Allergic Disease
Introduction
Allergic diseases are common: it has been estimated that 15% of the population will suffer from some sort of allergic reaction during their lifetime. It is clear that there has been an increase in atopic diseases since the Second World War. The precise cause of this change is unknown but undoubtedly reflects changes in lifestyle, in particular ‘improvements’ in housing, rendering houses more heavily colonized with dust mites. A reduction in breastfeeding may also have contributed, particularly to atopic eczema. The evidence for air pollution, particularly car exhaust fumes, contributing to the increase is conflicting. It is also likely that the improvements in public health, leading to elimination of parasitic infections in the Western world, may contribute through a lack of physiological function for the IgE-mast cell axis. This has been formalized in the hygiene hypothesis (‘dirt is good for you!’).
In the mind of the public, allergy is responsible for all ills, but in most cases the blame is wrongly apportioned. This perception has led to a proliferation of alternative practices pandering to these beliefs and using diagnostic techniques and treatments that have little to do with allergy as understood by immunologists and more to do with the gullibility of members of the public. That these practitioners can flourish indicates that we are failing our patients in being unable to cure their perceived illnesses, either through lack of knowledge or through lack of appropriate allergy facilities.
Anaphylaxis
Anaphylaxis represents the most severe type of allergic reaction and a medical emergency.
Cause
Sudden massive degranulation of mast cells, releasing histamine.
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.
Presentation
Usual features are:
generalized giant urticaria
angioedema, often involving face, lips, tongue, and larynx, causing stridor
bronchospasm
hypotension with loss of consciousness
gastrointestinal symptoms (nausea, vomiting, abdominal cramps, diarrhoea).
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.
Substances causing anaphylaxis
Any substance may cause anaphylaxis, but the most common causes are as follows.
Venoms: bee and wasp venoms.
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).
In some cases a cofactor is required for the reaction, such as exercise or concomitant aspirin ingestion with the food. It is probable that these cofactors alter the amount of allergen entering the circulation.
Immunological features
Involvement of IgE requires prior exposure to sensitize the patient. In childhood, sensitization to peanut may occur via formula milk which may contain peanut oil. Following sensitization, only tiny amounts may be required to trigger subsequent reactions.
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-Larginine 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.
Immunological diagnosis (see Box 3.1)
History is all-important, particularly the timing of reaction in relation to the suspected trigger. If the trigger is not clear, a detailed review of all exposures over the preceding 24 hours is required.
Reaction should be graded.
Mild: a feeling of generalized warmth, with sensation of fullness in throat, some localized angioedema and urticaria, but no significant impairment of breathing or features of hypotension.
Moderate: as for mild, but with more widespread angioedema and urticaria, some bronchospasm, and mild gastrointestinal symptoms.
Severe: intense bronchospasm, laryngeal oedema, with severe shortness of breath, cyanosis, respiratory arrest, hypotension, cardiac arrhythmias, shock, and gross gastrointestinal symptoms.
Attention must be paid to other conditions which may appear similar clinically:
pulmonary embolus
myocardial infarction (but this may follow anaphylaxis in those with pre-existing ischaemic heart disease)
hyperventilation
hypoglycaemia
vasovagal reactions
phaeochromocytoma
carcinoid
systemic mastocytosis
rarely, the symptoms may be factitious (typically occur in those who also have true anaphylaxis).
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.
Box 3.1 Testing for anaphylaxis
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Management of anaphylaxis
Immediate management comprises adrenaline (epinephrine) given intramuscularly in a dose of 0.5-1mg (0.5-1mL of 1:1000) for an adult. The dose can be repeated if required.
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.
Cochrane Reviews of antihistamines and steroids in the treatment of anaphylaxis conclude that evidence is lacking for both, but custom and practice recommend continued use.
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.
For venom-allergic patients with ischaemic heart disease, there may be advantages of continuing with β-blockers
Angiotensin-converting (ACE) inhibitors should be avoided, as bradykinin-mediated effects will be worse during reactions (increased severity).
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.
Indications for prescription of adrenaline for self-injection (EpiPen®, Anapen®, Jext®)
Adrenaline for self injection should be given when:
the patient has had a severe allergic reaction
there is a risk of re-exposure or the allergen cannot easily be avoided
the patient has had a moderate reaction, but access to rapid medical assistance is impossible
the patient has asthma—reactions are likely to be more severe
pregnancy is not a contraindication, as the risk to the fetus from hypoxia due to anaphylaxis is greater than the risk of adrenaline.
