Immune system diseases

Food allergies in children present with a wide spectrum of clinical manifestations, including anaphylaxis, urticaria, angioedema, atopic dermatitis and gastrointestinal symptoms (such as vomiting, diarrhoea and failure to thrive). Symptoms usually begin in the first 2 years of life, often after the first known exposure to the food. Immediate reactions (occurring between several minutes and 2 hours after ingestion) are likely to be IgE-mediated and can usually be detected by skin prick testing (SPT) or measuring food-specific serum IgE antibody levels. Over 90% of IgE-mediated food allergies in childhood are caused by eight foods: cows milk, hens egg, soy, peanuts, tree nuts (and seeds), wheat, fish and shellfish. Anaphylaxis is a severe and potentially life-threatening form of IgE-mediated food allergy that requires prescription of self-injectable adrenaline. Delayed-onset reactions (occurring within several hours to days after ingestion) are often difficult to diagnose. They are usually SPT negative, and elimination or challenge protocols are required to make a definitive diagnosis. These forms of food allergy are not usually associated with anaphylaxis. The mainstay of diagnosis and management of food allergies is correct identification and avoidance of the offending antigen. Children often develop tolerance to cows milk, egg, soy and wheat by school age, whereas allergies to nuts and shellfish are more likely to be lifelong.

Katrina J Allen MB BS, FRACP, PhD · David J Hill MB BS, FRACP · Ralf G Heine FRACP, MD

Eosinophilic oesophagitis (EO), an isolated eosinophilic inflammation of the oesophagus, is the most common of the eosinophilic gastrointestinal disorders. EO is of increasing clinical significance in many developed countries,1 in parallel with the recent increase in food allergic disorders. A retrospective study of Western Australian children reported a dramatic rise in prevalence of EO (from 0.05 cases per 10 000 children in 1995 to 0.89 cases per 10 000 children in 2004) (Level III-2).2 The estimated prevalence in the US population aged 0–19 years is even higher, at 4.3 cases per 10 000 individuals.3 Clinical features. Patients present with symptoms indistinguishable from those of gastro-oesophageal reflux (GOR); however, unlike people with GOR, they are generally unresponsive to treatment with proton pump inhibitors (Level III-2). Infants often have additional clinical features, including feeding difficulties, feeding refusal and/or poor weight gain. In older children and adults, oesophageal food impaction is the most characteristic symptom (Level III-3), and should alert clinicians to include EO in the differential diagnosis. Typically, patients with EO have associated atopic disorders, including asthma and eczema. Mucosal appearance in EO Cause. The cause of EO is not clear, but the condition is closely associated with atopic disorders, and there is evidence that both IgE- and non-IgE-mediated food allergy are involved in its aetiology. Foods commonly implicated include cows milk, soy, wheat and egg.3 Data from animal experiments and anecdotal clinical observations suggest that inhalant allergens may also contribute. In keeping with murine models, recent gene array studies in people with EO have shown increased gene expression for eotaxin-3, a chemokine that promotes the migration of eosinophils into the oesophagus.1 Diagnosis. The diagnostic hallmark of EO is a dense, eosinophilic infiltrate involving the entire oesophageal mucosa, which is normally free of eosinophils. Key diagnostic criteria are basal layer hyperplasia and the presence of more than 20 eosinophils per high power field (× 400 magnification) in gastroscopic biopsies of the lower and upper oesophagus (Level III-3). Although oesophageal eosinophils are also seen in patients with reflux oesophagitis, mucosal eosinophil counts in such patients are lower (< 5 per high power field), and the eosinophils are limited to the lower oesophagus. There is a typical mucosal appearance in many patients with EO (thickened mucosa, with longitudinal furrowing and superficial white plaques [Box]) — although in about a third of patients the mucosa will look macroscopically normal. Skin prick testing (SPT) and atopy patch testing (APT) (the application of food or food extracts to the skin for 48 hours) are thought to be helpful in identifying potential causative food allergens,3 but prospective studies are needed to evaluate their predictive value. Management. To date, no completed randomised controlled trials evaluating the benefits and adverse effects of medical treatments for EO are available. Infants and young children may respond to dietary allergen restriction or an elemental diet. A diagnostic trial of an amino acid-based formula (AAF) for 6–8 weeks may be useful in determining whether a patient is diet-responsive. The treatment response needs to be assessed by repeat endoscopy, as not all patients will improve. If remission is achieved, food items can be gradually reintroduced into the diet, as tolerated, taking SPT and APT findings into consideration.3 In older children and adults, an elemental diet is often impractical and poorly tolerated due to the taste of AAF. These patients can be treated with swallowed topical corticosteroid aerosols (fluticasone) or, in refractory cases, with systemic corticosteroids.1 Other drugs, including cromoglycate and montelukast, have been used in uncontrolled trials, but their efficacy is poorly documented. Novel monoclonal antibodies against interleukin-5 may also be of benefit in treating EO, but prospective studies are not yet available. Evidence-based practice tip Infants and young children with eosinophilic oesophagitis often respond to an elemental diet, while older children and adults have been successfully treated with swallowed topical corticosteroid aerosols (fluticasone) (Level III-2).* * NHMRC levels of evidence. Prognosis. The long-term prognosis for EO is largely unknown. In some infants and young children with food protein-induced EO, the disease may remit due to development of oral tolerance to the offending food protein. However, EO usually follows a chronic relapsing course. To date, no studies have shown an increased risk of malignancy in patients with EO, but there is evidence that uncontrolled chronic eosinophilic inflammation may cause subepithelial fibrosis and remodelling, which eventually may cause obstructive dysphagia, strictures or persistent oesophageal narrowing.

