Chronic urticaria in childhood

Authors


Professor Malcolm W. Greaves, MD, PhD, FRCP
St John'sInstitute of Dermatology
St Thomas' Hospital
Lambeth Palace Road
LondonSE1 7EH
UK

Most of the literature on urticaria deals with urticaria in adults. Publisheddata on urticaria in children are not only relatively hard to come by, butalso less informative. This is due to the frequently uncertain distinctiondrawn between acute and chronic urticaria, paucity of confirmatory challengetest results for the physical urticarias and supposed food-derived urticaria,and fundamental differences in databases (e.g., primary care, general hospital-based,or national urticaria referral centre services), leading to different patientselections. In the UK, the published figure of 3.4% ( 1 ) for all forms of urticaria in children (acute, intermittent, andchronic) is probably fairly accurate. Henz et al. ( 2) give a range of 2.1–6.7%.

However, only a small proportion of these are chronic or intermittent.In a national referral centre for urticaria, i.e., ours at the St John'sInstitute of Dermatology, only 5% of the urticaria patients are aged16 years or below, and nearly all of them have chronic or intermittent urticaria.Acute urticaria in either adults or children is a rarity in our practice,and we surmise that most of these are dealt with in a primary care or districtgeneral hospital setting.

Definitions

Chronic urticaria is conventionally defined as the occurrence of dailyor almost daily wheals with or without accompanying angioedema for at least6 weeks. There is no consensus definition of intermittent urticaria, but,for the purposes of this paper, it is defined as the occurrence of repeatedrelapses of chronic urticaria, as defined above, with intervals of at leasta week between each relapse. The present account is considered equally applicableto intermittent and chronic urticaria, and no distinction is made betweenthem.

Classification

The types of chronic urticaria considered in the present account are listedin Table 1 .

Table 1.  Chronic urticaria in children
Physical urticarias
 Symptomatic dermographism
 Cholinergic urticaria
 Cold urticaria
 Delayed pressure urticaria
 Solar urticaria
Chronic “idiopathic” urticaria
Urticarial vasculitis
Mastocytosis
 Urticaria pigmentosa
Papular urticaria
Miscellaneous
 Muckle-Wells syndrome

Physical urticarias

More than one kind of physical urticaria may occur concurrently in thesame individual. Common combinations include symptomatic dermographism andcholinergic urticaria, or cholinergic urticaria and cold urticaria. It ismost important to identify patients in whom a physical urticaria is the soleor principal cause of discomfort and disability. This is because, apart fromconfirming the diagnosis of the physical urticaria by appropriate challengetesting, with rare exceptions no further investigations are indicated.

Symptomatic dermographism (syn. factitious urticaria)

Clinical features and prognosis

This disorder is relatively rare in childhood. Harris et al. ( 3 ) found no cases among 94 children with chronic urticaria. However,a more recent study ( 4 ) identified 1.3% of226 children with chronic urticaria in whom this physical urticaria was deemedto be the principal problem. Patients may draw attention to the immediateitching and whealing response to light pressure or friction, or to the developmentof itchy wheals at the sites of pressure from their clothes. More often, especiallyin children, no connection is made in the patient's mind between localpressure or rubbing and the appearance of urticarial lesions, although, whenquestioned, the patient may admit that scratching or rubbing makes the whealsworse. It is useful to get the child (or the mother) to assess the durationof each individual wheal, which should normally be no more than 30 min. Thisdistinguishes symptomatic dermographism from delayed pressure urticaria, sincethe latter takes several hours to develop after application of pressure andlasts for 24 h or more. Examination may yield little or nothing on first inspection.The child has often been told not to scratch, in which case, if he or sheis obedient, the skin may appear clear. More often, linear, itchy wheals canbe seen which follow the lines of scratching. They fade within a few minutes.I have not seen convincing oropharyngeal whealing in patients with this physicalurticaria. Dermographic whealing can occur anywhere but is less frequent inthe face and extremities. It is worth asking the patient or parents whetherthe wheals or the itch is the major problem. This is important from a managementpoint of view (see below). The condition runs an average course of 2–3years before finally resolving spontaneously.

Pathomechanisms

Skin perfusion studies in adults have clearly demonstrated an associationbetween histamine release and development of wheals and itching ( 5 ). How light touching or stroking of the skin can elicit whealingand itching due to mast-cell degranulation is unclear, although a circulatingfactor may be involved ( 6 ).

Diagnosis and differential diagnosis

The diagnosis is established by gentle stroking of the skin to elicit anisomorphic whealing response in the skin along the line of the applied pressure.I use a spring-loaded dermographometer for this purpose ( Fig. 1 ). The wheal occurs within 1–5 min and lasts about 30min. The only other condition in which a similar reaction to stroking of theskin may occur is urticaria pigmentosa. Unlike symptomatic dermographism,the wheal in urticaria pigmentosa, although linear, is less regular, beingmore prominent in association with the papules and macules of mast-cell infiltration.All antihistamines should be withdrawn 48 h before challenge testing. Delayedpressure urticaria, as the name suggests, does not develop for 2 or more hoursafter application of the pressure, and the wheals last for 24 h or more. Oncethe diagnosis of symptomatic dermographism has been confirmed by challengetesting, no further investigations are indicated. There is no evidence forinvolvement of systemic infections or infestations, or dietary factors.