Adrenaline should not be given when:
the reaction is mild (urticaria or urticaria with minimal angioedema not involving throat)
the allergen is avoidable
the patient is unable to use an injection device
the patient has or is at risk of ischaemic heart disease; this may include the elderly
the patient is on β-blockers—this is a relative contraindication and there is some evidence that the effect is not significant: however, it is recommended that the dose of adrenaline be halved in patients on β-blockers to avoid paradoxical hypertension due to unopposed α-adrenergic activity
the patients is on tricyclic antidepressants or abuses cocaine (increased risk of cardiac arrhythmias).
Problems with adrenaline self-injection devices
Confusingly, Anapen® and EpiPen® are fired differently; because of this, they should not be interchanged.
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).
‘Anaphylactoid’ reactions
These may be every bit as severe as IgE-mediated reactions. In most cases they are due to activation of mast cells directly or via other mechanisms that will indirectly activate mast cells.
Causes
The most common causes are as follows.
Direct mast-cell stimulation: drugs (opiates, thiamine, vancomycin, radiocontrast media, some anaesthetic agents, especially those dissolved in cremophor, tubocurarine), foods (strawberries), physical stimuli (exercise, cold, trauma), venoms.
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).
Immunological diagnosis
History usually gives the clue. No tests are entirely specific. Challenge is very risky.
Tryptase will be elevated.
Specific IgE will not be detectable.
Management
Acute management is the same as for anaphylaxis.
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.
Angíoedema
Angioedema is a deep-tissue swelling that must be distinguished from urticaria. It is rarely itchy, and tends to give discomfort from pressure. In hereditary angioedema and sometimes in idiopathic angioedema, there is often a premonitory tingling before the swelling occurs. Any part of the body (including gut) may be involved.
Causes
Allergic (accompanied by other features such as urticaria, anaphylaxis, etc.).
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).
Idiopathic (rarely involves larynx)—other causes excluded.
Immunological features
Mechanism is thought to involve activation of the kinin system with bradykinin production, leading to tissue oedema.
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.
Diagnosis (see Box 3.2)
History will give useful clues: family history, connective tissue disease, lymphoma (may be occult), drug exposure, association with physical stimuli.
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.
C4 will be low, even between attacks;
C1-inhibitor will be low in type I but high in type II (Chapter 1).
Levels of C2 are said to distinguish acquired from inherited C1-esterase inhibitor deficiency (low in inherited deficiency) but this test is not reliable.
If acquired C1 esterase inhibitor deficiency is suspected, check:
for lymphadenopathy and splenomegaly clinically
serum immunoglobulins
serum and urine electrophoresis;
serum free light chains
Consider chest/abdominal CT scan.
Box 3.2 Testing for angioedema
Acute treatment
Treatment is dependent on the cause.
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.
Purified C1-esterase inhibitor may be required in acquired C1-esterase inhibitor deficiency;
Frequent doses may be required because of the presence of inhibitory antibodies: in severe cases, plasmapheresis and immunosuppression may be required;
FFP is less effective and may actually make the angioedema worse by providing extra substrate.
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.
Table 3.1 Differential diagnosis of facial swelling | ||||||||||||||||||
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Prophylactic treatment
Control may be helped with antifibrinolytics (tranexamic acid, 2-4g/day), or modified androgens (stanozolol 2.5-10mg/day; danazol 200-800mg/day):
monitor LFTs every 4-6 months
regular ultrasound liver (every 1-3 years).
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.Episodic angioedema with eosinophilia
Angioedema associated with cyclic weight gain (up to 15%), fever, urticaria, and eosinophilia.
Cause unknown.
Said to be benign.
Urticaria 1
Urticaria is common, affecting 10-20% of individuals at some time. Urticaria depends on mast cells and histamine is the principal mediator. The reaction may be due to IgE on mast cells or stimuli that directly activate mast cells (see ‘Anaphylactoid reactions’, p.125). Urticaria may occur alone or be accompanied by more systemic symptoms, including angioedema, although (as noted above) histamine is not involved in the latter.
Causes
Urticaria may be acute or chronic (duration more than 1 month). Chronic urticaria is often idiopathic (75% of cases) and rarely associated with allergy. 5% of the population may develop a physical urticaria. Idiopathic urticaria may disappear spontaneously after 1-2 years.
Most common causes are as follows.
Stress.
