CME CLINICAL IMMUNOLOGY Clinical Medicine 2011, Vol 11, No 4: 376–80

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tion that is often reversible either sponta neously or with treatment.2 CME Clinical immunology An individual with atopic asthma will have mast cell-bound IgE molecules Joe Unsworth, consultant immunologist, North Bristol NHS Trust residing in their airways. Inhalation of the offending allergen leads to cross- linking of adjacent IgE molecules, causing mast cell activation and release Does this patient have atopic asthma? of mediators including histamine and tryptase. This leads to an immediate or acute-phase asthmatic reaction, peaking F Runa Ali, consultant respiratory physician diagnose allergy, only atopy. To confirm a at 15 minutes and resolving within an and allergist, London Chest Hospital, Barts directly causative allergy, a history also hour. Around 50% of asthmatics also and the London NHS Trust has to be taken. experience a late-phase reaction at about Although atopy can be asymptomatic, six hours, due to a Th2 lymphocyte- The prevalence of asthma and other nonetheless it remains the strongest mediated influx of inflammatory cells, allergic diseases such as eczema, identifiable predisposing factor for eosinophils in particular, and further rhinoconjunctivitis and food allergies developing asthma in the future. A 10–20 release of mediators. This can be repli 3 has increased dramatically over the past fold increased risk may be observed, cated under experimental conditions or 30 years. Asthma, in particular, is a with around 25–30% of atopic subjects in clinical practice when investigating 4 serious global health problem and now developing asthma. The initial sensitisa occupational asthma using an inhaled the most common chronic condition in tion to environmental allergens typically allergen challenge with nebulised soluble industrialised nations,1 with 300 million occurs in childhood. allergen extract (Fig 1). The late-phase people affected worldwide in 2009 and reaction is associated with subsequent 250,000 deaths recorded.2 Atopic asthma Atopic asthmatic reactions: bronchial hyperreactivity and symptoms is the most common form of asthma, pathophysiology to non-specific stimuli, such as exercise affecting 70–90% of children and about and cold air, for about a further week. The Global Initiative for Asthma defines 50% of adult sufferers. Exposure to envi asthma as a chronic inflammatory dis ronmental proteins called allergens is order of the airways with airway hyperre Airborne allergens responsible for the characteristic symp sponsiveness, recurrent wheezing, toms. Allergens are ubiquitous. Outdoor allergens coughing and shortness of breath (partic Knowledge of an individual’s provoking ularly at night or in the early morning), Airborne allergens represent the most triggers via a careful history may lead to and widespread, variable airflow limita common environmental factors that can successful avoidance measures. Where conventional treatment fails, immunomodulation may be considered in the most severe cases. 3.0 Bronchial challenge Normal saline Definitions: atopy versus allergy 2.5 There is a general misconception that ‘atopy’ and ‘allergy’ are interchangeable. Animal dander ‘Atopy’ refers to a hereditary predisposition (litres) (litres)

2.0 to high levels of immunoglobulin (Ig) E 1

against common environmental proteins. FEV This immune state is widespread, affecting 1.5 about 30% of the UK population, but it Early reaction Late reaction can be totally asymptomatic with no need (EAR) (LAR) for avoidance measures. Only a subset of atopic individuals actually develops symp 1.0 toms, which is when the term ‘allergy’ or 0 1 2 3 4 5 6 7 8 24 ‘atopic disease’ may be used. Time (hours) This distinction is important as random skin-prick tests and specific IgE (previously called RAST) tests do not &ŝŐϭ͘/ŶŚĂůĞĚǁŚŽůĞĂůůĞƌŐĞŶĐŚĂůůĞŶŐĞ͘

