Allergic diseases

Allergic disease is an increasingly common problem in the community, affecting up to 40% of children. The allergic conditions include asthma, eczema, allergic rhinitis and allergies to food, insects or drugs. Children who have allergic diseases are often atopic; that is, they produce IgE antibodies to common allergens such as house dust mite, animal dander, pollens and foods. The presence of IgE antibodies (i.e. sensitisation) to these allergens does not necessarily cause disease; however, exposure to an allergen to which a patient is sensitised may exacerbate or precipitate symptoms (e.g. inhalant, food, insect or drug allergy).

Allergy tests include skin-prick tests (SPT) and radioallergosorbent tests (RAST). Both detect specific IgE antibodies against allergens. SPT and RAST are available for numerous allergens. Testing should be individualised for each clinical situation and is used to confirm suspected allergy. Testing to ‘routine’ allergen panels is not recommended.

Skin-prick tests

• Preferred because they are highly sensitive, inexpensive, simple and rapid.
  
• Age is not a contraindication to skin-prick testing. Skin-prick testing can be done from early infancy, but a negative skin test in infancy does not preclude the later development of sensitisation.

Limitations

• SPTs have a poor positive predictive value (<50%) for the presence of clinical allergy in the absence of a previous clinical reaction. The finding of a positive SPT to a food in this context does not necessarily indicate presence of clinical allergy.
  
• May be affected by medications. Antihistamines should be withheld for 2–4 days. Inhaled â2-agonists, oral theophylline and corticosteroids do not interfere with SPTs.
  
• Dermatographism may complicate the interpretation of SPTs. Saline and histamine controls must be done.

Indications

• Evaluation of suspected IgE-mediated food reactions. A negative SPT almost eliminates the possibility that a food will induce an IgE-mediated immediate reaction. A positive SPT must be correlated with the history. When there is a clear history of reaction to a specific food, a positive SPT confirms food allergy. If the history is uncertain, a positive test only indicates the possibility of food allergy and a cautious supervised inpatient food challenge in a specialist centre is required to confirm the presence or absence of allergy. SPT should not be routinely used to screen for the presence of food allergy. If there is a high suspicion of food allergy, refer the child to a specialist.
  
• Skin-prick testing to the relevant environmental allergens can identify major allergic factors that may exacerbate or contribute to symptoms and can guide the application of appropriate environmental modification. Consider performing in:

– Patients with asthma or rhinitis who require maintenance steroid therapy to control symptoms, including patients with frequent episodic asthma.

– Patients with moderate or severe eczema despite appropriate medical therapy.

Radioallergosorbent tests

• Have reduced sensitivity, are more expensive and have a slower turnaround time.
  
• Are useful alternatives to SPTs if there is dermatographism, widespread skin disease, or if antihistamines cannot be discontinued.
  
• May be useful in the primary care setting as initial limited investigation to confirm a suspected, simple allergy (e.g. confirmation of IgE-mediated food allergy to cow’s milk, egg or peanut; or assessment for HDM, pet dander or pollen sensitisation in asthma or allergic rhinitis).

Interpretation of SPT and RAST

• A positive SPT or RAST only identif es the presence of specific IgE against an allergen (i.e. sensitisation).
  
• A positive test does not prove that an allergic disease exists, nor does it necessarily predict that the patient will develop symptoms on exposure to that substance. For example, only 50% of individuals with a positive SPT to a food allergen will develop symptoms when exposed to that food.
  
• In general, the larger the SPT and/or the higher the RAST result, the greater the likelihood of clinical allergy.

In vivo challenges

• In vivo challenges are primarily used for diagnosis of food allergy and the evaluation of antibiotic reactions.
  
• They may also be used to assess the development of tolerance to foods.
  
• They are highly specialised procedures that should only be done in specialist centres with facilities for the early identif cation and management of allergic reactions.
  
• They are usually not done if there is a clear history of food allergy or anaphylaxis and the trigger has been identif ed.
  
