Urticaria generally represents a type 1 hypersensitivity reaction that can be triggered by a wide variety of factors, both immunologic and nonimmunologic. Acute and chronic forms exist, with the chronic form lasting more than 6 weeks. The great majority of urticaria cases resolve within a few weeks. This disease process can occur anytime from infancy to adulthood. Overall, it is estimated to occur in about 20% of people in their lifetime.¹

This type 1 hypersensitivity reaction can be caused by immunologic triggers or nonimmunologic factors that lead to mast cell release. Acute urticaria resolves within 6 weeks. In young children, common causes are infections such as a viral illness, medications such as anticonvulsants and antibiotics, and foods. Chronic urticaria recurs for more than 6 weeks and is less common in children than in adults; idiopathic and autoimmune causes are most common.² Children with chronic urticaria may have a higher rate of autoimmune thyroid disease.³ Chronic urticaria can also be caused by foods, medications, and parasitic infections.⁴,⁵ Cold urticaria is a type of physical urticarial that is induced by cold exposure; in children, one-third of patients can have anaphylactic reactions.⁶ Cholinergic urticaria results from activities such as exercise and hot water that raise core body temperature.²

Lesions are erythematous, edematous wheals frequently with central clearing that are very pruritic. They range in size from pinpoint papules to large plaques (Figure 6-1).
They are characteristically transient, with each individual lesion resolving within 24 hours. Lesions resolve without dyspigmentation or scarring. Dermatographism is common (Figure 6-2).

Urticaria multiforme, also called “acute annular urticarial,” occurs in pediatric patients and presents with characteristic annular, serpiginous, and polycyclic urticarial plaques and is often associated with acral or facial edema (Figure 6-3).

Lesions can be centrally dusky and can resemble ecchymosis. This condition is more common in children ranging from ages 2 months to 4 years.⁷ Children may have fever but are overall well appearing; they can have symptoms of concurrent illness such as upper respiratory infection, otitis media, or other viral symptoms.⁷ This rash is self-limited and generally resolves in 1 to 2 weeks. Clinical findings can often be confused for erythema multiforme and serum sickness-like reactions (SSLR).⁷,⁸ Papular urticaria is typically seen in children, but can also be present in adolescents and young adults. It is characterized clinically by pruritic, edematous, and erythematous papules and wheals of variable size (3-10 mm). The lesions are located on the extremities and face, with sparing of the axillae and groin. The lesions can last for days to weeks, and leave residual hyperpigmentation at the affected sites. Recurrence following exposure to the causative agent is very frequent, although hyposensitization to the antigen can occur upon multiple reexposures.⁹

Urticaria is one of the conditions where the clinical finding can be quite drastic, but the histologic aspects are very underwhelming (Figure 6-4). Urticaria is one of the conditions that enter the pathologic diagnosis of “normal skin.” Early lesions of urticaria show intravascular clusters of neutrophils within the lumen, without much inflammation extravasated outside the vessels. Later on, there is a superficial and deep, or superficial to mid dermal, perivascular and interstitial mixed inflammatory infiltrate. The inflammatory cells include neutrophils, eosinophils, lymphocytes, and histiocytes. Papillary dermal edema and vascular congestion can
also be present. Chronic or resolving lesions of urticaria can show a slightly increased number of mast cells.¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷

Papular urticaria is not a well-characterized pathologic term, but show features that are similar and indistinguishable from a dermal hypersensitivity reaction to a medication or arthropod bite reaction.⁹,¹⁸ In some cases, there might be a mild degree of spongiosis, but most of the time the epidermis is relatively unremarkable. There is a superficial and deep, perivascular and interstitial dense inflammatory infiltrate, composed of lymphocytes, histiocytes, eosinophils, and neutrophils. In cases where there is an abundance of eosinophils, degranulated cells and occasional “flame figures” can be seen. The inflammation can also extend into the subcutaneous tissue.

It is important when evaluating a biopsy for urticaria to obtain multiple levels of section to search for evidence of leukocytoclastic vasculitis (LCV), hence excluding the diagnosis of urticarial vasculitis. Frequently, early lesions of urticarial vasculitis show a brisk perivascular neutrophilic infiltrate with leukocytoclasis (nuclear dust), but without significant fibrinoid necrosis or endothelial swelling. Other disorders that present with a clinical and histologic urticarial pattern can also be considered in the differential diagnosis of urticaria. Bullous pemphigoid (BP), although more common in adults, has also been described in the pediatric population. The early phases of BP present with an urticarial pattern. One of the main differences between the urticarial BP and urticaria is the aggregation of eosinophils in the papillary dermis, near the dermal-epidermal junction. Additionally, eosinophilic spongiosis can be present, a feature that is not typical of urticaria. Later on, BP shows a subepidermal blister with eosinophils and neutrophils (in the classic form), and sometimes a pauci-inflammatory subepidermal bulla (in the cell poor variant). Invariably, direct immunofluorescence reveals linear deposits of C3 and IgG along the dermal-epidermal junction. Other considerations included
in the differential diagnosis are dermal hypersensitivity reactions (from a medication), telangiectasia macularis eruptive perstans (TMEP), arthropod bite reactions, and gyrate erythemas. Dermal hypersensitivity reactions typically lack the edema of urticaria and the vascular collections of neutrophils. TMEP is uncommonly seen in children and has a blaschkoid distribution. Performing special stains (Giemsa, Leder) or immunohistochemistry for mast cells (CD117, mast cell tryptase) is capital to establishing the diagnosis of this condition. Arthropod bite reactions and popular urticaria show identical findings. Gyrate erythemas can also have dermal edema, but the infiltrate is mostly lymphocytic, and the number of eosinophils is low, if present.