Figure 1.

Dermographism. Elicitation by spring-loadeddermographometer.

Treatment

The parents should be told that the prognosis is for eventual resolution,and that no blood or skin tests or special diets are indicated. Woollen clothingnext to the skin should be avoided, and the child's bedroom kept cool.Application of 1% menthol in aqueous cream is often appreciated bythe child. A low-sedation H1 antihistamine is usually effectivein suppressing symptoms. Loratadine syrup or cetirizine oral solution canbe administered daily in a dosage of 2.5–5.0 mg daily, depending uponage. The timing of the dose depends on when the child's symptoms aremost severe. In adults, coadministration of an H2 antihistamine(cimetidine or ranitidine) may be useful, but this has not been shown to beof value in children.

Cholinergic urticaria

Clinical features and prognosis

Cholinergic urticaria is also rather uncommon in very young children, butcommoner in teenagers. A figure of 2.7% incidence in 226 children hasbeen reported ( 4 ). Cholinergic urticaria is commonerin children with an atopic background. Its natural history shows spontaneousresolution in 2–3 years, but it can be very persistent. Typically, patientsreport that exercise, heat – for example, a hot bath or shower –anxiety, and, less commonly, temperature-hot food or drinks cause rapid outbreakof a pruritic papular eruption. Areas usually affected include the neck; flexorsurfaces of the elbows, knees, and wrists; and inner thighs. However, therash, which is intensely pruritic, can be generalized ( Fig. 2 ). Wheals can become confluent, leading to larger areas ofangioedema. If the patient cools down, the rash usually subsides in 30–60min. Systemic symptoms are common and range from wheezing and headache tosyncope. Unusual variants, which I have only seen in adults, include persistentcholinergic erythema ( 7 ) and exercise-induced angio-edema ( 8 ). The diagnosis (9) can present problemsin heavily pigmented skin. If the rash is macular it may not be readily visible.In this case, the patient may present with pruritus induced by exercise, heat,or emotion. Even in these cases, it is usually possible to visualize the rashwith angled lighting.

Figure 2.

Cholinergic urticaria. Note mainly pinhead-size,monomorphic, symmetric wheals.

Pathomechanisms

Development of the eruption is dependent upon activation of the stimulusfor sweating; but sweating itself is not essential, since the condition hasbeen described in patients with anhidrosis ( 10 ).A recent report of the association of sweat allergy with cholinergic urticariahas not been confirmed ( 11 ). However, the developmentof the rash is clearly dependent upon a cholinergic mechanism, since it canbe blocked by anticholinergics ( 12 ), and upon histamine,since it can be suppressed by antihistamines ( 13). Patients with cholinergic urticaria tend to have lowered plasma proteaseinhibitor levels ( 14 ), but the extent to which thisis relevant to the pathogenesis of the wheals is unclear.

Diagnosis and differential diagnosis

The diagnosis is confirmed by challenge testing. A warm bath or shower,or exercise is usually adequate to provoke the typical rash ( 9 ). All antihistamines should be withdrawn 48 h before challengetesting. Intradermal testing with acetyl-beta methyl choline or another cholinergicis, in our experience, unhelpful, although these agents do tend to producea larger wheal-and-flare reaction in patients with cholinergic urticaria thanin controls. The difficulties in making a diagnosis in black or dark brownskin have already been alluded to. The diagnosis is clinical, but confirmationcan be made by atropinization of a small area of skin with 6% hyoscineaqueous lotion, which blocks cholinergic urticaria. Care must be taken notto allow the hyoscine to get in the child's eyes. Localized contact heaturticaria is very rare. This physical urticaria occurs directly only at thesite of application of heat. The rash of the equally rare aquagenic urticariaclosely resembles that of cholinergic urticaria but is evoked only by contactwith water irrespective of its temperature.

Treatment

Some patients, by regulating the degree of exertion and the temperatureof the bath and shower, and by avoiding anxiety, can limit the severity ofthe eruption to within acceptable limits. This is obviously more difficultin small children, although possible in teenagers. Although patients withonly minor symptoms may require no treatment, low-sedation H1 antihistamines represent the lynchpin of treatment. As with other physicalurticarias, loratadine syrup or cetirizine oral solution can be administeredin a dosage of 2.5–5.0 mg daily. Regular daily treatment achieves betterresults than intermittent dosage, since there is, to some extent, a “build-up”therapeutic effect with regular dosage. In view of the above-mentioned loweredplasma levels of protease inhibitors, anabolic steroids have proved to beof value in severely incapacitated adults ( 15 ),but this treatment is unsuitable in children.