• Cautious inpatient challenge is used to test the clinical relevance of a positive SPT where the history is unclear.
  
• In these circumstances, less than half of the patients with a positive SPT to a food will react to the food during a challenge. In general the larger the SPT size the greater the likelihood of clinical allergy. However, the size of a SPT does not correlate with the severity of reaction.
  
• Diagnosis of delayed non-IgE-mediated reaction to foods requires a formal food challenge, as there are no skin-prick or blood tests for this type of food reaction.

Allergic rhinitis

Traditionally, allergic rhinitis has been classified as perennial (symptoms throughout the year, commonly due to HDM sensitisation), seasonal (symptoms occurring in a particular season, i.e. seasonal rhinitis/hay fever) or related to a specific allergen (e.g. cats or horses). More recently an alternative classification has been proposed which describes symptoms as ‘persistent’ (symptoms for >4 days a week and >4 weeks a year) or ‘intermittent’ (symptoms <4 days a week or <4 weeks a year), and as mild, moderate or severe (Fig. 19.1). Both classification systems may be used in combination.

Diagnosis requires the demonstration of an allergic basis for symptoms. Other causes of rhinitis should be considered: nonallergic rhinitis with eosinophilia syndrome (NARES), infective rhinitis, vasomotor rhinitis, hormonal rhinitis or rhinitis medicamentosa (rhinitis induced by excessive use of topical decongestants).

Fig. 19.1 Classification of allergic rhinitis. (Reproduced with permission from ARIA Workshop Executive Summary. (2002) Allergy. 57; 2002: 841–855.)

Perennial allergic rhinitis

• Can occur at any age and is more common than seasonal rhinitis in preschool and primary school children.
  
• Sneezing and congestion are prominent especially on waking in the morning. There may be significant nasal obstruction and snoring at night.
  
• House dust mite is the major allergen involved but concurrent sensitivity to pollens is also common.
  
• Consider the possibility of perennial allergic rhinitis in any atopic child – this diagnosis is frequently missed.
  
• Any patient with allergic rhinitis and significant obstructive symptoms is at risk of obstructive sleep apnoea.

Seasonal allergic rhinitis

• More frequent in teenagers and young adults.
  
• Seasonal sneezing, itching and rhinorrhoea are prominent. Nasal symptoms are frequently associated with symptoms of itchy, red and watery eyes.
  
• Symptoms occur in the relevant pollen season.
  
• In general, trees pollinate in early spring, grasses in the late spring and summer, and weeds in the summer and autumn, although there is some overlap. Rye grass is the commonest provoking antigen in Australia, but multiple sensitivities to tree, grass and weed pollens are also seen.

Examination

No examination is complete until you have looked in the nose!

• Assess the nasal mucosa and nasal airflow.
  
• Pale oedematous mucosa and swollen turbinates indicate ongoing rhinitis. In seasonal rhinitis, examination may be normal outside the relevant pollen season.

Management

• Topical corticosteroid nasal sprays are the treatment of choice for both allergic and non-allergic rhinitis. The presence of congestion, nasal drainage or persistent symptoms (>4 days a week and >4 weeks per year) warrants treatment with topical corticosteroid nasal sprays. In general, full strength (prescription requiring) forms of nasal corticosteroid are recommended where there is significant rhinitis. Refer to Table 19.1.
  
• Continuous topical corticosteroid therapy for allergic rhinitis has not been shown to cause suppression of the hypothalamic–pituitary–adrenal axis. In seasonal rhinitis, commence treatment 1 month prior to the relevant pollen season and continue over the symptomatic period.
  
• Topical sodium cromoglicate is generally not effective.
  
• Topical anti-inflammatory treatment must be taken regularly for benefit. Improvement may not be apparent for 3–4 weeks and an initial course of treatment should last for 2–3 months.
  
