Managing the Allergic Child

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Chapter 14 Managing the Allergic Child

GLENIS K. SCADDING, MA MD FRCP

Introduction

Children with allergies present a special challenge to the physician. First, they are frequently affected at more than one body site and may, in countries like the UK where allergists are scarce, be under the care of several different specialists. Second, the condition can progress. There is a well-described atopic march in which children born with atopic dermatitis can go on to develop asthma and then rhinitis/conjunctivitis. Children who are monosensitized to peanut tend to develop allergy to additional tree nuts over time.

A switch also occurs in the allergens recognized, with many children being initially food allergic (milk, egg, wheat, soya), losing these allergies only to develop inhalant allergies at around the age of 4–6 years. Thus there is a need to treat not only the existing condition, but also to attempt to prevent further disease progression.

Allergy and infection frequently coexist in children – recognition and appropriate treatment of both is important.

Epidemiology/Prevalence/Burden

Allergic diseases exist worldwide and are highest in westernized countries. In the UK, which leads the world for asthma symptoms, the burden in 13–14 year olds as judged by the International Study of Asthma and Allergy in Childhood (ISAAC) study, shows 32% reporting symptoms of asthma, 9% eczema and 40% allergic rhinitis. In the UK some 12 million people are affected by allergic disease in any one year. One in 70 children is peanut allergic and this figure is rising. Highly atopic children can be severely disabled by their disease with gastrointestinal symptoms including gastroesophageal reflux disorder (GERD), failure to thrive, severe atopic dermatitis, and life-threatening anaphylaxis. Even those children with less problematic disease such as seasonal allergic rhinitis can be disadvantaged because of poor sleep, decreased concentration, and a reduction in examination performance.

Classification of the Problem

Children are usually classified by the allergic disorders from which they suffer. These are likely to include one or more of atopic dermatitis, atopic gastrointestinal disease (gastroesophageal reflux, food allergy, failure to thrive, eosinophilic esophagitis, etc.), atopic respiratory disease (asthma, rhinoconjunctivitis), anaphylaxis, urticaria (rarely allergic in childhood), and drug allergy. Children very rarely exhibit allergy to occupational allergens such as latex, nor to aspirin. An alternative classification is by allergen sensitivity – food allergy, inhalant allergy, or both.

Secondary conditions, often infective, are frequent. For example, the child with rhinitis may develop rhinosinusitis or otitis media with effusion, or suffer a viral URI which exacerbates existing asthma.

At the Royal National Throat, Nose and Ear Hospital we have a multidisciplinary approach with allergist, pediatrician, ENT surgeon, audiologist, and dietician present in the same clinic together with an allergy nurse. In this way the many problems of an individual child can be addressed in one visit without excessive time off school.

Relevant Anatomy and Physiology

Children are not simply small adults, and therefore allergic disorders present differently. For example, the short relatively horizontal Eustachian tube means that nasal disease frequently impinges on the middle ear in children. The mild immunoincompetence seen in most children under 2–3 years (due to the time of maturation of the IgG2 response and delayed maturation of IgA) means that allergic respiratory disease is often accompanied by infection, which may mask the underlying allergy.

The physiology of children can also differ from that of the adult. Children are relatively tolerant of severe allergic reactions (anaphylaxis) and of epinephrine (adrenaline) treatment, probably because of their atheroma-free cardiovascular systems. Drug metabolism can differ: small children may exhibit paradoxical excitement with antihistamines. Many drug therapies available for adult disease have not been adequately tested in childhood, especially in children under 5 years.

Pathophysiology

The pathophysiology of the allergic response is similar in children to adults. It is now thought that a T-helper (Th) 2 bias exists during pregnancy to prevent fetal rejection. The baby is born with a Th2 biased immune system, but this gradually switches over the following months to one with a preponderance of Th1 responses. In atopic individuals the Th2 responses do not wane, but persist – initially largely directed against food allergens; later inhalant allergens form the major response provokers.

Diagnosis

▪ History

Taking an adequate allergy history is vital, especially in children. This should involve not only the presenting complaint, its duration, timing, provoking factors, relieving factors, etc., as in adults, but should also involve a history of pregnancy, birth, postnasal issues, and development including early feeding and the presence or absence of colic, failure to thrive, etc. It is necessary to ask about possible allergic symptoms at other sites.

A family history of atopic disease should be noted as well as a very detailed environmental history, feeding, pets, nursery placement, smoking in the home, etc. Many children lead complicated lives and live in a least two places – symptoms occurring at one only can give a clue to causation, for example the child who coughs when visiting his father who has a cat. Any treatments given, including alternative and complementary ones, need to be accurately recorded, plus the response to these.