Urticarial vasculitis (UV) is a small-vessel vasculitis that is frequently associated with an underlying condition such as connective tissue disease. It is distinguished into two main groups: normocomplementemic and hypocomplementemic. Systemic disease is more commonly associated with the hypocomplementemic form.¹⁹ This condition is more commonly seen in adults and is rare in children.²⁰

UV is known to be triggered by underlying conditions including autoimmune conditions, infections, medications, and malignancy. In children, it is frequently preceded by an upper respiratory infection.¹⁹,²¹ It can also be an idiopathic condition.

Clinical lesions of UV can be distinguished from urticaria by their persistence past 24 hours and their dusky and purpuric appearance (Figure 6-5).¹⁹ Lesions can be painful in addition to pruritic and can resolve with hyperpigmentation. They tend to be on the trunk and proximal extremities. Angioedema and joint pains can also occur.²¹ Confirmation of diagnosis often requires a biopsy, because it can present very similarly to urticaria. If confirmed, physical exam and labs are indicated to evaluate for underlying trigger. Hypocomplementemia, ANA, and anti-C1q antibodies are associated with a poor prognosis of the disease and with a systemic involvement. Nevertheless, these findings are exceptional in childhood.

The pathologic criteria for the diagnosis of UV are less rigorous than for other LCV, because the infiltrates are sparser, and the vasculitic changes can be focal and subtle. Pathologically, there is a perivascular and interstitial neutrophilic and eosinophilic infiltrate, with either focal small-vessel neutrophilic vasculitis (evidence of fibrinoid necrosis) or focal perivascular leukocytoclasis without fibrin deposition, and with or without extravasated red blood cells (Figure 6-6). Therefore, the minimal histologic criteria for the diagnosis of UV include the presence
of perivascular leukocytoclasis, or fibrin deposits, with or without extravasated red blood cells. In hypocomplementemic UV, diffuse dermal neutrophilic infiltrates can be seen. Dermal eosinophils are more typical of the normocomplementemic forms of UV.²²

True serum sickness (SS) is a type 3 hypersensitivity reaction that was more frequently seen in the past after the administration of horse or rabbit serum. SSLR are more common and can present with similar symptoms, but do not involve immune complex formation. SS is rarely seen in the pediatric population; in recent years, it has been reported in relation to rituximab.²³ SSLR can occur occasionally in children. It is classically seen most often with cefaclor; however, other medications such as antibiotics, antifungals, psychiatric medications, and vaccinations have also been reported.²⁴,²⁵,²⁶,²⁷ Interestingly, children who develop SSLR to cefaclor usually do not have a similar reaction with other cephalosporin medications.²⁸,²⁹

True SS involves deposition of immune complexes that are formed between host antibody and foreign protein, leading to an inflammatory cascade that includes the activation of complement. Deposition of these immune complexes in target tissues such as the vascular endothelial and glomerular basement membrane leads to damage of these areas.³⁰,³¹ SSLR is thought to be caused by an inflammatory response to metabolites of the offending medication.³⁰

Classic symptoms of both diseases include fever, rash, and joint pains. The skin eruption in SS develops about one week after exposure and is generally morbilliform, with or without an urticarial component on the trunk before spreading to the extremities; the rash resolves within 2 weeks (Figure 6-7). A characteristic serpiginous erythema develops on the sides of the hands and feet.³¹,³² Patients can also have systemic manifestations including vasculitis, arthralgias/arthritis, gastrointestinal (GI) symptoms, nephritis causing proteinuria, and lymphadenopathy. SSLR presents with a rash about 1 to 2 weeks after the triggering medication that tends to be more urticarial and polycyclic; centrally, the lesions may have a violaceous discoloration. Joint swelling can occur, especially around the knees. Children can have facial swelling, myalgias, and headache. Nephritis and vasculitis do not happen because there are no immune complexes involved. This disease is generally selflimited and subsides within 2 to 3 weeks of discontinuing the medication.³⁰,³³

Because of the rare circumstances when a biopsy is performed, the pathologic findings are poorly characterized. Skin biopsies of these patients reveal limited lymphocytic and histiocytic perivascular infiltrates with only rare neutrophils. Fibrinoid necrosis is not typically seen, although there have been subsequent reports of true small-vessel vasculitis in SS. Some have documented the presence of abundant neutrophils and eosinophils in this condition.³⁴,³⁵

Arthropod reactions can occur in reaction to various bites, including by mites, ticks spiders, lice mosquitoes, fleas, bees, and bedbugs. This section focuses on two common distinct arthropod reactions in children: scabies and papular urticaria.

Scabies infestation is caused by the Sarcoptes scabiei mite and presents as a very pruritic rash. It is most often transmitted by direct human contact with an infested individual, although it can also be spread by contact with infested clothing and bedding. This infestation occurs in all ages, from infancy to adulthood, with the highest prevalence under age 2.³⁶ Women and children appear to be infested more often, as well as immunocompromised individuals and those with mental or physical handicap.