• Allergen avoidance measures should be considered for patients using topical anti-inflammatory therapy. These are most feasible with certain allergen triggers (e.g. pets in animal dander sensitivity, house dust mite allergen in perennial rhinitis with dust mite sensitivity). Dust mite reduction involves washing bedding in hot water weekly, removing soft toys and soft furnishings from the bedroom, vacuuming carpet and damp-dusting hard surfaces (including hard flooring) weekly and using allergen-impermeable covers for the mattress, pillow and doona or duvet. Avoidance of grass pollens is generally not possible.
  
• Antihistamines are not helpful in relieving nasal obstruction and are not indicated as first line treatment for significant rhinitis. Antihistamines may be used for intermittent symptoms (<4 days per week or <4 weeks a year) in the absence of congestion or signifi-cant rhinorrhoea (see Table 19.2). They may also be useful for control of break-through sneezing, itching or rhinorrhoea while on topical corticosteroid therapy or prophylactically before allergen exposure in allergen-specific rhinoconjunctivitis (e.g. cats or horses). Second-generation less-sedating antihistamines (loratadine and cetirizine) are well tolerated. Terfenadine and astemizole should be avoided as they may cause cardiac arrhythmia when taken with other medications.

Table 19.1 Nasal corticosteroids

Table 19.2 Antihistamines

Allergic conjunctivitis

Food allergy

– Give Allergy Action Plan (without an EpiPen) which is available from www.allergy.org.au

• Anaphylaxis:

– Avoid causative food.

– Refer for specialist allergy advice.

– In the interim period, consultation with a clinical immunologist, allergist, paediatrician or emergency physician should be sought to determine the need for an EpiPen.

– Prescription of an EpiPen must be accompanied by education on its use and provision of an Anaphylaxis Action Plan (available at www.allergy.org.au).

– Dose for EpiPen:

   Child >20 kg, EpiPen 300 mcg.

   Child 10–20 kg, EpiPen Jr 150 mcg.

   Child <10 kg, not usually recommended (discuss with specialist).

Note: This is different to current product information dosage guidelines, where Epipen 300 mcg is recommended for children >30 kg.

Investigation

• Confirm the presence of mild–moderate IgE-mediated reaction (not anaphylaxis) to the suspected food if it is one of the common food allergens (e.g. milk, egg, peanut) with a SPT or RAST to that food. A negative SPT or RAST almost eliminates the possibility of an immediate IgE-mediated reaction to that food. A positive SPT or RAST confirms food allergy if there is a convincing history. If the history is uncertain, further evaluation by formal challenge is required. Parents should not challenge children with a suspected food at home as severe reactions and even death have occurred.
  
• Performing SPT or RAST to other common food allergens (egg, milk, wheat, soy, peanut, shellfish, fish) to which the child has not yet been exposed may be indicated.

Refer to paediatric allergy specialist

• Children with anaphylaxis.
  
• Children suspected of having multiple food allergies, including children with confirmed allergy to one food and not yet exposed to one or more of the other common food allergens.
  
• Children with an unclear history or those who are likely to require retesting or challenge.
  
• Children with multiple atopic diseases.

Non-IgE-mediated and mixed IgE/non-IgE mediated food reactions

• Non-IgE-mediated food reactions are much less common.
  
• Generally these are delayed reactions occurring 24–48 h after food ingestion, although some infants may have immediate non-IgE-mediated food reactions that occur within 1–2 h of food ingestion.
  
• Typically, gastrointestinal symptoms are prominent with vomiting, diarrhoea and abdominal cramps. Occasionally there may be malabsorption, weight loss or slow weight gain. Worsening of eczema may also occur.
  
• In severe cases (e.g. food protein induced enterocolitis syndrome, FPIES) there may be cardiovascular collapse.
  
• Cow’s milk and soy proteins are the most common foods implicated.
  
• Diagnosis requires elimination of the suspected food followed by formal food challenge.
  
• Skin-prick testing is usually negative, but may be positive if there is a mixed aetiology, which includes some IgE-mediated reaction.
  