A history (questionnaire) is often helpful as it can be filled whilst waiting to be seen and focuses the attention of parents.

▪ Physical Examination

Many children are initially shy, so it is worthwhile spending time getting to know them and amusing and involving them in the consultation prior to making any attempt at examination. Much information can be gained by quiet observation whilst taking the history: an allergic salute may be seen, a double allergic crease under the eyes may be noticed, dry eczematous skin can be apparent. The quiet withdrawn child may not be able to hear properly.

Prior to the consultation the child should have the weight and height recorded by the clinic nurse, and it is sensible to repeat these at each visit, especially if the child is receiving either nasal, inhaled, and/or topical corticosteroids.

The skin should be examined for signs of atopic dermatitis particularly on the face and in the elbow and knee flexures. Examination should involve looking at ears, nose, and throat. An otoscope is useful for all three, but may need to be supplemented by nasal endoscopy in older children if rhinosinusitis is suspected. Chest examination should include observation of chest shape: an indrawn lower chest suggests an upper airway obstruction. Wheezing may be audible. The abdomen should be examined if there is any gastrointestinal complaint.

Investigations

▪ Skin Prick Tests

These can be undertaken in children from a few months of age. In small children it is sensible to have them cuddled up to their parent or caretaker and the back can be used for a few skin tests as directed by the history. Older children may tolerate testing on the forearm. We employ a play leader to distract the child – often by getting them to blow bubbles – during the process.

Skin prick tests in children tend to be regarded as positive when they are 2 mm larger than the negative control rather than the 3 mm cut-off point commonly used in adults. As in adults correlation with the history is vital. As with adults, if there has been previous anaphylaxis then skin prick testing should be undertaken with care and the allergen may need to be tested in dilutional titers.

▪ Laboratory Tests

If skin prick testing cannot be undertaken due to severe atopic dermatitis, recent drug therapy such as antihistamines (children’s cough medicines often contain antihistamine and can be confounding factors), anaphylaxis, dermatographism, then blood can be taken for antigen-specific IgE tests as an alternative.

Other blood tests which may be useful are:

• Tests for immune deficiency.
• CBC, white cell count, differential ESR.
• Total IgG, IgA and IgM and IgG subclasses, specific antibody responses to Pneumococcus, Haemophilus, and tetanus.
• Celiac screen as a differential diagnosis for allergic gastrointestinal problems.

▪ Nitric Oxide

Exhaled nitric oxide is usually low (<20 ppb), but is raised when there is lower respiratory tract inflammation from any cause. The test is usually possible in children over 5 years and can be a useful pointer to underlying asthma. Conversely normal levels in the coughing child suggest that the problem is located in the upper respiratory tract.

▪ Nasal Nitric Oxide

This is useful when very low as this should raise the suspicion of primary ciliary dyskinesia as an alternative diagnosis to chronic allergic rhinitis. Specialized tests of ciliary beat frequency and electromicroscopy are then indicated.

High levels suggest inflammation which could be allergic. Mid range values do not necessarily imply normality.

Treatment

▪ Allergen Avoidance

This is the most logical form of therapy, but is often difficult to achieve. It is mandatory in children with food-induced anaphylaxis, for example due to peanuts, milk, egg. Help from a pediatric dietician with experience in food allergy is required to ensure: (1) that the diet does completely exclude the relevant allergens plus any cross-reactive allergens such as lupine flour (which is made from the seeds of lupin plants and mixed with wheat flour; 45% of French peanut allergic children react to this) and (2) that the diet is nutritionally adequate and palatable.

Avoidance of inhalant allergens such as housedust mite is problematical. However, a recent study in asthma intervention with six major classes of allergens (dust mites, cockroaches, pet dander, rodents, passive smoking, and mold) that trigger asthma symptoms did show benefit in the intervention group compared to control children. The 408 children in the intervention group had 19% fewer unscheduled clinic visits, 13% reduction in their use of salbutamol inhalers, and 38 more symptom-free days over the course of the 2-year study compared to 392 control children.

▪ Pharmacologic Therapy

Corticosteroids

These act at multiple sites in the allergy cascade and are the single most effective treatment for rhinitis, asthma, and atopic dermatitis. Topical use in microgram amounts is possible via the inhaled nasal and dermal routes. However, since many allergic children suffer not only from asthma, but also rhinitis and atopic dermatitis and are treated with corticosteroids at all three sites the microgram amounts can become sufficient to cause adrenal suppression and other corticosteroid side effects. Thus continued monitoring of the child, particularly of growth which is a very sensitive measure of corticosteroid systemic effect, is mandatory. This is also a reason for just one allergist physician looking after the child rather than three separate physicians or surgeons each treating one site.