Cold urticaria

Clinical features and prognosis

Although a rather rare physical urticaria, cold urticaria is at least ascommon in children as in adults. Reports of frequency among children withchronic urticaria range from 8/94 to4/226 ( 3, 4 ). This compares with a figure of 14/554 patientsof all ages ( 1 ). Children with cold urticaria presentwith redness, swelling, and itching on exposed skin within minutes of goingoutside (e.g., to school) on a cold day, getting splashed by cold water, orswimming in a pool. Avoidance of cold leads to resolution of whealing in 30–60min. Sucking an iced lollipop causes redness, itching, or even angioedemaof the lips and, less commonly, of the tongue and palate. Systemic symptomsof headache, fatigue, faintness, vomiting, diarrhoea, and dyspnoea are notuncommon, especially after widespread exposure, as in swimming in sea water.Fatalities have occurred due to drowning. The prognosis is for eventual spontaneousimprovement in most patients over a period of up to 1–2 years. Occasionally,this physical urticaria may be persistent. Rarely, cold urticaria may be familial( 16 ).

Pathomechanisms

The molecular links between fall of skin temperature and degranulationof mast cells, leading to release of histamine and other mast-cell-derivedmediators, is unclear. Besides histamine, a number of other mediators havebeen identified. These include eosinophil chemotactic factors and eicosanoids( 17–19 ). Cold urticaria has been demonstratedto be passively transferable by serum ( 20 ), butthe serum factors responsible have not been clearly identified. Histologicexamination of a biopsy of skin repeatedly cold-challenged has been demonstratedto show evidence of vasculitis ( 21 ) in the absenceof evidence of circulating immunoreactants. Although frequently sought, evidenceof cryoglobulins, cold agglutinins, and cryofibrinogens is rarely found incold urticaria ( 22 ). The onset of cold urticariahas been preceded by a virus infection ( 23 ) in someinstances.

Diagnosis and differential diagnosis

The diagnosis is confirmed by challenge testing for an isomorphic coldreaction with an ice cube sealed in a thin, waterproof bag and placed on thepatient's skin for 10–15 min. A few additional minutes must beallowed for rewarming of the chilled skin to allow a positive test to developafter removal of the ice cube ( Fig. 3 ). Inpatients who have concurrent dermographism, a modified challenge test by immersionof a forearm in water at 4°C for 10 min should be used to avoid false-positivereactions. All antihistamine therapy should be stopped 48 h before the test.

Figure 3.

Positive ice cube test in cold urticaria.

Treatment

The condition may be mild and self-limiting, in which case avoidance ofexcessive cold exposure (wearing tracksuits for games and swimming only inwell-heated pools) may be sufficient. Children with cold urticaria shouldnever bathe in a swimming pool unsupervised. In more severely affected children,regular daily dosage with H1 antihistamines (loratadine syrup2.5–5.0 mg daily; cetirizine oral solution 2.5–5.0 mg daily) isusually sufficient. However, some patients with severe cold urticaria seemunresponsive even to large doses of antihistamines. Cold tolerance treatment(regular exposure of affected skin to cold depletes the skin of stores ofhistamine) is effective ( 24 ) and surprisingly welltolerated by some motivated children. This treatment can be employed on anad hoc basis, as, for example, when the family is going on holiday and frequentrecreational cold exposure is anticipated. For rare patients with cryoglobulinaemia,intravenous immunoglobulin immunotherapy may be considered.

Delayed pressure urticaria

Clinical features and prognosis

When delayed pressure urticaria is present, it invariably coexists withchronic “idiopathic” urticaria (CIU). I am not personally awareof any patient who had delayed pressure urticaria without spontaneous whealingas well. In adults, about 40% of patients with CIU also have delayedpressure urticaria ( 25 ). Since CIU is rare in children,delayed pressure urticaria is also uncommon. Most authors do not mention it,but Volonakis et al. report one child out of 226 with chronic urticaria whowas given this diagnosis ( 4 ). Characteristicallyitchy, tender, or painful wheals occur at sites of local pressure includingthe waistband, soles of feet, or palms of hands. The wheals do not developfor at least 2 h after application of pressure, and thus the connection maybe overlooked by parents and child alike. They are also persistent, lastingat least 24 h and frequently for 48 h or more. Like other physical urticarias,the wheals eventually fade without leaving a mark except for bruising dueto vigorous rubbing or scratching. Delayed pressure urticaria tends to bepersistent, lasting for several years.

Pathomechanisms

The delayed onset and prolonged duration of the wheals of delayed pressureurticaria set it apart from other types of physical urticarias. Histologically,it closely resembles the late-phase immunologic reaction with involvementof CD4 T cells, eosinophils, mast-cell degranulation, and ad- hesion moleculeexpression ( 26 ). However, its molecular basis isunknown.

