Aetiology
Urticaria/angio-oedema involves the release of mediators, predominantly by mast cells, but also by basophils, in the epidermis (urticaria) and deeper dermis (angio-oedema). Although multiple mediators are released, the majority are histamine-like and result in swelling, vasodilation and pruritus.
The exact mechanism by which various factors cause mast cell degranulation is not completely understood (with the exception of IgE-mediated allergen activation). While multiple diseases can cause acute and chronic urticaria/angio-oedema, most cases of chronic urticaria are idiopathic and likely caused by an autoimmune phenomena. People with acute urticaria/angio-oedema more frequently have associated identifiable causes.
Acute urticaria/angio-oedema
May be attributable to allergy, direct mast cell activation, infection, systemic disease, physical causes, or other aetiologies.
Allergy
Many allergic reactions resulting in urticaria/angio-oedema are the result of IgE-mediated type 1 hypersensitivity.
Foods and food additives: children with food and food additive allergies associated with urticaria are usually allergic to milk, egg, soy, wheat, peanuts, and tree nuts, while adults react to shellfish, fish, tree nuts, and peanuts. However, almost every food has been implicated.
Medications: antibiotics, such as penicillin, are the drugs most likely to cause mast cell mediator release via an IgE-mediated mechanism. However, there are case reports of many other medications being associated with type 1 mediated urticaria/angio-oedema, such as anaesthetics, muscle relaxants, and anti-epileptic agents.
Stinging insects: these include members of the Hymenoptera family (including bees, wasps, hornets, fire ants), and bed bugs.
Latex: particularly among patients who are chronically exposed, such as those with spina bifida.[8]
Direct mast cell activation
Various agents are capable of causing mast cell and basophil mediator release in a direct and non-immunological fashion.
Foods and food additives: young children often have urticarial reactions to fruits and vegetables, such as strawberries and tomatoes. These foods may also cause reactions via an IgE-mediated mechanism in some patients.
Medications: agents typically capable of direct mast cell degranulation include vancomycin, opiates and opioid derivatives, such as morphine, fentanyl, codeine, and dextromethorphan.[9] Non-steroidal anti-inflammatory medications (NSAIDS) inhibit COX-1, resulting in overproduction of leukotrienes, which may cause urticaria in susceptible patients (pseudoallergic reactions).
Radiocontrast media: older preparations with high osmotic loads are more likely to result in mast cell mediator release.
Infection
Viral and bacterial infections are believed to be responsible for urticaria/angio-oedema in the majority of children with acute urticaria.
Viral: viruses causing upper respiratory tract infections and acute gastroenteritis in younger children (e.g., respiratory syncytial virus [RSV], rhinovirus, rotavirus) have often been associated with urticaria/angio-oedema. Urticaria may precede active disease caused by chronic and indolent viral entities, such as hepatitis, cytomegalovirus (CMV), and Epstein-Barr virus (EBV).
Bacterial: agents that cause respiratory infections and gastroenteritis, such as streptococcal agents and Helicobacter pylori, have been implicated. Many other bacteria have been associated with urticaria in case reports.
Parasitic: various parasites have been associated with urticaria/angio-oedema, including Strongyloides, Toxocara and Fasciola. Usually, these patients have a history of travel to endemic areas.
Systemic disease
In rarer instances urticaria/angio-oedema precedes development of systemic diseases.
Autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjogren’s syndrome have been associated with urticaria/angio-oedema. Although not well understood, mechanisms may include complement-mediated pathways and direct mast cell activation. Patients with vasculitis, either as a primary immune disease (e.g., idiopathic urticarial vasculitis) or as a component of other autoimmune diseases (e.g., Sjogren’s syndrome), may present with urticaria as a separate disease or a mixed picture, as in urticarial vasculitis (skin disease with elements of urticaria and vasculitis).
Malignancies: various malignancies have been associated with pathogenesis of urticaria/angio-oedema, particularly those with dysregulated expression of antibodies, such as paraproteinaemias. Others include lymphoreticular diseases, such as chronic lymphocytic leukaemia. Complement-mediated pathways are likely to be involved, although exact mechanisms are unknown.
Endocrinopathies: autoimmune thyroid disease has been most commonly associated with urticaria/angio-oedema. Thyroid autoimmunity has been associated with acute urticaria and some small studies suggest that treatment of thyroid disease results in resolution of the skin disease.[10]
Autoinflammatory syndromes: genetic diseases, usually of childhood, wherein overt inflammasome (a multimeric protein complex) response to perceived danger signals result in persistent expression of inflammatory peptides, such as interleukin-1. Many of these children have cold-induced urticaria in addition to arthralgias, and eye diseases; some have more severe systemic disease, such as amyloidosis, sensorineural deafness, and central nervous system inflammation. This is likely a spectrum of illness, with familial cold-induced urticaria being the least clinically severe, to Muckle-Wells syndrome and neonatal onset multi inflammatory disease (NOMID), the most severe.