• Treatment is with avoidance of the offending food. Specialist consultation is recommended.
  
• Infants with non-IgE-mediated cow’s milk allergy should be given an extensively hydrolysed protein formula.
  
• 50% of cases resolve within 1–2 years.

Food-protein-induced enterocolitis syndrome (FPIES)

• A form of non-IgE mediated food allergy seen in young infants usually <6 months.
  
• Usually due to cow’s milk, soy or cereals (e.g. rice).
  
• Can be seen in exclusively breast-fed infants.
  
• Can be seen in older children with other foods (e.g. egg).
  
• Typically delayed onset (>1–2 h) of projectile vomiting (that may become bilious) and protracted diarrhoea.
  
• May be associated with hypotension in 15% of cases (significant pallor and lethargy) that may be misdiagnosed as sepsis.
  
• Stool: occult blood, polymorphonuclear cells (PMNs), eosinophils, reducing substances.
  
• Symptoms resolve within 72 h of substance elimination.

Food-protein-induced enteropathy

• A spectrum of disorders that present with protracted diarrhoea, vomiting in 2/3 and slow weight gain.
  
• Cow’s milk is the most frequent cause. Others include soy, egg, wheat, rice, chicken and fish.
  
• It has been suggested that coeliac disease represents the most severe form.
  
• Endoscopy/biopsy shows patchy villous atrophy with cellular infiltrates.
  
• Symptoms resolve after 6–12 weeks of elimination of the responsible food allergen. Improvement in appetite, vomiting, and diarrhoea may occur within 2–4 weeks; however, weight gain may take 8–12 weeks.

Food-protein-induced colitis

• First weeks to months of life.
  
• Usually cow’s milk or soy, but 50% of infants with this condition are breast-fed.
  
• Present with isolated bloody stool (gross or occult).
  
• Otherwise clinically well.
  
• Endoscopy shows mucosal oedema, ulceration, erosions that are restricted to distal bowel.
  
• Symptoms resolve within 72 h of elimination of the offending food.

Eosinophilic oesophagitis

• May be a cause of gastroesophageal reflux (GOR).
  
• Up to 40% of GOR in infants <1 year that is unresponsive to medical therapy may be due to cow’s milk allergy.
  
• May present as infantile colic.
  
• Infants often have other allergic disease, elevated IgE, peripheral blood eosinophilia and positive SPT to foods.
  
• Can occur in older children and adults, where it commonly presents as dysphagia.
  
• Endoscopy shows eosinophilic infiltrates in the oesophagus.
  
• Symptoms resolve within 72 h of elimination of the offending food.

Eosinophilic enteritis

• Presents with postprandial symptoms of nausea, vomiting, abdominal pain and diarrhoea.
  
• Other presentations include slow weight gain in infants, iron deficiency anaemia, hypoalbuminaemia and steatorrhoea in adults.
  
• Endoscopy shows eosinophilic infiltrates in the stomach and/or duodenum.
  
• Symptoms resolve within 72 h of elimination of the offending food.

Allergic factors in atopic dermatitis (eczema)

Allergic factors in asthma

Urticaria and angio-oedema

• Symptomatic: treat with second-generation antihistamines. Cetirizine is particularly effective (for doses see Table 19.2).
  
• Manipulation of the diet is generally not helpful and is not indicated in children. A small number of subjects may respond to a preservative and colouring-free diet; however, this should only be considered if symptoms are particularly troublesome.
  
• In resistant cases, the combined use of an H2 antihistamine (cimetidine) with standard H1 antihistamines may be considered but success is limited.

Hereditary angio-oedema

Refer to the Clinical Practice Guideline www.rch.org.au/clinicalguide [C1 Esterase Inhibitor Deficiency].

• Adrenaline, antihistamines and corticosteroids have no role in the management.
  
• Tranexamic acid may be considered in mild episodes to shorten the duration of symptoms.
  