Diagnosis and differential diagnosis

The location of the wheals at pressure sites and their prolonged time courseare important clinical pointers. The diagnosis is confirmed by challenge testingby pressure applied perpendicular to the skin. My laboratory uses a hand-heldspring-loaded dermographometer ( Fig. 1) thatis suitable for children. To elicit delayed pressure urticaria, it is appliedvertical to the skin. The test is read 4 h after application. Urticarial vasculitis(see below) is also localized at pressure sites, it is delayed, and its whealslast for over 24 h. Only a skin biopsy can enable delayed pressure urticariaand urticarial vasculitis to be confidently distinguished from each other.The distinction is important because no investigations are required once thediagnosis of delayed pressure urticaria is confirmed, whereas urticarial vasculitisrequires substantial laboratory work-up (see below).

Treatment

It is important to identify delayed pressure urticaria in patients withCIU. Delayed pressure urticaria responds poorly, if at all, to antihistaminesand accounts for the poor response of many patients with CIU to treatment.I have not found any treatment to be consistently effective in delayed pressureurticaria. Large dosages of oral corticosteroids do suppress pressure-inducedwhealing but at the unacceptable cost of severe steroid toxicity.

Solar urticaria

Clinical features and prognosis

This physical urticaria is rare in adults and very rare in children. Thereis one case report of a 2-year-old infant who developed unequivocal solarurticaria ( 27 ). A recent report ( 28 ) of 25 cases states that the ages at first consultation rangedfrom 17 to 71 years, but does not give the ages of onset. Redness, itching,and whealing develop within a minute or two of sun exposure. These symptomssubside in 30–60 min if sun exposure is avoided. Systemic symptoms arerare. The condition usually runs a course of several years in adults beforesubsiding.

Pathomechanisms

The action spectrum for whealing ranges from UV-B (290–310 nm) throughto visible light ( 28 ). Autologous serum skin phototesting( 29 ) suggests the involvement of a photoallergenin cutaneous mast-cell degranulation and histamine release after sun exposure.

Diagnosis and differential diagnosis

The hallmark of solar urticaria is the development of itching, whealing,and redness on exposed skin immediately after sun exposure. The differentialdiagnosis includes the very common polymorphic light eruption. In this photodermatosis,erythema and itching occur several hours, not minutes, after sun exposure,and the rash persists for several days even if sun exposure is avoided. Mostpatients diagnosed initially as having solar urticaria turn out to have polymorphiclight eruption. In children, itching and burning of exposed skin immediatelyafter sun exposure occur in the rare inborn error of metabolism, erythropoieticproto-porphyria. In this condition, fluorescence of UV-irradiated red bloodcells can be demonstrated on photomicroscopy. Children with this disorderalso usually manifest superficial linear fine scars on the nose, cheeks, andchin.

Occasionally cholinergic urticaria may cause diagnostic confusion becausesolar heat can induce wheals on the face and neck in this physical urticaria.Exercise or hot-shower challenge testing should resolve this issue. Moreover,the whealing of solar urticaria, unlike cholinergic urticaria, cannot be blockedby atropinization with 6% aqueous hyoscine. No further investigationsare warranted once the diagnosis of solar urticaria has been made in a child,apart, possibly, from excluding erythropoietic protoporphyria, as mentionedabove. Determination of the action spectrum may be useful in fine-tuning sun-protectivetreatment.

Treatment

Avoidance of sunlight and use of an appropriate sunscreen (depending uponthe action spectrum in each individual case) may be sufficient in mildly affectedpatients. H1 antihistamines (cetirizine oral solution or loratadinesyrup 2.5–5.0 mg daily) are usually helpful. Tolerance treatment hasbeen advocated in more severely affected patients ( 29, 30 ).

Chronic idiopathic urticaria (CIU)

Clinical features and prognosis

The occurrence of spontaneous wheals daily or almost daily for at least6 weeks characterizes chronic “idiopathic” urticaria (CIU) ( Fig. 4 ). Although the urticarial wheals do not affectmucous membranes, angioedema, which can involve mucous membranes, occurs in38–87% of adult patients with CIU ( 31). When angioedema, in association with CIU, affects the oropharynx, patientsmay be acutely distressed, but I have personally never seen a death from angioedemaassociated with CIU. By definition, the duration of wheals of CIU is lessthan 24 h. Unlike the wheals of most physical urticarias, the wheals of CIUlast at least 6–8 h and usually longer. They fade without leaving amark in the skin. However, CIU is also complicated by delayed pressure urticariain about 40–50% of patients ( 25 ), thepressure-induced wheals individually lasting 24 h or longer (see above). However,it should be emphasized that these figures come from adult studies; thereare few or no comparable data from children with CIU. CIU is less common inchildren than adults, although Harris et al. ( 3 )appear to have identified as many as 79 children with “idiopathic”chronic urticaria out of a total of 94 with chronic urticaria. The overallprognosis in children is unclear; 50% of adult patients experienceremission in 3–5 years ( 32 ).

Figure 4.

Chronic “idiopathic” urticariain 11-year-old. This child, previously rendered cushingoid by steroids, wasfound to have anti-Fcε RIα autoantibodies and subsequentlyresponded very well to intravenous immunoglobulin infusions, allowing oralsteroids to be withdrawn.