CME Clinical immunology

induce an atopic asthmatic reaction. The Food allergens containing the active ingredient versus main cause of seasonal asthma in the UK placebo. is grass pollen, particularly perennial rye Typically, food allergy causes multiple, quick onset (minutes, often immediate) and timothy grass. Symptoms peak Assessing the patient during June and July. Symptoms in symptoms and signs. Features include spring are commonly due to tree pollens, oral itch, a widespread urticarial rash, The British Thoracic Society (BTS) guide whereas in late summer and autumn they nausea and gastrointestinal upset, as well line on the management of asthma5 rec may be due to weed pollens and mould as rhinitis, wheeze or other respiratory ommends a diagnosis of asthma if there is spores including Alternaria alternata and symptoms. Isolated respiratory features a combination of characteristic symptoms Cladosporium herbatum. Some asth would be unusual. with suggestive changes in lung function matics are also sensitised to the fungus Patients allergic to birch and certain tests. In most cases, an allergic element to Aspergillus fumigatus. other pollens may also have cross-reac the disease can be elicited by a careful clin tions with various plant-derived foods – ical history alone, without need for further the so-called ‘oral allergy syndrome’. Indoor allergens testing. However, skin-prick testing Classically, raw uncooked fruits and veg (answer within minutes in clinic) or The predominant indoor allergens are etables provoke symptoms but cooking equivalent allergen-specific IgE blood tests from house-dust mites, cats, dogs and destroys the trigger allergens. can help to support (or discount) an cockroaches. Bird feathers (in pillows) allergy diagnosis. can also cause allergy, although testing Non-IgE mediated reactions shows patients to be more commonly Skin-prick testing and specific IgE allergic to the coexisting house-dust Non-IgE mediated immediate asthmatic blood tests mite. Most particles carrying house- reactions may occur with food additives dust mite and cockroach allergens and colourings, including benzoates, sal Soluble extracts of suspected allergens are relatively large (30 �m) and settle icylates, sulphites and tartrazine. are pricked into the skin to provoke a quickly. Therefore exposure is Preservatives such as sulphites are com cutaneous wheal and flare (early-phase largely confined to close exposure to monly sprayed on lettuce to maintain reaction). Antihistamines should be dis fabrics in bedding, carpets and soft freshness. They are also present in dried continued for at least 48 hours before furnishings. fruit, including apricots, as well as in testing and positive (histamine) and neg alcoholic drinks where they occur both ative (diluent) controls must be naturally (from grapes) and are further included. Alternatively, serum levels of Domestic cats added to prevent microbial growth. specific (individual) IgEs against aller Proteins from domestic cats are some of Salicylate sensitivity is another poten gens may be measured (formerly known the most potent elicitors of allergic dis tial problem. High levels of natural sali as RAST tests) to demonstrate sensitisa ease, affecting 10% of the population in cylates are found in grapes, yeast, wines, tion. Unfortunately, unlike aero-aller industrialised countries. The allergen, beers and other foodstuffs, including cer gens, food allergen extracts are poorly carried by small airborne particles, is tain fruit, vegetables, herbs and spices. standardised, affecting the results of both ubiquitous in the environment, Unfortunately, there are no diagnostic skin-prick testing and specific IgE tests, including public places such as schools tests for reactions to additives and/or sometimes generating misleading results. and transportation, and is carried on colourings as the reactions are non-IgE The number of available tests is limited. clothing. Even after permanent removal mediated. Diagnosis depends on suspi With foods, the ‘prick-prick’ method of a cat from the home, it may take cion and the use of elimination diets or, using the actual foods can extend the many months before the reservoir rarely, blinded challenges with capsules repertoire, in many cases generating more allergen concentration returns to normal. Key points Occupational asthma Allergic disease is widespread and causes significant morbidity Occupational asthma can be triggered by a wide range of protein allergens (eg A careful history will identify triggers to avoid rodent urine, grain, flours, latex, harvest Sensitisation can usually be confirmed by skin prick or specific IgE tests moulds and bacillus subtilis enzymes (in detergents)), as well as low-molecular Stepwise treatment should be followed weight chemicals, including pinewood Consider immunological therapies in resistant disease resin, isocyanates, platinum salts and acid anhydrides. KEY WORDS: allergen immunotherapy, allergens, anti-IgE therapy, atopy, desensitisation