First generation corticosteroids such as betamethasone and dexamethasone should be avoided, or used very briefly at the start of treatment, since these are highly systemically available. The most recent corticosteroids such as fluticasone and mometasone are the least absorbed from the nose. Fluticasone is more readily absorbed from the large surface area of the lung and care must be taken to keep within the recommended dose range appropriate for age since high inhaled doses have been associated with adrenal suppression. Once disease control is established the dose of corticosteroid should be reduced to the minimum which will maintain control; it may need to be increased when inflammation increases (e.g., during infections).

For rhinitis it is advisable to use a nasal steroid with low systemic bioavailability at the lowest possible dose to control symptoms. Unlike most antihistamines topical corticosteroids reduce nasal congestion and obstruction. Intermittent use may be beneficial due to rapid vasoconstrictor effect. Compliance is improved if the child is taught how to use the nasal spray.

For relief of nasal congestion, short-term use (<14 days) of corticosteroid nose drops or decongestant may be helpful. The best position for administration of nose drops is with the child lying, head back. A short course of oral steroids may be beneficial in relieving nasal congestion with significant systemic symptoms in seasonal allergic rhinitis. Surgical referral for submucosal resection of the inferior turbinate bones is rarely indicated.

Oral corticosteroids are highly effective, but need to be used with extreme caution because of systemic side effects. Their place is at the start of treatment when airway obstruction is very severe, the smallest dose compatible with quick symptom relief (usually 0.5–1 mg per kg), orally for a few days, together with inhaled and/or nasal therapy.

Antihistamines

These provide good symptomatic relief of symptoms such as itching, rhinorrhoea, and sneezing. Antihistamines are useful in rhinitis and urticaria, but their place is doubtful in atopic dermatitis and asthma.

The first generation of antihistamines have side effects which include sedation, dry mouth, and psychomotor retardation. These include chlorphenamine, diphenhydramine (which also has the most significant effect on cardiac potassium channels of all antihistamines). For these reasons they are not suitable for regular use in any allergic condition. Chlorphenamine is still used as a rescue therapy in the acute allergic reaction as it is available in syrup form and can be administered easily with rapid effect.

Second generation antihistamines such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, and mizolastine have less sedative effects in most children and are equally efficacious as the first generation with no tachyphylaxis. Once daily administration of a long-acting antihistamine will ensure better compliance than medication which requires multiple daily doses. These are useful if rhinorrhoea and sneezing are main symptoms, or for conjunctivitis or urticarial rashes. Desloratidine, levocetirizine, and fexofenadine may also be beneficial for symptoms of nasal congestion.

New theories of antihistamine effect suggest that they act as inverse agonists, that is they stabilize the inert form of the histamine receptor (a G-protein coupled seven-loop transmembrane receptor), rather than acting as direct antagonists of histamine at the receptor. This means that in practice regular use of antihistamine is liable to be more effective than as-needed use and also implies that sudden cessation of treatment could give rise to disease exacerbation as the histamine receptors revert to an active form.

Topical intranasal antihistamines are effective for rhinitis in children. Topical antihistamines should not be used on the skin where they are potent sensitizers.

Regular use of antihistamines in children with atopic dermatitis has been shown to reduce the progression to asthma in two small studies using ketotifen. In a larger study with cetirizine (Early Treatment of the Atopic Child, ETAC) subgroup analysis showed that children with positive skin prick tests to housedust mite, cat, and grass pollen were protected to some extent by the regular antihistamine therapy from progression to asthma. This protective effect needs to be weighed against any side effect of such chronic drug therapy such as sedation and weight gain. In the ETAC study this was carefully monitored and no major adverse effects were noted.

Anti-leukotrienes

This new class of drug became available within the last decade and has, in children as in adults, shown a spectrum of effectiveness with some individuals experiencing extreme benefit whilst others are not responsive. The leukotriene receptor antagonists can be helpful in childhood asthma where they are especially effective against exercise-induced bronchospasm. They also show benefit in associated rhinitis, and may have other useful effects in atopic disorders such as urticaria.

As yet there is no way of predicting the responder patient so a trial period of therapy with monitoring of disease by peak flow or symptom score chart is sensible. The side effects of leukotrienes are essentially mild and equate to those of placebo in pediatric studies.