Pathomechanisms

Most patients (or their parents) with CIU believe that food factors areinvolved although, at least in adults, this can rarely be substantiated. Placebo-controlledfood challenge tests remain the “gold standard” ( 33 , 34 ). Exclusion diets are invariablylong-drawn-out, with poor compliance and ambiguous results. However, by placebo-controlledchallenge testing, about 5% of adult CIU patients can be shown to reactadversely to one or more food additives, and these patients may be helpedby appropriate dietary advice ( 35 ).

Other causes frequently cited in the literature include infections of diversenatures. Most recently, Helicobacter pylori infection of the stomachand duodenum has been frequently implicated as a causative agent for CIU inadults ( 36 ), but recent reports appear not to confirmthis association ( 37 , 38). In some parts of the world ( 39 ), almost 50%of children are infected with H. pylori. Overall, the “focusof infection” theories have never stood the test of time for CIU.

Parasite infestation has never been confirmed as a cause of CIU in anyof my patients. However, it is conceivable that this could be a causativefactor in regions where heavy parasite loads are endemic. Further criticalstudy of this association in children and adults would be worthwhile.

Until recently, the cause of promiscuous activation of dermal mast cellsin CIU was unknown in most cases. To an extent, this still remains true, butrecent work indicates that in at least some of these otherwise puzzling patients,the mechanism is autoimmune in character. As early as 1974, ex vivo histamine-release studies of blood basophils of patients with CIU indicatedthat one or more circulating histamine-releasing factors could be involved,at least in some patients ( 40 ). However, this findingwas not followed up until over 10 years later, when, in 1986, Grattan et al.reported ( 41 ) the presence of a serologic mediatorof whealing in some patients with chronic urticaria. Further characterizationof this activity showed that it was almost entirely attributable to an IgGautoantibody directed against the alpha chain of the high-affinity IgE receptor(Fcε RIα) of mast cells and basophils or, less commonly,against IgE itself ( 42 , 43). This finding was subsequently confirmed by several independent groups ( 44–46 ). The proportions of patients in whoman autoimmune basis can be demonstrated ranges from 25% ( 43 ) to almost 50% ( 46 ). I am notaware that these autoantibodies have been looked for systematically in childrenwith CIU, and this needs to be done. However, some details of our autoantibodymeasurements in patients aged 16 years and below are given in Table 2 .

Table 2.  Functional histamine-releasing autoantibodiesin children with CIU
PatientAge (years)Anti-Fcε RIAnti-IgE
  1. Autoantibody positivity was tested foragainst low- and high-IgE donor basophils as previously described ( 43 ).
    *Not done.

M.C.13pos.—*
N.K.16pos.neg.
K.M.12neg.—*
D.M.15pos.neg.
A.S.16neg.neg.
S.T.13neg.neg.
L.W.10neg.neg.

Subsequent studies have demonstrated these anti-Fcε RI autoantibodiesto be predominantly IgG1 and IgG3 subtypes ( 47 ).The specificity of these autoantibodies has been investigated. They have notbeen found in healthy individuals or in patients with atopic eczema, psoriasis,or physical urticaria ( 42 , 43). However, immunoreactive but non-histamine-releasing anti-FcεRI autoantibodies have been detected in small numbers of patients with otherautoimmune diseases including dermatomyositis, pemphigus, and pemphigoid ( 47 ). In these cases, the IgG subtypes have been predominantlyIgG2 and IgG4. As far as I am aware, functional (i.e., histamine-releasing)anti-Fcε RIα autoantibodies have been demonstrated onlyin CIU. That some patients with CIU have an autoimmune basis is not especiallysurprising since an association between CIU and thyroid autoimmunity has beendemonstrated ( 48 , 49 ).Furthermore, increased frequency of HLA-class II alleles HLA DRBI *04(DR4) and DQBI*0302 (DQ8) in autoimmune urticaria is in keeping with itsimmunologic basis ( 50 ). It has been suggested ( 51 ) that these autoantibodies, although demonstrable inCIU, may not be of pathogenetic significance. That they are in fact the causeof the clinical picture is evident from their functional histamine-releasingactivity, direct quantitative relationship with disease severity ( 52 ), and clinical response to removal or suppression by plasmapheresisor intravenous immunoglobulin ( 52 , 53 ). Whether or not IgG-anti-Fcε RI autoantibodiesfix complement is a controversial issue. Our own ( 42, 43 ) evidence is that anti-Fcε RIautoantibody histamine-releasing activity is thermostable, a fact which arguesagainst complement involvement. However, recent evidence ( 54 ) suggests that under circumstances in which there is a low mast-cellor basophil surface population density of high-affinity IgE receptors, monovalentrather than divalent cross-linking of these receptors by anti-Fcε RIα autoantibodies may occur, and in these circumstances complementmay be involved. This would be more likely to occur in individuals with lowserum IgE. In view of the absence of evidence of mast-cell activation in therespiratory tract in patients with autoimmune chronic urticaria, it is ofinterest that, unlike skin mast cells, lung mast cells do not express complementreceptors.