• Severe angio-oedema episodes can be fatal. I.v. C1 esterase inhibitor concentrate should be administered.
  
• Children undergoing surgery: preoperative discussions with the anaesthetist, immunologist and intensive care unit are recommended. Consider the use of danazol for 5–10 days before surgery.

Antibiotic allergy

Latex allergy

Immunotherapy

Guidelines for the investigation and treatment of immunodeficiency

• An FBE with differential and immunoglobulin levels (IgG, IgA and IgM) will identify the vast majority of treatable primary immunodeficiencies (e.g. agammaglobulinaemia, common variable immune deficiency, selective IgA deficiency and SCID). IgG subclass levels should not be done as part of a basic immunological screen, as isolated IgG subclass deficiency is of uncertain clinical significance.
  
• Note that immunoglobulin levels vary with age and are lower in infancy and early childhood. It is therefore important that the relevant age-related reference ranges are used (see Table 19.3).
  
• If these tests are normal and the clinical suspicion of immune deficiency persists, referral to a clinical immunologist for further evaluation is indicated.

Specific antibody responses

• Only consider when there is evidence of persistent or recurrent suppurative upper and/or lower respiratory tract infection and hypogammaglobulinaemia has been excluded.
  
• Ask the question: ‘If an antibody defect is found, does this clinical condition warrant regular gammaglobulin therapy?’
  
• The most important question is whether appropriate antibodies can be made to specific protein and polysaccharide antigens. Abnormal IgG subclass levels may be a clue to an evolving antibody deficiency. However, isolated abnormalities of IgG subclasses with normal specific antibody responses rarely result in clinical problems. In general, regular gammaglobulin therapy is only indicated for severe recurrent infections when a specific antibody defect has been identif ed.

T-lymphocyte numbers and function

• Consider a chest radiograph to look for absent thymic shadow when a T-lymphocyte defect is suspected.
  
• Specialised T-lymphocyte function tests are used to help in the diagnosis of SCID and Di George syndrome (absent thymus, hypocalcaemia and cardiovascular anomalies). Referral to an immunologist is recommended if these conditions are suspected.

Neutrophil function tests

• Specific defects of neutrophil function (e.g. chronic granulomatous disease and leucocyte adhesion deficiency 1) are very rare. They are almost always associated with gingivitis and careful examination of the mouth is important when considering abnormalities of neutrophil function.
  
• Markedly elevated circulating neutrophil counts and delayed separation of the umbilical cord (>4 weeks) suggest the possibility of a leucocyte adhesion deficiency.
  
• Suspected cases of defective neutrophil function should be referred to an immunologist for further evaluation.

Table 19.3 Immunoglobulin normal ranges (5^th to 95^th percentile)

Source: Davis et al. IFCC-standardised pediatric reference intervals for 10 serum proteins using the Beckman Array 360 system. Clin Biochem, Oct 1996; 29(5): 489–92.

Complement studies

• Deficiencies of complement are rare.
  
• The best screening test for congenital deficiency is a CH50, which measures the function of the classical complement pathway.

HIV tests

HIV testing should be considered in the setting of recurrent, severe or unusual infections, particularly if there is hypergammaglobulinaemia. Testing requires informed consent and appropriate counselling. This specialised immune function testing is best undertaken in consultation with a clinical immunologist.

Immunodeficiency treatment

Immunisation

See also chapter 9, Immunisation.

• As a general rule, all live viral vaccines should be avoided in immunodeficiency unless advised by a specialist.
  
• Patients with a T-cell defect and their immediate family should receive the killed injectable polio (Salk) vaccine, not live oral polio vaccine. This is now the standard form of polio vaccine in Australia.
  
• In certain circumstances, measles immunisation may be given to patients with a T-cell defect (e.g. Di George syndrome or paediatric HIV infection) as the risks of wild-type measles infection are considerable, but adverse reactions to the vaccine are largely theoretical.
  