Physical causes (physical urticaria):
Various physical factors can cause mast cell and basophil mediator release.
Water (aquagenic)
Increase in core body temperature, such as with exercise or emotion (cholinergic)
Cold, such as from swimming in cold water or cold wind exposure
Heat, such as from a hot bath
Pressure, such as from sitting, lying, tight clothing (delayed pressure)
Pressure to skin or minor trauma (dermatographism)
Exercise (cholinergic or exercise-induced)
Sunlight (solar)
Use of vibrating tools or driving and gripping the steering wheel (vibratory).
Other aetiologies for urticaria:
Serum sickness: immune complex formation in response to exogenous antigens, such as medications and antitoxins, may activate mast cells and basophils. Urticarial rashes may result, along with systemic symptoms of fever, arthritis/arthralgias, and lymphadenopathy. Even though this condition is associated with urticaria, it is generally not classified as a subtype of urticaria, rather a differential diagnosis to consider.
Progesterone-associated urticaria: women on hormone therapy may experience urticaria or exacerbation of underlying urticaria. This may also occur in some patients during menstrual cycles.
Mastocytosis: involves the presence of abnormally high numbers of mast cells, with both cutaneous and systemic manifestations.[11] Clinical features of mastocytosis are primarily due to mast cell mediator release and infiltration into skin, gastrointestinal tract, liver, spleen, lymph nodes, and bone marrow. The resulting signs and symptoms can include flushing, pruritus, abdominal pain, diarrhoea, hypotension, syncope, and musculoskeletal pain.[12] Cutaneous mastocytosis is more frequently seen in children, whereas the majority of adults are diagnosed with systemic mastocytosis.[13] Cutaneous disease manifestations include urticaria pigmentosa, diffuse cutaneous mastocytosis, and mastocytoma. There is persistence of hyper-pigmented areas after initial urticaria has resolved.
Chronic urticaria/angio-oedema
The only criteria for acute urticaria to become chronic urticaria is persistence of skin disease for ≥6 weeks.[14] This means that any acute urticaria/angio-oedema aetiology that persists ≥6 weeks can be an aetiology for chronic urticaria.
Infectious agents: hepatitis, EBV, and CMV may be associated with chronic urticaria. The majority of bacterial and viral infections resolve within 6 weeks, with or without treatment, and are more likely to be associated with acute urticaria/angio-oedema.
Foods: most food allergies occur within minutes to hours of ingestion; therefore, patients know to avoid them. In rare cases, food antigens may be hidden in processed foods (such as soy) and patients may unknowingly continue to ingest them, resulting in chronic urticaria/angio-oedema.
Medications: chronic urticaria/angio-oedema may, in rare cases, be caused unknowingly by continued ingestion of certain medications/supplements, or may occur when there is no alternative treating agent.[9]
Latex: used in many materials; in rare cases, chronic exposure to latex may result in chronic urticaria.[8]
Systemic diseases: may be indolent and subclinical for long periods of time. Chronic urticaria/angio-oedema may be early manifestations of these illnesses.
Physical urticarias: often aetiologies of both acute and chronic urticaria/angio-oedema.
Mastocytosis or mast cell activation syndrome: urticaria associated with mastocytosis or mast cell activation syndrome is often chronic in adults, as the underlying disease is often persistent.[13][15]
Progesterone associated: urticaria may be chronic but symptoms will often wax and wane with hormone fluctuations.
Chronic urticaria in people with good health and in the absence of identifiable triggers
Approximately 80% to 90% of chronic urticaria/angio-oedema in patients with a normal clinical history and physical examination (e.g., absence of signs or symptoms of infections or systemic disease) and no identifiable triggers is idiopathic. This is termed chronic spontaneous urticaria, formerly known as chronic idiopathic urticaria.[1][16] Of these patients, up to half may have an anti-IgE receptor antibody resulting in chronic release of mast cell mediators.[4][17][18][19] This may be associated with a family or personal history of autoimmunity (e.g., autoimmune thyroiditis, vitiligo, pernicious anaemia, rheumatoid arthritis, insulin-dependent diabetes, alopecia areata), but can also occur in its absence.[20] Whether these patients are at higher risk of developing autoimmune disease or malignant transformation is yet to be determined, but seems unlikely.
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