CME Clinical immunology

reliable results. Requesting a total IgE level shown to reduce subsequent develop alternative to SCIT, thus far with a better alone is unnecessary and provides no ment of asthma in children with allergic safety profile and greater convenience since information on the specific offending rhinoconjunctivitis.9 it may be self-administered at home.11 allergen. Anaphylaxis has, however, been reported in Subcutaneous immunotherapy (SCIT) a patient being treated with multiple allergen extracts.12 There can be variable Allergen avoidance Specific immunotherapy is usually efficacy,13 but it is particularly effective in undertaken via the subcutaneous route Reducing allergen exposure will reduce the treatment of grass pollen allergy.14 (SCIT) and has proven efficacy. It takes not only the frequency of immediate about three years and involves the injec reactions but also the severity of airway tion of increasing doses of allergen Anti-IgE therapy: omalizumab hyperresponsiveness and susceptibility to extracts. There is a risk of IgE-mediated further allergen-induced attacks. Omalizumab is a recombinant humanised adverse events, including anaphylaxis, so Avoidance measures for a single domi monoclonal antibody used as add-on the idea of using SCIT for atopic asthma nant allergen, such as cat, or in occupa therapy for severe atopic asthma. It works has always been controversial. tional asthma are particularly effective. by forming complexes with circulating A recent Cochrane meta-analysis Measures to decrease house-dust mites IgE, thus blocking the interaction of IgE examined 88 trials of SCIT in atopic have not been shown to have an effect on with mast cells and basophils, and also asthma,10 mostly for house-dust mite asthma severity. A Cochrane systematic inhibiting other pathways that involve allergy. Unfortunately, blinding was ade review concluded that house-dust mite allergen trapping and focusing by IgE. quate in only 16 trials and there was sig control measures cannot be recom Single doses of omalizumab rapidly nificant heterogeneity. However, overall mended.6 Mite avoidance measures reduce serum-free IgE concentrations by there was a significant reduction in asthma include use of mite-proof covers for bed over 95%.15 A significant reduction in the symptoms and medication and improve ding, removal of carpets and high tem rate of clinically significant asthma exac ment in bronchial hyperreactivity. There perature washing of bed linen.7 erbations, severe exacerbations and emer was no consistent effect on lung function. gency visits in patients with inadequately It was estimated that if nine patients were controlled severe persistent asthma Allergen immunotherapy treated with immunotherapy, one would (despite high-dose inhaled corticosteroid, be expected to develop a local adverse The BTS stepwise pharmacological man long-acting beta-2 agonist therapy and reaction, and if 16 patients were treated, agement of asthma should be followed.5 often additional therapy) has been found one would be expected to develop a sys However, some patients may remain in patients using omalizumab.16 temic reaction. Currently, SCIT is not used resistant to conventional treatment and Omalizumab is now recommended by to treat atopic asthma in the UK and need immunological therapy (Table 1). the National Institute for Health and chronic asthma is a contraindication for Specific immunotherapy (whole-allergen Clinical Excellence (NICE) as a treat use of SCIT to treat allergic rhinitis. immunotherapy or desensitisation) is ment for severe persistent allergic asthma in patients with sensitivity to perennial performed in specialist allergy clinics for Sublingual immunotherapy (SLIT) intractable allergic rhinitis or venom trigger allergens, confirmed via history allergy to induce both immunological Sublingual (SLIT) administration using and skin-prick tests/specific IgE tests and clinical tolerance.8 It has also been allergen extracts is an emerging effective (Table 2; Case 1). Whether omalizumab

dĂďůĞϭ͘WƌŽƐĂŶĚĐŽŶƐŽĨŝŵŵƵŶŽůŽŐŝĐĂůƚŚĞƌĂƉŝĞƐ͘ Treatment Drug type Mode of action Pro Con