Diagnosis and differential diagnosis

Inflammatory skin lesions lasting less than 24 h are, by definition, urticarial.However, the patient's perception of duration of individual wheals isoften inaccurate. The most important differential diagnosis is urticarialvasculitis, and in this condition the wheals last more than 24 h – oftenas long as 48 h or even longer. Unlike CIU, the wheals of urticarial vasculitismay leave purpuric staining of the skin. Only a skin biopsy can resolve thisissue. Urticarial vasculitis should not be deemed to be confirmed in the absenceof histologic evidence. Facial angioedema is occasionally confused with anumber of causes of facial swelling including acute contact allergic dermatitis,Crohn's disease, Melkersson-Rosenthal syndrome, and dermatomyositis.

Apart from skin biopsy (see above), the value of laboratory work-up inCIU is limited. The presence of blood eosinophilia should prompt a searchfor parasite infestation, but this is an exceptional finding, at least ina UK population. Placebo-controlled oral challenge for evidence of food-additivereactivity is worth carrying out in adults, but I have no experience of itsfeasibility or value in children with CIU. It should be possible to carryout autologous serum skin testing in older children as a screening test forautoimmune urticaria ( 41 ). The sensitivity and specificityof this test have recently been optimized ( 55 ).However, confirmation of the presence of anti-Fcε RI autoantibodiesrequires demonstration of histamine release from basophils of healthy, low-serum-IgEdonors ( 43 ) or immunoblotting ( 44 ), although, as indicated above, false positives can be elicitedby this technique. Confirmation of the autoantibody alpha-chain specificityis obtained by inhibition experiments with the human recombinant alpha chain.Anti-IgE autoantibodies are detected by basophils of high-serum-IgE donors,with confirmation by inhibition with monoclonal IgE. Reliable, sensitive,and specific ELISAs for these autoantibodies are badly needed.

Treatment

It is important to reassure parents and teachers that, in the vast majorityof patients, CIU is not an outward manifestation of a sinister underlyingdisease. Common-sense measures are helpful, including avoidance of coarse,tight, woollen underclothes and an overheated environment to allay itching.Intercurrent febrile infections almost invariably cause nonspecific flare-upsof CIU, and parents should be warned about this. Oropharyngeal angioedemais rarely, if ever, life-threatening, but it can be frightening to the child,parents, and teachers alike. Administration of two to three puffs of a 2%aqueous ephedrine spray is safe and effective at the onset of an attack andat 10-min intervals up to a maximum of three doses. It is most reassuringfor all concerned to have this emergency treatment on hand. Aspirin and aspirin-containingmedications should be avoided. The risk of taking other NSAID is more controversial,but it is probably prudent to avoid them where possible.

The first line of treatment for any patient with CIU, whatever the cause,is to prescribe H1 antihistamines. For small children, at leastin the UK, the choice is limited. Only hydroxyzine (dosage 5–15 mg daily)is recommended for infants of 1 year or less as a syrup. Above 2 years, thechoice is wider but, of the low-sedation H1 antihistamines, onlycetirizine (formulated as an oral solution) and loratadine (as a syrup) arerecommended for 2–6-year-old children. It is reasonable, in more severelyaffected children, to prescribe a low-sedation antihistamine in the morningand hydroxyzine at night. The value of combined H1 and H2 antihistamines is not proven in children.

Oral steroids should be rarely necessary. If administered at all, for severelydisabled children unresponsive to antihistamines, only short tapering coursesshould be employed. In such children who are shown to be autoantibody positive(either anti-Fcε RI or anti-IgE), it may be preferable to administerintravenous immunoglobulin, although my own published series ( 53 ) and subsequent unpublished practice have not included its usein children.

Cyclosporin will probably be effective in children with autoantibody-negativeCIU, although, again, I have no personal experience in this age group. However,cyclosporin is of proven safety in children ( 56 ).Relapses may be expected after withdrawal, but, at least in adults, no reboundoccurs. Renal function and blood pressure should be carefully monitored beforeand during cyclosporin treatment. It should be emphasized that CIU in childrenis an unlicensed indication for cyclosporin.

Urticarial vasculitis

Clinical features and prognosis

Urticarial vasculitis appears to be exceptionally rare in children. Harriset al. ( 3 ) report three of 94 children with chronicurticaria who had juvenile rheumatoid arthritis, a positive ANA with arthritis,and a low serum CH50 level, respectively. One or more of these three childrenmay well have had urticarial vasculitis, but there is no confirmatory histologicevidence. However, three cases of hypocomplementaemic urticarial vasculitiswere reported recently in children ( 57 ). These childrenhad prominent systemic manifestations. There is an understandable reluctanceon the part of clinicians to carry out a skin biopsy in children with chronicurticaria, but this is the only satisfactory way to make the diagnosis.

