Hives on the back of a teen-age male.
Hives on the back of a teen-age male.
Hives are common in children and an arbitrary distinction is made between acute urticaria (less than 6 weeks) and chronic urticaria (hives occuring at least twice per week and lasting more than 6 weeks). Most urticaria in children clears completely before 6 weeks. Chronic urticaria, especially urticaria unresponsive to anti-histamine is fortunately less common in children than adults. Children probably have more serum-sickness-like reactions to antibiotics than adults but less chronic autoimmune urticaria.
"Urticaria represent transient localized areas of edema within skin or mucous membrane tissue. Lesions that affect the superficial dermis are called wheals. Wheals are usually oval in shape and pruritic. Initially, wheals have pale centers surrounded by rings of erythema, whereas slightly older lesions are more uniformly pink in color. Individual wheals resolve completely within 24 hours of onset; lesions lasting longer should raise suspicion for the diagnosis of vasculitis presenting as urticarial lesions (ie, urticarial vasculitis). Transient localized edema within deeper areas of skin or mucous membrane tissue are referred to as angioedema and are typically painful, rather than pruritic." Blauvelt, Hwang, Udey 2003
It is my intention to review some of the information in the literature on urticaria although some of the literature is weak especially on physical urticaria, a common form of urticaria in children. Physical urticaria is hiving that occurs in relationship to a physical triggering stimulus.
Table I. Clinical classification of urticaria/angioedema after Gratton, Sabroe, Greaves 2002 and British Guidelines 2001
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It has been suggested that hives in adults can be distinguished based on how long individual hives last. Greaves has suggested that hives from physical urticaria except delayed pressure last less than 1 hour, while hives from contact urticaria last 1-2 hours, hives from "ordinary" urticaria last 1 - 24 hours and hives from urticarial vasculitis can last from 1 - 7 days. Gratton, Sabroe, Greaves 2002 Black suggests that hives that appear bruised and persist for days are due to either delayed pressure urticaria or urticarial vasculitis. Black 2001
Table 2. Aetiologies of urticaria and angio-oedema From British Guidelines 2001Idiopathic - essentially unknown Immunological
Non-immunological
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Serum-Sickness-like reactions were described in case reports with reactions to the antibiotic, Cefaclor shortly after it was marketed. Murray et al, 1980 Lovell, Reid, 1982 Hebert et al 1991 Vial et al. 1992 The reactions usually occur in younger children, late in the course of the antibiotic use and can occur up to three or four weeks after finishing the treatment. As a result the antibiotic may not be recognised as the cause of the reaction. These reactions can be associated with hives, sore joints (about 30% of reactions), purple discoloration especially as the hives fade (about 20%) and dermographism (about 20%). In the initial case reports, when the sore, swollen joints were a prominent feature, the reaction was termed serum-sickness-like (Lovell, Reid) but when the purple discoloration was more prominent the reactions were termed erythema-multiforme-like (Murray). We also found dermographism (also called dermatographism) in a percentage of cases (unpublished). Dermographism can also result from viral illnesses in the absence of antibiotic use. The hives do not stop until the dermographism fades.
Heckbert et al. examined the incidence of serum-sickness-like reactions (sslr) to antibiotics SSLR after antibiotic use 1990 They found that reactions were more common after Cefaclor compared to Amoxicillin but the reactions can occur after many antibiotics or for that matter any medication Reider et al. sslr 2003 . Others have confirmed that the reactions occur more frequently with Cefaclor compared to other antibiotics. Martin, Abbot 1995 Stricker, Tijssen, 1992. Joubert et al. examined the treatment prescribed in the emergency department for these reactions to Cefaclor and found that when the reaction was called erythema multiforme-like, an antihistamine was prescribed but when the reaction had significant joint involvement and was called serum-sickness-like, an antihistamine plus steroid was more likely to be recommended. Joubert et al. 1999
Anti-thyroid autoantibodies:
The first example of autoimmune urticaria was described by Leznoff and his co-workers who found that some cases of chronic urticaria, resistant to antihistamine, were associated with anti-thyroid autoantibodies even when the patient was euthyroid.
Leznoff 1983
Leznoff 1989
Levy 2003
Kikuchi Y,2003, full article
Anti-receptor autoantibodies:
Over a decade ago, Greaves observed that serum from patients with chronic urticaria often had histamine-releasing factors such that when it was injected into the skin of the patient, a wheal would form at the site. Greaves later found that the factors in the serum were autoantibodies to the IgE receptor, or even IgE itself, on the surface of Mast cells and Basophils. Greaves 1991 At least 30%-50% of patients with chronic `idiopathic' urticaria (CIU) have histamine-releasing autoantibodies which degranulate mast cells and basophils by binding high affinity IgE receptors or IgE bound to them. These cases are increasingly being known as autoimmune urticaria and the observation has been both confirmed and extended. autoantibodies 1993 Sabroe RA et al 2002 Asero et al 2001 Nettis et al 2002
Cross-linking of specific IgE on mast cells and basophils by allergens can cause contact urticaria, anaphylaxis and some cases of acute ordinary urticaria, but immediate hypersensitivity reactions are hardly ever the cause of chronic disease.