KŵĂůŝǌƵŵĂď DŽŶŽĐůŽŶĂůď ŝŶĚƐƚŽĂŶĚƌĞĚƵĐĞƐ ŶĂƉŚǇůĂǆŝƐƌĂƌĞ ^ƵďĐƵƚĂŶĞŽƵƐ ;ĂŶƚŝͲ/ŐƚŚĞƌĂƉǇͿ ĨƌĞĞ/ŐůĞǀĞůƐ ĨĨĞĐƚŝǀĞ ŝŶũĞĐƚŝŽŶƚǁŽͲŽƌĨŽƵƌͲǁĞĞŬůǇ͘ ĨŽƌĂƚŽƉŝĐĂƐƚŚŵĂ ƵƌĂƚŝŽŶƵŶŬŶŽǁŶ͘ ^ĞŶƐŝƚŝƐĂƚŝŽŶͬƐǇŵƉƚŽŵƐƚŽ ƉĞƌĞŶŶŝĂůĂĞƌŽĂůůĞƌŐĞŶ;ƐͿ ƌĞƋƵŝƌĞĚ͘ ůůĞƌŐĞŶŝŵŵƵŶŽƚŚĞƌĂƉǇ ůůĞƌŐĞŶĞǆƚƌĂĐƚƐ /ŶĚƵĐĞƐƚŽůĞƌĂŶĐĞƚŽ ^/d ĨĨĞĐƚŝǀĞ ^/d ,ŝŐŚƌŝƐŬŽĨ ;ĚĞƐĞŶƐŝƚŝƐĂƚŝŽŶͿ ƐƉĞĐŝĨŝĐĂůůĞƌŐĞŶ;ƐͿ ƵƌĂƚŝŽŶƚŚƌĞĞǇĞĂƌƐ ĂŶĂƉŚǇůĂǆŝƐ ĨŽƌĂůůĞƌŐŝĐƌŚŝŶŝƚŝƐ ^>/d EŽŶͲŝŶũĞĐƚŝŽŶƌŽƵƚĞ ^>/d sĂƌŝĂďůĞĞĨĨŝĐĂĐǇ dĂŬĞŶĂƚŚŽŵĞ &ĞǁĞƌƐǇƐƚĞŵŝĐ ƐŝĚĞ ĞĨĨĞĐƚƐ