Epinephrine (adrenaline)

Children who are likely to undergo anaphylaxis should have with them at all times two injections of epinephrine (adrenaline). Some disagreement exists about the recommended dose of epinephrine. Although almost all of the literature agrees on 0.01 mg/kg in infants and children, North American guidelines suggest a dose in adults of 0.3–0.5 ml of adrenaline diluted 1 : 1000 (0.3–0.5 mg), whereas European literature suggests 0.5–1.0 mg. No comparative trials have been conducted. For most patients only one dose is needed, although repeat doses may be given at 5-minute intervals until symptoms improve. Each parent, carer, school teacher, nurse who looks after the child at any stage should be trained in the use of these emergency devices and, if old enough, the child should also be trained.

Each child should have a proforma detailing when and how to use this rescue treatment. The form needs to be countersigned by anyone who is looking after the child. The form should detail the likely allergen, the possible reactions and those which need merely antihistamines (localized itching or rash), compared to those which require epinephrine therapy such as a generalized reaction involving either collapse or airway problems.

At school or nursery there should be a box with the child’s name on it containing instructions plus all the rescue medication. A second box with the child’s name on it with special safe food treats to use if other children are having food containing the relevant allergens is sensible.

Our practice is to review these children and their carers annually to ensure that they are still capable of using the epinephrine device and know when such use is appropriate.

Families with this problem need careful advice and counseling. In the UK this is often provided by the Anaphylaxis Society.

Any child with a tendency to anaphylaxis should also be tested for asthma. If there is any evidence of asthma then regular prophylactic therapy with inhaled corticosteroid must be instigated and used regularly.

▪ Immunotherapy

This is the only form of treatment which can alter the natural history of allergic disease.

Classical Immunotherapy

Subcutaneous injection of the relevant allergen, determined by history and skin prick tests, can result in a reduction of allergic responsiveness over time. Initial injections involve minute quantities of allergen given usually at weekly intervals with gradual increase in dose. There is a decrease in frequency once the up dosing phase is over and maintenance level reached. Therapy is usually continued for 3 years and the effects persist for at least another 4 years. The mechanism is thought to be via reduction of Th2 responsiveness by T-regulatory cells towards Th1 or Th0 responses and by the production of allergen-specific IgG which blocks IgE-facilitated antigen presentation.

Unfortunately, side effects can be very severe and can involve asthma and anaphylaxis. Deaths have been reported in young adults, usually those with concomitant chronic asthma. Therefore in the UK subcutaneous immunotherapy is contraindicated in chronic asthma.

Immunotherapy in nonasthmatic children appears relatively safe and has been reported as reducing the progression from allergic rhinitis to asthma and reducing new allergic sensitization.

Other Forms of Immunotherapy

Since classical immunotherapy involves multiple hospital and clinic visits and injections it is not popular with many patients and their families. Other forms have been sought including oral, nasal, sublingual, and swallow immunotherapy. Of these sublingual immunotherapy appears to offer promise since several recent trials have proved positive. A Cochrane meta-analysis suggests that the therapy is effective, though probably less so than subcutaneous therapy. It is however far safer, with major side effects being sore throat and occasional difficulty in swallowing after the first dose. For this reason the first dose is always given in the hospital setting, but subsequent doses are given on a daily basis at home. Unfortunately, the high dose of allergen needed (75 000 international units for grass pollen) renders this an expensive form of treatment.

In the future, immunostimulatory molecules may provide additional benefit with a concomitant reduction in allergen dose.

▪ Other Therapies

Douching with saline has been proved effective in allergic rhinitis in children. Sprays are available over the counter for this purpose.

For refractory rhinorrhoea, ipratropium bromide 0.03% may be helpful.

Probiotic therapy given to the mothers of children predisposed to atopic disease in the last 6 weeks of pregnancy and to the child for the first 6 months of life resulted in a reduction in the expected incidence of atopic dermatitis in the actively treated group. The incidence of asthma and rhinitis was not affected by this treatment. Further studies obviously need to be undertaken.

Future Directions

Combinations of therapy which may prove useful include the following:

• Anti-IgE may be beneficial as an adjunct to immunotherapy in severe cases.
• CpG motifs (C = cytosine, G – guanine; only found in bacterial DNA) plus allergen immunotherapy.
• Probiotic plus allergen immunotherapy.

Education

A vital part of pediatric management is education of the whole family regarding the nature of allergy, the need for long-term treatment in many patients, plus reassurance about safety of the treatment being advised. Demonstration of the correct use of nasal sprays, inhalers, spacers, wet wraps, and Epipens by a trained nurse, plus provision of a telephone helpline for further advice, is helpful and probably improves concordance with therapy.