• In cases of antibody deficiency, T-cell deficiency and combined immunodeficiency, immunisation with killed vaccines will not promote a significant antibody response.
  
• If the patient is on immunoglobulin replacement therapy, passively acquired antibody will prevent viral infections such as measles and chickenpox. See also chapter 9, Immunisation.
  
• Patients of any age with asplenia should be immunised with Hib, pneumococcal and meningococcal vaccines.

Immunoglobulin therapy

• Immunoglobulin therapy (400–600 mg/kg i.v. monthly) is given when a significant deficiency of antibody production is demonstrated in a patient with clinically significant infections (usually sinopulmonary).
  
• In hypogammaglobulinaemia, immunoglobulin therapy is generally lifelong.
  
• In patients with combined immunodeficiency, immunoglobulin treatment may be discontinued once normal B-cell function can be demonstrated following bone marrow transplantation.
  
• In patients with IgG subclass deficiency, immunoglobulin therapy is indicated only if a significant functional antibody deficit is demonstrated and the patient has significant symptoms. In this instance, a trial of immunoglobulin therapy may be used for a restricted period of time to determine if there is clinical benef t. This should only be instituted in conjunction with a clinical immunologist.
  
• The f nding of a low immunoglobulin subclass level alone is not a sufficient indication for immunoglobulin therapy. Immunoglobulin therapy is not indicated for isolated IgA deficiency. These patients should be referred to a specialist for further evaluation and/or follow up.
  
• Three forms of immunoglobulin are currently available for i.v. administration in Australia: Intragam P (produced from Australian plasma), Octagam and Sandoglobulin (imported products).

– IgG concentrations and rates of administration differ in the different products and need to be taken into account when these products are administered.

• The subcutaneous route for administration of immunoglobulin for replacement purposes is being used widely overseas and increasingly in Australia. Potential benef ts include ease of administration in patients where venous access is limited and capacity for home immunoglobulin delivery. A more concentrated immunoglobulin product is used for these purposes.

Antibiotics

• As immunoglobulin therapy does not provide significant levels of IgA antibody (the mucosal surface antibody), aggressive treatment of respiratory infections in patients with antibody deficiency is important in order to prevent bronchiectasis and permanent damage to the lungs.
  
• In severe cases, prophylactic rotating antibiotics are used to prevent recurrent severe sinopulmonary infections.
  
• Antibiotic prophylaxis with cotrimoxazole 2.5/12.5 mg/kg (max. 80/400) p.o. b.d. 3 days per week is indicated in patients with T-cell or combined immune deficiency to prevent infection with pneumocystis.

Use of blood products

• If it is suspected or known that the patient has a significant T-cell deficiency, blood products that contain cells (e.g. whole blood, packed red cells or platelets) should be irradiated to prevent graft versus host disease.
  
• In infants with SCID or any significant T-cell deficiency, attempts should be made to provide cytomegalovirus (CMV) antibody-negative blood, as CMV infection can be a significant problem in such patients. If this is not possible, the blood product should be filtered to remove contaminating white blood cells as it is delivered to the patient. If possible, Epstein–Barr virus (EBV) antibody-negative blood should also be given, as EBV can induce lymphoproliferative states in severely immunodeficient subjects.
  
• Patients with IgA deficiency may develop IgE antibodies to IgA and have an anaphylactic reaction to blood products containing IgA (i.v. immunoglobulin, packed red cells, platelets). Immunoglobulin preparations that are depleted of IgA should be used and packed cells or platelets should be washed four times in physiological saline before infusion.

Bone marrow transplantation

• Bone marrow transplantation is the definitive treatment for SCID. It may also be useful for the treatment of other immune deficiencies (e.g. chronic granulomatous disease, hyper IgM syndrome).
  
• The cure rate can be of the order of 80% if the transplant is from a matched sibling or a parent.
  
• Survival is less, in the order of 50%, if the transplant is only partially matched and from an unrelated donor.

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