ď= ĂŶƚŝďŽĚǇ͖^/d= ƐƵďĐƵƚĂŶĞŽƵƐŝŵŵƵŶŽƚŚĞƌĂƉǇ͖^>/d= ƐƵďůŝŶŐƵĂůŝŵŵƵŶŽƚŚĞƌĂƉǇ͘

CME Clinical immunology

will be effective in patients with negative (for healthcare professionals). and Prevention. NIH Publication 02–3659, skin tests or specific IgE tests (ie with 2 Allergy UK: www.allergyuk.org (for issued January 1995 (last updated 2009). non-atopic asthma; Case 2) remains to patients). www.ginaAsthma.com 3 Holgate ST. Genetic and environmental be determined and is currently the sub- interaction in allergy and asthma. J Allergy ject of ongoing studies. References Clin Immunol 1999;104:1139–46. 4 Holt PG, Macaubas C, Stumbles PA, Sly 1 Barnes PJ. The size of the problem of man- PD. The role of allergy in the development Suggested websites aging asthma. Respir Med 2004;98(Suppl of asthma. Nature 1999;402(Suppl): B):S4–8. B12–7. 1 British Society for Allergy and 2 Global Initiative for Asthma (GINA). 5 British Thoracic Society Scottish Clinical Immunology: www. bsaci.org Global Strategy for Asthma Management Intercollegiate Guidelines Network. British guideline on the management of asthma. Thorax 2008;63(Suppl 4):iv1–121. Revised dĂďůĞϮ͘KŵĂůŝǌƵŵĂďĨŽƌƐĞǀĞƌĞƉĞƌƐŝƐƚĞŶƚĂůůĞƌŐŝĐĂƐƚŚŵĂ͗EĂƚŝŽŶĂů/ŶƐƚŝƚƵƚĞĨŽƌ,ĞĂůƚŚ June 2009. ĂŶĚůŝŶŝĐĂůǆĐĞůůĞŶĐĞ;E/ͿŐƵŝĚĂŶĐĞĨŽƌĞůŝŐŝďŝůŝƚǇ͘ 6 Go tzsche PC, Johansen HK, Schmidt LM, Burr ML. House dust mite control measures ŐĞ ĚƵůƚƐĂŶĚĂĚŽůĞƐĐĞŶƚƐ;�ϭϮ ǇĞĂƌƐͿ for asthma. Cochrane Database Syst Rev dŽƚĂů/ŐƌĂŶŐĞ ϯϬ–ϭ͕ϱϬϬŝƵͬŵů 2004;(4):CD001187. Update in: Cochrane tĞŝŐŚƚ ϮϬ–ϭϱϬ ŬŐ Database Syst Rev 2008;(2):CD001187. < 7 Simpson A, Simpson B, Custovic A, Craven &s ϴϬйƉƌĞĚŝĐƚĞĚ ϭ M, Woodcock A. Stringent environmental ƚŽƉŝĐƐƚĂƚƵƐ WŽƐŝƚŝǀĞƐŬŝŶͲƉƌŝĐŬƚĞƐƚƐŽƌƐƉĞĐŝĨŝĐ/ŐƚŽƉĞƌĞŶŶŝĂůĂĞƌŽĂůůĞƌŐĞŶ;ƐͿ͕ control in pregnancy and early life: the ĐŽŶĨŝƌŵĞĚĂƐƚƌŝŐŐĞƌ;ƐͿǀŝĂŚŝƐƚŽƌǇ long term effects on mite, cat and dog ƵƌƌĞŶƚƚƌĞĂƚŵĞŶƚ KƉƚŝŵŝƐĞĚƐƚĂŶĚĂƌĚƚŚĞƌĂƉǇ allergen. Clin Exp Allergy 2003;33: ǆĂĐĞƌďĂƚŝŽŶƌĂƚĞ �ϮŚŽƐƉŝƚĂůĂĚŵŝƐƐŝŽŶƐŽƌŽŶĞĂĚŵŝƐƐŝŽŶƉůƵƐƚǁŽΘĂƚƚĞŶĚĂŶĐĞƐ 1183–9. ŝŶƉĂƐƚǇĞĂƌ 8 Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for = = Θ ĂĐĐŝĚĞŶƚĂŶĚĞŵĞƌŐĞŶĐǇ͖/Ő ŝŵŵƵŶŽŐůŽďƵůŝŶ͘ allergic diseases. A WHO position paper. J Allergy Clin Immunol 1998; 102(4 Pt 1):558–62. ĂƐĞϭ 9 Jacobsen L, Niggemann B, Dreborg S et al. DĂůĞ͕ĂŐĞϯϳǇĞĂƌƐ͕ǁĂŝƚĞƌŝŶ/ŶĚŝĂŶƌĞƐƚĂƵƌĂŶƚ͘ Specific immunotherapy has long-term preventive effect of seasonal and perennial >ŝĨĞůŽŶŐĂƐƚŚŵĂ͕ǁŽƌƐĞƐŝŶĐĞĂƌƌŝǀĂůŝŶh<ϭϬǇĞĂƌƐĂŐŽ͕ŽŶƐĞƚŽĨƉĞƌĞŶŶŝĂůƌŚŝŶŝƚŝƐ͘ asthma: 10-year follow-up on the PAT ,ŽŵĞ͗ƌĞŶƚĞĚĨůĂƚǁŝƚŚĨĂŵŝůǇ;ĐĂƌƉĞƚƐ͕ƐŽĨƚƚŽǇƐͿ͘ study. Allergy 2007;62:943–8. ^ǇŵƉƚŽŵƐǁŽƌƐĞŝŶŵŽƌŶŝŶŐ͕ďĞƚƚĞƌĂƚǁŽƌŬďƵƚƐƚŝůůƵŶǁĞůů͘ 10 Abramson MJ, Puy RM, Weiner JM. hƐŝŶŐĐŽŵďŝŶĂƚŝŽŶŝŶŚĂůĞƌ͕ŵŽŶƚĞůƵŬĂƐƚ͕ŝŶƚƌĂŶĂƐĂůƐƚĞƌŽŝĚƐ͘ Injection allergen immunotherapy for asthma. Cochrane Database Syst Rev &ƌĞƋƵĞŶƚƉƌĞĚŶŝƐŽůŽŶĞ͕ŚŽƐƉŝƚĂůĂĚŵŝƐƐŝŽŶƐ͘ 2010;(8):CD001186. dƌŝĞĚŚŽƵƐĞͲĚƵƐƚŵŝƚĞƌĞĚƵĐƚŝŽŶŵĞĂƐƵƌĞƐ͕ŝŶĐůƵĚŝŶŐŵŽǀŝŶŐƚŽĨůĂƚǁŝƚŚŚĂƌĚĨůŽŽƌŝŶŐ 11 Radulovic S, Calderon MA, Wilson D, Durham S. Sublingual immunotherapy for dĞƐƚƐ͗&sϭ ϲϴ% ƉƌĞĚŝĐƚĞĚ͕ĞůĞǀĂƚĞĚƐƉĞĐŝĨŝĐůŐƚŽŚŽƵƐĞͲĚƵƐƚŵŝƚĞ;ŐƌĂĚĞϰͿ͕ĞůĞǀĂƚĞĚƚŽƚĂůůŐ ;ϱϴϬŝƵͬŵůͿ͘ allergic rhinitis. Cochrane Database Syst Rev 2010;(12):CD002893. ŝĂŐŶŽƐŝƐ͗ƐĞǀĞƌĞƉĞƌƐŝƐƚĞŶƚĂƚŽƉŝĐĂƐƚŚŵĂ͖ĐŽŵŵĞŶĐĞĚŽŵĂůŝǌƵŵĂď͘ 12 Dunsky EH, Goldstein MF, Dvorin DJ, KƵƚĐŽŵĞ͗ƌĞĚƵĐĞĚĞǆĂĐĞƌďĂƚŝŽŶĨƌĞƋƵĞŶĐǇ͕ŶŽƌĞŐƵůĂƌƉƌĞĚŶŝƐŽůŽŶĞ͕ŝŵƉƌŽǀĞĚYŽ>ƐĐŽƌĞƐ͘ Belecanech GA. Anaphylaxis to sublingual immunotherapy. Allergy 2006;61:1235. 13 Greenberger PA, Ballow M, Casale TB, ĂƐĞϮ Platts-Mills TA, Sampson HA. Sublingual &ĞŵĂůĞ͕ĂŐĞϰϵǇĞĂƌƐ͕ƐƵƉĞƌŵĂƌŬĞƚƐŚĞůĨƐƚĂĐŬĞƌ͘ immunotherapy and subcutaneous ƐƚŚŵĂƉĂƐƚĨŝǀĞǇĞĂƌƐ͕ƐŵŽŬĞĚďƌŝĞĨůǇĂƐƚĞĞŶĂŐĞƌ͖ǁŚĞĞǌǇŽŶĞǆĞƌƚŝŽŶ͘ immunotherapy: issues in the United States. J Allergy Clin Immunol /ŶŚĂůĞƌƚĞĐŚŶŝƋƵĞƉŽŽƌ͘ 2007;120:1466–8. <ĞĞƉƐĂĐĂƚ͕ĚĞŶŝĞƐĂĐƚƐĂƐƚƌŝŐŐĞƌ͕ŶŽƌŚŝŶŝƚŝƐ͘ 14 Calderón M, Brandt T. Treatment of grass EŽƐĞĂƐŽŶĂůŽƌƉĞƌĞŶŶŝĂůƚƌŝŐŐĞƌƐŝŶŚŝƐƚŽƌǇ͕ŶŽĨĂŵŝůǇŚŝƐƚŽƌǇŽĨĂƚŽƉŝĐĚŝƐĞĂƐĞ͘ pollen allergy: focus on a standardized tĞŝŐŚƚŐĂŝŶǁŝƚŚĞǆĐĞƐƐŝǀĞƵƐĞŽĨƉƌĞĚŶŝƐŽůŽŶĞ͘ grass allergen extract – Grazax. Ther Clin Risk Manag 2008;4:1255–60.

