diagnosis of Kawasaki disease is crucial as it can lead to complications such as coronary artery aneurysms or myocarditis. Treatment involves high-dose intravenous immunoglobulin (IVIG) and aspirin to reduce the risk of complications (61).

Papular urticaria results from a chronic, recurrent hypersensitivity reaction that often develops late after insect bites (62, 63). The lesions may look like urticaria, but urticaria lesions last shorter than 24 h and the lesions disappear without leaving a mark. Erythematous itchy papules, isolated or combined, sometimes with vesicles overlying, are apparent on mainly exposed areas such as the face and extremities (63) (Figure 7). Vesicle or itching at the bite site or a crust may be noticed at the site of the ruptured vesicle. The lesion reaches its maximum size in 2–3 days but may persist for longer and will heal spontaneously (64). No further laboratory examinations are required.

Urticaria multiforme, previously referred to as “acute annular urticaria” (65, 66), describes a cutaneous reaction that often follows a viral infection and shares morphological characteristics with acute urticaria. However, unlike typical urticaria, urticaria multiforme presents as polycyclic to annular urticarial lesions with bruise-like areas, resembling SSLR (55, 57). The central dusky appearance within an annular, erythematous, urticarial plaque may be mistaken for erythema multiforme (Figure 8). Urticaria multiforme is commonly observed in children between the ages of 4 months and 4 years, but can occur at any age. Preceding the development of the rash, symptoms may include a fever lasting 1–3 days, with/without other viral illness-related symptoms such as common cold, otitis media, and gastroenteritis (67).

Diagnostic criteria for urticaria multiforme include: (i) Annular to polycyclic urticarial lesions with transient ecchymotic skin changes, (ii) Individual lesions lasting less than 24 h, (iii) Presence of angioedema or acral edema, (iv) Dermatographism, (v) Increased levels of acute phase reactants, (vi) Favorable response to antihistamines (63). Unlike erythema multiforme, urticaria multiforme lacks true target lesions, skin necrosis, mucous membrane involvement, or blistering (63). Although it shares pathogenic similarities with urticaria, urticaria multiforme exhibits distinct morphological features. The occurrence of a hemorrhagic morphology within urticarial lesions in children is commonly observed, although the exact reasons for this remain unknown. In a prospective study on urticaria in children aged 1 to 36 months, the characteristic hemorrhagic pattern now recognized as urticaria multiforme was observed in nearly half of the cases (65, 66).

Juvenile idiopathic arthritis (JIA) is an inflammatory disease that occurs before the age of 16 years, and is characterized by arthritis lasting at least 6 weeks. It is the most common form of arthritis in childhood (68).

Cutaneous involvements are non-fixed erythematous rashes. The rash associated with systemic-onset JIA typically appears early in the course of the disease, often before arthritis develops. It is usually one of the first noticeable signs, together with systemic symptoms such as fever, fatigue, and other general malaise. The rash in systemic-onset JIA is characterized by salmon-pink or light red spots, and it is often described as “evanescent” because the rash comes and goes, changing its location and appearance. The rash can be transient, with individual spots lasting for a few hours to a few days and then disappearing. New spots may appear while others fade away, leading to a migratory pattern (69).

Studies have shown that IL-6 plays a role in the pathogenesis of the disease, and therefore, tociluzumab, an anti-IL-6 receptor antibody, is beneficial in the treatment of the disease (70).

Mastocytosis is a rare disorder characterized by the abnormal accumulation and activation of mast cells in various tissues throughout the body (71, 72). Cutaneous mastocytosis, which primarily affects the skin, is more common in children. The most common subtype is known as urticaria pigmentosa, which is characterized by the presence of reddish-brown patches or raised lesions on the skin (Figure 9). When rubbed or irritated, these skin lesions can become itchy and cause hives or flushing (Darrier sign) (73). Most patients have maculopapular lesions. Other common forms of rash are plaque and nodular. Diffuse cutaneous mastocytosis also presents with spontaneous urticaria plaques, not only on the itchy area but also on normal-appearing skin, due to spontaneous or triggered mast cell degranulation. High tryptase levels are measured in mastocytosis, particularly in the presence of widespread multiple or large lesions (72). It can be asymptomatic or sometimes itchy. The systemic forms are associated with flushing and occasionally with wheezing, abdominal pain, diarrhea, and syncope (74).

Systemic mastocytosis is a form that involves the proliferation of mast cells in various organs and tissues throughout the body, including the bone marrow, gastrointestinal tract, liver, spleen, and lymph nodes. Symptoms can vary widely and may include flushing, itching, abdominal pain, diarrhea, low blood pressure, and symptoms associated with allergic reactions (74).

The diagnosis of mastocytosis involves a combination of clinical evaluation, physical examination, skin biopsies, and laboratory tests. Specialized testing, such as bone marrow biopsy and genetic analysis, may be required to assess the extent and subtype of the condition (75).