Infections: in association with common viral infections (concomitant drug therapy usually gets the blame!); Helicobacter; prodrome of hepatitis B, Lyme disease, cat-scratch disease; acute or chronic bacterial infections; parasitic infections.
Allergic: ingested allergens, injected allergens (e.g. cat scratch).
Autoimmune: autoantibodies to IgE and to Fc RI (probably rare); also in association with connective-tissue diseases (antibodies to C1q): SLE.
Physical: sunlight (also think of porphyria), vibration, pressure (immediate and delayed, dermographism), aquagenic, heat.
Cold: familial (autosomal dominant—C1AS1 gene mutations (see Chapter 13)); acquired (cryoglobulins, cryofibrinogen, mycoplasma infections).
Cholinergic (much smaller wheals, often triggered by heat and sweating).
Adrenergic: provoked by stress.
Contact (e.g. urticaria from lying on grass, wearing latex gloves, occasionally from aero-allergens).
Urticaria pigmentosa: rare disease with reddish-brown macules in skin (accumulations of mast cells).
Vasculitis: usually a leucocytoclastic vasculitis, painful not itchy; also serum sickness (immune complex). See also ‘Urticarial vasculitis’, p.325.
Hormonal: autoimmune progesterone-induced urticaria related to menstrual cycle; occasionally other steroids may cause the same reaction; hypothyroidism.
Papular urticaria: related to insect bites (may last several days).
Rare syndromes: Muckle-Wells and related syndromes (see Chapter 14); mastocytosis (see p.132); PUPP (pruritic urticaria and plaques of pregnancy).
Urticaria may occur with iron, B12, and folate deficiency.
Immunological features
Mast-cell activation is the cause, with local release of mediators and activation of other pathways, complement, and kinin.
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.
Diagnosis
The history is everything! The appearances of the lesions may give clues (distinctive lesions in cholinergic urticaria).
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.
Urticaria 2: treatment
Treatment
Urticaria may be difficult to manage, especially cold urticaria. Most common failing is inadequate dosage of antihistamines. The new antihistamines are safe in doses well above the recommended doses and do not interfere with cardiac potassium channels, causing prolonged QT interval.
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.
Doxepin, an antidepressant with potent H1 and H2-blocking activity.
Ketotifen, which has mast-cell stabilizing activity in addition to anti-H1 activity (it increases appetite and is sedating).
Mirtazapine is also a valuable third-line agent and has antihistaminic properties.
Calcium-channel blockers may have some beneficial effect as they stabilize mast cells (nimodipine is said to be better than nifedipine).
β2-agonists (terbutaline) and phosphodiesterase inhibitors (theophylline) may help in rare cases.
Pentoxifylline has been reported to reduce cytokine synthesis by macrophages and may be helpful.
Colchicine is helpful in delayed pressure urticaria but is poorly tolerated.
Leukotriene antagonists may also be helpful in some patients.
Resistant urticaria may respond to low-dose warfarin (mechanism unknown).
Modified androgens (stanozolol, danazol)—require monitoring of LFTs.
Methotrexate—reduces neutrophil accumulation and decreases leukotriene sysnthesis.
Non-familial cold urticaria may respond to cyproheptadine, calciumchannel 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.
Urticarial vasculitis
Urticarial vasculitis is distinguished from ordinary urticaria by the persistence of the lesions for >24 hours. Lesions usually fade to leave brown staining due to erythrocyte extravasation.
Biopsies show evidence of cutaneous vasculitis.
Antihistamines are ineffective.
The condition is discussed in more detail in Chapter 13.
Mastocytosis
Mastocytosis includes a range of related disorders characterized by excessive accumulations of mast cells in tissues.
Classification
Cutaneous mastocytosis:
urticaria pigmentosa
solitary mastocytoma
diffuse cutaneous mastocytosis (rare)
telangiectasia macularis eruptive perstans.
Systemic mastocytosis:
involvement of gut, bone marrow, bone.
Mastocytosis in association with haematological disorders:
leukaemia
lymphoma
myelodysplastic syndrome.
Lymphadenopathic mastocytosis with eosinophilia.
Mast-cell leukaemia (very rare!).
Presentation
Cutaneous involvement with itchy brown macules; Darier’s sign— urticaria on rubbing or scratching cutaneous lesions. Dermographism.
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.
Diagnosis
Biopsy of skin, bowel; bone marrow examination if systemic form expected; endoscopy will be required for gut involvement.
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.
Treatment
High-dose antihistamines (H1 and H2).
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.
Histamine intolerance
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