Urticarial vasculitis and urticarial reactions to blood products are thought to result from the lodging of immune complexes in small blood vessels. The angio-oedema of C1 esterase inhibitor deficiency is caused by complement-derived kinins.
In a study of 526 adult patients with urticaria, Nettis and colleagues found that only 2% of adults with chronic urticaria could be shown to be due to reactions to food additives, 6 cases to tartrazine and 4 cases to sodium benzoate. Aspirin caused aggravation of hives and swelling in patients with ongoing urticaria in 10% of cases Nettis et al 2003. This was lower than the 20 - 40 percent usually quoted in the literature Champion et al 1969
Simon has reviewed the treatment of ASA and NSAID sensitivity and apart from avoidance has suggested desensitization. This discussion is beyond the scope of this review. RA Simon treatment 2003
Zuberbier has published studies that suggest restriction diets can improve chronic idiopathic urticaria. Zuberbier 1995 This group have found a small number of children with chronic urticaria that respond to their restriction diet although they suggest that unlike adults where the factors are in fruit and vegetables, in children food colourings and preservatives can play a role. Ehlers, Niggemann, Binder, Zuberbier 1998 zuberbier et al 2002
In contrast, other investigators have found that challenges with food-additives and preservatives can rarely be shown to elicit hives. Simon 2003 Simon MSG 2000 In fact Zuberbier has suggested that only a small number of the patients who respond to the diet, will show a reaction on oral challenge. In their study, patients (n = 64) were screened for common causes of urticaria and then evaluated for possible benefits of a stringently controlled pseudoallergen-free diet. Double-blind, placebo-controlled oral provocation tests with food additives were performed on those patients benefitting from diet. In 73% of patients, symptoms ceased or were greatly reduced within 2 weeks on diet, although only 19% of them responded to individual pseudoallergens on provocation tests. Of the remaining patients, 11% responded to treatment of an associated inflammatory disease, and in 16%, no cause of the urticaria was ascertained. Zuberbier 1995
Moreover, the patients must maintain the dietary restrictions until the process clears permanently which in children can be very difficult. The British guidelines on the management of Urticaria have suggested: "Although some food additives and natural salicylates may aggravate aspirin-sensitive chronic urticaria, the value of avoidance is controversial. In one prospective open study of chronic urticaria inpatients, 73% of 64 improved within 2 weeks of a strict pseudoallergen diet, but confirmed exacerbations on provocation testing with individual pseudoallergens were only demonstrated in 19% of them. (Quality of evidence III, Strength of recommendation B)".
Kozel M et al. followed the course of chronic urticaria in 220 adult patients for three years. These were patients referred to a tertiary centre and are probably more severe than patients seen in a general practice. Spontaneous remission occurred in approximately 47% of the patients with chronic idiopathic urticaria and/or angioedema within 1 year after referral. In contrast only 16% of the patients with physical urticaria were free of symptoms after 1 year. Kozel et al. 2001
Hives are often associated with "physical" causes especially dermographism and less commonly cold or sweating. In the sections below, I will deal with cold urticaria, dermographism and cholinergic urticaria which are the commonest forms of physical urticaria.
Idiopathic cold urticaria (ICU) is characterized by the rapid onset of pruritus, erythema, and swelling after a cold stimulus in the absence of any abnormal circulating protein Wanderer 1971. The pathogenesis is still unclear. Autoantibodies to FcepsilonR1 or IgE are not always associated with disease.
Cold urticaria can be demonstrated by applying an ice-cube to the forearm for 5 minutes. The wheal can appear during the application or in the rewarming phase after removing the ice-cube. Wanderer et al. 1986 Kaplan et al have documented release of histamine from skin biopsies of patients with cold urticaria. Kaplan et al 1981In some instances, there can be systemic symptoms including hypotension which may be particularly dangerous when cold urticaria occurs while the subject is swimming. Lee Sheffer 2003
In rare instances, especially in children, the cold urticaria is associated with cryoglobulins Koeppel et al. 1996 Claudy 2001. Orfan et al. 1991.