Clinically, the diagnosis is suggested by the duration of individual wheals(>24 h), residual staining of the skin due to purpura, associated systemicsymptoms (arthralgia and abdominal symptoms), and poor response to antihistaminetreatment ( 58 ). In adults, the condition usuallyruns a protracted course. Livedo reticularis and rarely bullae are occasionallyassociated clinical findings. Systemic lupus may occasionally manifest urticarialvasculitis as a presenting feature ( 59 ). Acute haemorrhagicoedema of infancy is probably a rare form of urticarial vasculitis manifestingas purpuric angioedema ( 60 ). However, it has alsobeen taken to be a presentation of Henoch-Schönlein purpura ( 61 ). Urticarial vasculitis may also be a manifestation of drug hypersensitivityand serum sickness.

Pathomechanisms

The target cutaneous vessel in urticarial vasculitis is the postcapillaryvenule. Histologically, there is characteristically endothelial cell swelling,perivenular neutrophil leukocyte infiltrate, nuclear debris, diapedesis ofred blood cells, and fibrin deposition. These changes are brought about bydeposition of circulating immune complexes or, less commonly, paraproteinsin the skin. Hence, the lesions show a predilection for skin in which thecirculation may be congested, especially pressure sites such as the waistband,the lower extremities, and cold extremities. Immune complexes may occasionallybe demonstrable in serum, with or without hypocomplementaemia, but most patientsdo not show these features. Urticarial vasculitis may be a manifestation ofhepatitis B infection ( 62 ) and paraproteinaemia( 63 ). Schnitzler's syndrome ( 64 ) (urticarial vasculitis, fever, bone pain, and IgM monoclonalgammopathy) has not, so far as I am aware, been described in children.

The ESR is often raised in urticarial vasculitis, especially when systemicfeatures are present, and there may be protein and red blood cells in theurine. Immunologically, urticarial vasculitis can be characterized as an Arthus(type III in the Gell and Coombs classification) reaction.

Diagnosis and differential diagnosis

The diagnosis is clinical (individual wheals of greater than 24-h durationwith or without purpuric staining) backed up by histologic examination ofa biopsy specimen. An early lesion (<12 h duration) should be biopsied.Immunofluorescence examination of biopsy material for immunoreactants is usuallyunhelpful. Delayed pressure urticaria may cause confusion since the whealsin this physical urticaria are also of prolonged duration, but a skin biopsywill resolve this issue because there is no vasculitis in delayed pressureurticaria. In all patients, the blood should be examined for immune complexes,complement depletion, paraproteinaemia, and hepatitis B and C infection. Pulmonaryand renal function should also be examined, and evidence of lupus erythematosussought.

Treatment

The most important part of the management of urticarial vasculitis is thesearch for causes, as outlined above. General measures apply as for CIU. Patientswith urticarial vasculitis are usually poorly responsive to H1 antihistamines, although they are worth trying. Corticosteroids are alsopoorly effective and prone to toxicity. Indomethacin, dapsone, colchicine,and hydroxychloroquine are also worth trying, but of uncertain and only anecdotallyreported value ( 65–68 ).

Urticaria pigmentosa (cutaneous mastocytosis)

Clinical features and prognosis

Mastocytosis occurs infrequently in children, but with striking clinicalfeatures in most patients. It usually presents in the first 2 years of life.Indeed, half of all patients seen in our urticaria clinic develop diseasebefore puberty. The most common clinical form is the solitary mastocytoma,which may wheal, itch, and even blister upon rubbing. Due to release of histamineand other mediators, systemic symptoms may occur, including flushing, wheezing,and diarrhoea. Alternatively, cutaneous mastocytosis may present in childhoodas urticaria pigmentosa – a widespread pigmented maculopapular eruptionwith itching. Rubbing affected skin produces immediate, short-lived redness,whealing, and itching (Darier's sign) or, less often, blister formation.The development of bullae is almost entirely confined to juvenile cutaneousmastocytosis – blistering rarely occurs in adults with this disease.The disease runs a benign course in most paediatric patients, eventually clearingup with little more than residual pigmentation. However, systemic symptoms,including flushing, diarrhoea, gastrointestinal bleeding, and bronchospasm,may occur.

Pathomechanisms

The disease is due to a benign proliferation of cutaneous mast cells. Concordanceof urticaria pigmentosa in monozygotic twins supports the involvement of geneticfactors, at least in some patients ( 69 ). Somaticmutations of c-kit (a gene which encodes a tyrosine kinase membranereceptor expressed by mast cells) lead to disordered control of mast-cellproliferation. Its ligand is stem-cell factor (SCF). The same c-kit mutation may also occur in bone-marrow stem cells, leading rarely to associatedhaematologic malignancy ( 70 ). It is probable thatisolated nonhereditary cases involve somatic mu-tations of c-kit ,whereas familial cases involve germ-line mutations.