EŽĐůĞĂƌƐĞůĨͲŵĂŶĂŐĞŵĞŶƚƉůĂŶ͘ 15 Corne J, Djukanovic R, Thomas L et al.The ŝĨĨŝĐƵůƚŝĞƐǁŝƚŚĞŵƉůŽǇĞƌĚƵĞƚŽƐŝĐŬůĞĂǀĞ͘ effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE Tests: FEV1 88% predicted, skin prick tests negative, total IgE 24 levels in atopic subjects: efficacy, safety, and Diagnosis: non-atopic asthma pharmacokinetics. J Clin Invest Management: inhaler training, self-management plan, weight reduction, regular review by 1997;99:879–87. practice nurse/respiratory specialist nurse 16 Humbert M, Beasley R, Ayres J et al. Outcome: no requirement for prednisolone, weight loss, able to work without symptoms Benefits of omalizumab as add-on therapy in patients with severe persistent asthma

CME Clinical immunology Clinical Medicine 2011, Vol 11, No 4: 380–4

who are inadequately controlled despite best available therapy (GINA 2002 step 4 Does this patient have an treatment): INNOVATE. Allergy 2005;60:309–16. immunodeficiency? Address for correspondence: Dr F Runa Ali, Barts and the London Aarnoud P Huissoon, consultant mately one-quarter of them undiag NHS Trust, London Chest Hospital, immunologist; Mamidipudi Thirumala nosed.4 Neutropenia and other secondary Bonner Road, London E2 9JX. Krishna, consultant allergist and and iatrogenic immunodeficiencies are Email: Runa.Ali@bartsandthelondon. immunologist common but their prevalence is difficult to nhs.uk quantify. The prevalence of common vari Birmingham Heartlands Hospital able immunodeficiency (CVID), the most common primary antibody deficiency, is There is a good chance that most physi at least one in 50,000 in the UK but it is cians will have seen a patient with an likely that many cases are unknown. immune deficiency in the past year. This International estimates of prevalence of brief review aims to help decide when a CVID are as high as one in 10,000. patient needs to be investigated for Selective immunoglobulin A deficiency is immunodeficiency, what tests should be common (1 in 500–700) but most of these done and what to do with the results. individuals are asymptomatic and do not Detailed descriptions of individual suffer from infections. Complement, pri immunodeficiency disorders can be mary T lymphocyte and neutrophil disor found in reviews listed.1–3 Children with ders are relatively rare. suspected immunodeficiency require There is also a significant delay in the special consideration and are outside the diagnosis of immunodeficiency: 52% of scope of this article. adults with HIV infection are diagnosed late and 30% very late. In primary anti body deficiencies, delays of over seven Epidemiology and missed years between first presentation and final diagnoses diagnosis are common. For both diseases HIV infection is the most common cause patients have often been reviewed by sev of secondary immunodeficiency for eral physicians without the diagnosis which prevalence data are available. It is having been considered. Delays in diag estimated that 0.2% of men and 0.1% of nosis and treatment are associated with women in the UK are infected, approxi poor outcomes.

Key points

Patients with immunodeficiency often present with infections but these need not be unusual or severe

Immunodeficiency presenting in adults may be secondary (eg HIV, lymphoma, drugs) or primary (usually antibody deficiency)

FISHing (full blood count, immunoglobulins, serum complement, HIV test) will identify the most common immunodeficiencies

Adults with normal initial investigations may nonetheless have significant immunodeficiency: referral to an immunologist is recommended where there is a high index of suspicion

Non-infectious features such as splenomegaly, granulomata or autoimmunity (eg idiopathic thrombocytopenic purpura) increase the likelihood of identifying an immunodeficiency

KEY WORDS: common variable immunodeficiency, HIV infection, immunoglobulins, primary immunodeficiency, secondary immunodeficiency