Urticarial vasculitis is a rare condition that combines both urticaria and vasculitis. It is characterized by recurrent episodes of urticaria lasting longer than 24 h which leave behind purpura, a bruise-like discoloration (76, 77). The condition primarily affects the skin, but in some cases, it can involve internal organs and may be a sign of autoimmune disease such as systemic lupus erythetamatosis. The hives in urticarial vasculitis tend to be more persistent, often last for several days or weeks, and can be painful or uncomfortable. They may also be resistant to usual treatments, ie antihistamines, for acute urticaria (78). The hives in urticarial vasculitis may be associated with redness, swelling, and itching. As the hives resolve, there can be remaining purplish or brownish discoloration or induration that can persist for days or weeks (79). Diagnosing urticarial vasculitis involves a combination of clinical evaluation, physical examination, skin biopsies, and laboratory tests such as C3, C4, and C1q complements. Skin biopsy can reveal signs of vasculitis and confirm the diagnosis (80, 81).

Autoinflammatory urticarial syndromes, also known as “autoinflammatory diseases with urticarial rash”, constitute a group of rare genetic disorders characterized by recurrent episodes of urticarial rashes accompanied by systemic inflammation. These syndromes are classified within the broader category of autoinflammatory diseases, distinct from autoimmune diseases due to dysregulated innate immune responses instead of abnormal adaptive immune responses.

The hallmark of these syndromes is urticarial rashes presenting as red, itchy, raised patches on the skin with transient presence from hours to days. Lesions usually last up to 24 h and appear as flat erythematous swellings, mostly distributed on the trunk and/or extremities and which do not respond to H1- antihistamines. Often the lesions may be painful and may not be accompanied by itching.

Patients with autoinflammatory urticarial syndromes experience not only skin involvement but also episodes of systemic inflammation. This inflammation can affect various organs and tissues, leading to symptoms such as fever, joint pain, swelling, and occasionally, organ-specific manifestations such as abdominal or chest pain (82).

The primary cause of Autoinflammatory Urticarial Syndromes lies in genetic mutations impacting innate immune system proteins that regulate inflammation and immune responses. The genetic basis varies depending on the specific syndrome, with several genes implicated in different cases (83).

While certain triggers, such as infections, stress, or environmental factors, may exacerbate or provoke rash and inflammation episodes in some cases, they are not universally necessary for symptom development.

The age of onset and duration of symptoms can vary depending on the specific syndrome, with some presenting early in infancy or childhood, while others develop later in life (83).

Autoinflammatory urticarial syndromes encompass different diseases, each with a distinct genetic basis, clinical features, and management considerations.

Wells syndrome, also known as eosinophilic cellulitis, eosinophilic dermatitis, or hyper-eosinophilic syndrome, is a rare skin disorder characterized by recurrent episodes of skin inflammation with prominent eosinophilic infiltration (107). The episodes can last for several days to weeks and may recur over months or years. There may be symptom-free intervals between the episodes. Skin lesions are typically red, swollen, and itchy (108). The disease may present with rashes varying from permanent maculopapular rashes to long-lasting lesions in the form of plaque. Skin involvement is present in 50% of patients with HES, and the lesions are accompanied by itching. There are cases of erythematous papules, nodules, urticaria-like lesions, and even angioedema (107). The lesions can vary in size and shape and may tend to migrate or spread. Biopsy of the skin lesions shows a characteristic feature of eosinophil-rich inflammation. Some individuals with Wells syndrome may experience systemic symptoms such as fever, malaise, and eosinophilia (108).

After excluding causes of hypereosinophilia, further investigations should be performed regarding organ involvement, and genetic analysis can clarify the diagnosis (108).

Bullous pemphigoid is a chronic autoimmune blistering disorder that primarily affects the elderly, but it has been reported in a wide range of age groups. It generally starts with a non-specific itchy rash and may develop an urticarial appearance over time (109) (Figure 11). Lesions persist for days and may progress to bullae. They can be itchy or painful and may also occur on mucosal surfaces. Bullous pemphigoid is typically a chronic condition with periods of remission and flare-ups. The disease can persist for months to years.

Frey syndrome, also known as auriculotemporal syndrome, is a condition characterized by abnormal flushing of the skin on the face, typically triggered by eating certain foods (110). Frey syndrome is commonly seen during infancy or after surgical procedures/trauma involving the parotid gland. It occurs due to nerve damage or misdirection of nerve fibres, leading to abnormal connections between the auriculotemporal nerves (111). The syndrome manifests as the emergence of erythema (mimicking urticaria) and generally on the forehead region within the first few minutes of suckling/eating. During infancy, it can recur in feeding periods and is thought to be due to perinatal trauma of the auriculotemporal nerve. These patients may be misdiagnosed with food allergies, leading to unnecessary diagnostic tests and food eliminations (111).