Diagnosis and differential diagnosis

The clinical diagnosis of urticaria pigmentosa is made by gentle rubbingof lesional skin, an action which results in immediate local redness, whealing,and itching (Darier's sign). A similar reaction to stroking occurs insymptomatic dermographism, as already described. However, in this physicalurticaria, the reaction occurs in clinically normal-looking skin. The diagnosisis confirmed by a skin biopsy that shows greatly increased numbers of dermalmast cells. In symptomatic dermographism, there is no increase in dermal mastcells. When, as is frequently the case in infants, blistering occurs, diagnosticconfusion may occur with impetigo, epidermolysis bullosa, staphylococcal scaldedskin syndrome, and even incontinentia pigmenti. None of these disorders manifestlarge increases in the dermal mast-cell population upon skin biopsy. The urinaryexcretion of histamine and its major metabolite N-methyl histamine is normallyelevated. Measurements may be useful to monitor disease activity but are oflittle diagnostic value. In view of the anticipated favourable prognosis inchildhood of urticaria pigmentosa, needle aspiration of bone marrow, imagingof liver and spleen, and skeletal radiologic survey are not recommended.

Treatment

Parents should be reassured about the benign prognosis in most children.Avoidance of aspirin, muscle relaxants, opioid analgesics, codeine, and pethidene,which may activate mast cells, should be advised. Dextran and dye-containingradiocontrast media should also be avoided. Patients with mastocytosis aremore susceptible to anaphylactoid reactions from bee or wasp stings, and inan environment where stings are likely, injectable adrenaline (epinephrine)should be available. Children with symptomatic urticaria pigmentosa usuallyrespond reasonably well to combined H1 and H2 antihistamines.The newer low-sedating antihistamines offer advantages for daytime use. Abdominalsymptoms may be relieved by oral disodium cromoglycate, but this drug hasno effect on cutaneous mast cells. Potent topical steroids, under occlusion,may be of value in children with severe cutaneous involvement. Interferon-alphainjections are alleged to alleviate systemic mastocytosis ( 71 ), but I am unconvinced that the results justify the troublesomeside-effects and expense of the treatment. The aetiology, clinical features,pathology, and management of cutaneous mastocytosis have recently been reviewed( 72 ).

Papular urticaria (insect bite reactions)

Clinical features and prognosis

This is the commonest form of urticaria worldwide, especially in children.Characteristically, it presents as grouped or linear highly pruritic whealsor papules mainly on exposed skin. The reactions are due to immunologic hypersensitivityto the saliva of the biting insect. In more highly sensitized individuals,papular urticaria may present with large bullae. Newborn and very young infantsrarely suffer from this problem, and its incidence peaks before puberty. Commonculprits include mosquitoes, fleas, lice, and horseflies.

Pathomechanisms

According to Penneys et al. ( 73 ), immunity beginsto evolve with delayed hyper-sensitivity leading to itchy papules. A sensitivity-increasedIgE-mediated immediate hypersensitivity develops, leading to urticarial reactions.Ultimately, after repeated exposure, tolerance occurs. Rarely, anaphylacticsymptoms can develop. Secondary infection is common due to scratching.

Diagnosis and differential diagnosis

Louse and flea bites tend to present as linear or grouped papules or whealsaround the hems of clothing. Mosquito bites, with a similar arrangement, occurmainly on exposed skin. A skin biopsy is rarely necessary, but, if done, showsa characteristic histology with a lymphocyte infiltration and numerous eosinophils.

Conditions in children which may be confused with papular urticaria includephytophoto contact dermatitis, scabies, shingles, bullous impetigo, ordinaryurticaria, and lichenoides.

Treatment

Prevention is the most satisfactory approach to management. Sources (cats,dogs, and caged birds) should be removed. Insect repellents are messy andonly moderately effective. Secondary impetiginization should be treated bya topical anti-bacterial such as muperocin cream. An antihistamine such ashydroxyzine can be administered systemically for severe pruritus. Desensitizingimmunotherapy has been proposed but has not been validated. The problem ofpapular urticaria in children has recently been reviewed ( 74 ).

Muckle-Wells syndrome

This familial disorder was first described in 1962 ( 75 ). It is rare, dominantly inherited, but occasionally sporadic. Lesionsappear in adolescence and present as recurrent urticaria, arthritis, and limbpain, associated with progressive nerve deafness. Eventually, renal amyloidosisdevelops. Recurrent bouts of fever, raised ESR, and hypergammaglobulinaemiaare common. Generalized amyloidosis supervenes and the disease is ultimatelyfatal.

Conclusion

Chronic urticaria in children is poorly understood. There is a dearth ofaccurate information on the epidemiology of urticaria in childhood, the prevalenceof different types of urticaria in children, and their natural history inthis age group. Most of the information available is indirect, based uponextrapolation from adult data.

However, despite our ignorance of the characteristics of chronic urticariain childhood, taking a careful history and carrying out a thorough examinationwill pay dividends in terms of avoiding unnecessary investigations and inappropriatetreatment. Despite the limited choice available in this age range, antihistaminesremain the cornerstone of treatment.

Ancillary