Conclusion

Allergic children often have complex problems affecting more than one organ. They and their parents/carers can be helped by accurate diagnosis and effective therapy to lead happier, healthier lives.

SUGGESTED READING

1 Kalliomaki M, Salminen S, Poussa T, Arvilommi H, Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomized placebo-controlled trial. Lancet. 2003;361(9372):1869-1871.

2 Wilson DR, Torres Lima M, Durham SR. Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev. 2003. CD002893.

3 Alves B, Sheikh A, Hurwitz B, Durham SR. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2000. CD001936.

4 Stevenson J. ETAC Study Group: Relationship between behavior and asthma in children with atopic dermatitis. Psychosom Med. 2003;65:971-975.

5 Diepgen TL/Early Treatment of the Atopic Child Study Group. long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months. Pediatr Allergy Immunol. 2002;13:278-286.

6 Stevenson J, Cornah D, Evrard P, et al. ETAC Study Group: long-term evaluation of the impact of the H1-receptor antagonist cetirizine on the behavioral, cognitive, and psychomotor development of very young children with atopic dermatitis. Pediatr Res. 2002;52:251-257.

7 Wolkerstorfer A, Wahn U, Kjellman NI, Diepgen TL, De Longueville M, Oranje AP. Natural course of sensitization to cow’s milk and hen’s egg in childhood atopic dermatitis: ETAC study group. Clin Exp Allergy. 2002;32:70-73.

8 Warner JO, on behalf of the ETAC Study Group. A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment follow-up. J Allergy Clin Immunol. 2001;108:929-937.

9 Simon FE. Prospective, long-term safety evaluation of the H1-receptor antagonist cetirizine in very young children with atopic dermatitis. ETAC Study Group. Early Treatment of the Atopic Child. J Allergy Clin Immunol. 1999;104(2 Pt 1):433-440.

10 Bustos GJ, Bustos D, Romero O. Prevention of asthma with ketotifen in preasthmatic children: a three-year follow-up study. Clin Exp Allergy. 1995;25:568-573.

11 Iikura Y, Naspitz CK, Mikawa H, et al. Prevention of asthma by ketotifen in infants with atopic dermatitis. Ann Allergy. 1992;68:233-236.

12 Kharitonov SA, Walker L, Barnes PJ. Repeatability of standardized nasal nitric oxide measurements in healthy and asthmatic adults and children. Respir Med. 2005;99:1105-1114. EPub 2005 Mar 17.

13 Corbelli R, Bringolf-Isler B, Amacher A, Sasse B, Spycher M, Hammer J. Nasal nitric oxide measurements to screen children for primary ciliary dyskinesia. Chest. 2004;126:1054-1059.

14 Kurukulaaratchy RJ, Matthews S, Arshad SH. Defining childhood atopic phenotypes to investigate the association of atopic sensitization with allergic disease. Allergy. 2005;60:1280-1286.

15 Hahn EL, Bacharier LB. The atopic march: the pattern of allergic disease development in childhood. Immunol Allergy Clin North Am. 2005;25:231-246.

16 Spergel JM. Atopic march: link to upper airways. Curr Opin Allergy Clin Immunol. 2005;5:17-21.

17 Gilbert TW, Morgan WJ, Zeiger RS, et al. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol. 2004;114:1282-1287.

18 Mastrandrea F. The potential role of allergen-specific sublingual immunotherapy in atopic dermatitis. Am J Clin Dermatol. 2004;5:281-294.

19 Heymann PW, Carper HT, Murphy DD, et al. Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. J Allergy Clin Immunol. 2004;114:239-247.

20 Gruber C, Niggemann B, Wahn U. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol. 2004;113:925-931.

21 Leung DY, Boguniewicz H, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004;113:651-657.

22 Wuthrich B, Schmid-Grendelmeier P. The atopic eczema/dermatitis syndrome. Epidemiology, natural course, and immunology of the IgE-associated (“extrinsic”) and the nonallergic (“intrinsic”) AEDS. J Investig Allergol Clin Immunol. 2003;13:1-5.

23 Yimyaem P, Chongsrisawat V, Vivatvakin B, Wisedopas N. Gastrointestinal manifestations of cow’s milk protein allergy during the first year of life. J Med Assoc Thai. 2003;86:116-123.

24 Austin JB, Kaur B, Anderson HR, et al. Hay fever, eczema, and wheeze: a nationwide UK study (ISAAC, international study of asthma and allergies in childhood). Arch Dis Child. 1999;81:225-230.

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