Dermographism can be associated with spontaneous hiving and the patient might not notice that they wheal with pressure. I find it helpful to ask if they have noticed long hives in the shape of scratch marks where they have been scratching. Dermographism can also be associated with other physical urticarias. Cold urticaria 1985
Dermographism is not a threat but can be annoying. It usually responds to antihistamines with suppression of the wheal although the "red" axon reflex remains. The spontaneous hiving usually clears when the dermographism clears and that occurs in a variable period of time but commonly within 4 - 6 weeks. Familial dermographism does not clear completely but may become milder so that spontaneous hiving does not occur.
The pathogenesis of cholinergic urticaria is still not clear. Intracutaneous injection of cholinergic agents such as acetylcholine chloride locally produces weals in approximately one-third of the patients. Thus, acetylcholine released from sympathetic nerve endings has been hypothesised to induce histamine release in some way. Cholinergic agents released at the nerve ending may become excessive and stimulate the sensory nerves directly, resulting in cholinergic itching and pain. Itakura, et al. 2000
Urticaria in childhood is usually due to histamine release from skin mast cells or basophils and usually responds to anti-histamine. The newer non-sedating antihistamines are very effective and have a rapid onset of action that lasts 24 hours although a review of the literature does not indicate that many blinded-placebo-controlled studies have been done in acute urticaria. Most of the studies have been done in chronic urticaria (hiving for 6 weeks or more). Lee, Maibach 2001 Simons has published the result of treatment of young children with atopic dermatitis with cetirizine or placebo for 18 months. Acute urticaria occurred in 16.2% of the placebo-treated children and in 5.8% of the children treated with cetirizine (P <.001). The protective effect of cetirizine disappeared when treatment was stopped. In the study population as a whole, urticaria episodes were most commonly associated with intercurrent infection or with food ingestion or direct skin contact. Simons 2001 Since most episodes of acute urticaria in children clear within 3 weeks, antihistamines are the first line management choice, perhaps starting with Benadryl (diphenhydramine Hydrochloride) but switching to a newer non-sedating, long-acting antihistamine if the hives persist more than a few days.
The newer, non-sedating antihistamines are the first line treatment for chronic urticaria. Asero review treatment 2003 desloratidine 2003 foxfenamine 2000 The short-acting Benadryl is often used for quick relief since its onset of action is presumed to be faster than the long-acting anti-histamines. The anti-histamines do not cure the urticaria but provide relief while "nature" cures the hives. If the hives are occurring daily or every second day then a longer-acting anti-histamine should be used daily for three weeks or so with the hope that the process will clear during that time. The anti-histamine can then be stopped to determine if the process is still continuing. If the hives are occurring more intermittently, then the anti-histamine can be used intermittently, started at the onset of the hives. The short-acting anti-histamine, Benadryl, can be used and gives about 4 hours of relief but it also creates more sleepiness than the newer agents. The newer less-sedating anti-histamines can be used intermittently and in my experience, they start acting quickly enough to be satisfactory.
If the urticaria is unresponsive to anti-histamine or persists longer than six weeks and is poorly responsive to anti-histamine, a laboratory investigation can be done. A published review of studies in adults found that laboratory investigation is rarely helpful Kozel et al 2003 My clinical experience suggests the same conclusion would be true in children. When the hives are unresponsive to anti-histamine, treatment becomes more difficult, often requiring more than one agent. This occurs more commonly in adults than children.
Hives usually respond to H1-antihistamines often requiring higher than usually recommended doses but if the response is incomplete an anti-H2 blocker can be added. Black, Greaves 2002 Several studies have shown that the addition of an H2-antihistamine (ranitidine, cimetidine) to an H1-antihistamine can give better relief of symptoms than an H1-antihistamine alone. Monroe et al 1981 Paul, Bodeker 1986 Ring, Behrendt 1990 Bleehen et al. 1987 Generally the response to the combined H1 and H2 blocker is incomplete.
More recently the data suggesting that 40 - 50% of chronic urticaria patients have an autoimmune mechanism associated with autoantibodies to the IgE receptor on Mast cells and Basophils Sabroe et al 2002 has suggested that a more aggressive "immunomodulatory" approach might be undertaken in patients unresponsive to anti-H1 blocking antihistamines alone. Asero et al 2003 In this approach, oral corticosteroid might be used 7 - 14 days in patients unresponsive to H1-antihistamines (since oral corticosteroids very effectively suppress chronic urticaria). But if the hives recur when the oral steroid is discontinued then the next step would be the addition of a leukotriene receptor antagonist (LTRA). The data on the use of of LTRAs in chronic urticaria is still fragmentary with a small number of studies or case reports with small numbers of patients in each of the studies (at most level 3 in levels of evidence). Erbagci 2002 Pacor et al double blind 2001 Nettis et al 2003 Other immunosuppressive agents have been used in adults but the use of such agents in children has not been reported and there would be very little indication for their use.
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