Alyson Kakakios MB BS, FRACP · Ralf G Heine MD, FRACP

Most drug reactions are pharmacological reactions rather than hypersensitivity reactions. In assessing drug reactions, a detailed clinical history and careful documentation of reactions are most important. Elucidating the nature and time course (first versus subsequent exposure, immediate versus non-immediate) of a reaction can help to distinguish immune from non-immune hypersensitivity, as well as IgE-mediated from T cell-mediated allergy. Skin testing and in-vitro tests are of predictive value for only a limited group of IgE-mediated drug allergic reactions. Drug provocation challenges can be used to eliminate suspicion of a low-probability drug reaction, find a safe alternative to a proven or probable drug reaction, or as a means of desensitisation. If a patient taking an angiotensin-converting enzyme (ACE) inhibitor develops angioedema, the cause must be assumed to be the ACE inhibitor until proven otherwise.

Francis C K Thien MD, FRACP

Latex allergy (LA) is an IgE-mediated reaction to latex proteins. It is a relatively new phenomenon, first described convincingly in 1979 and increasingly recognised in subsequent years.1 Much has been achieved from years of research into the problem, including: an understanding of the causes and mechanism of sensitisation; implementation of effective public health measures to reduce the incidence of sensitisation; identification of the major allergens of natural rubber latex; and delineation of cross-reactive allergens. Who is at risk? LA is primarily an occupational disease, with health care workers and other highly exposed workers at greatest risk of becoming sensitised. Other at-risk groups include children with spina bifida and people who have had multiple surgical procedures.1 Clinical signs of LA occur in less than 1% of the general population.2 Screening sera from blood donors shows that about 7% of samples contain latex-specific IgE antibodies,2 but this observation can be explained by cross-reactivity between latex and certain plant food and pollen allergens. Risk factors. Atopy is a risk factor for developing LA: a hospital worker who is atopic has a 17% greater chance of developing LA than a non-atopic worker. Australian and other studies have demonstrated that pre-existing hand dermatitis is also a major risk factor for occupational sensitisation. But the greatest risk factor for developing LA is high exposure to powdered latex gloves. Routes of sensitisation and clinical features. Exposure may occur by cutaneous contact, in which case urticaria is the most common clinical manifestation. Sensitisation via the respiratory route occurs when there is airborne allergen in the environment, most commonly caused by airborne powder particles carrying latex allergen. This exposure may produce systemic reactions, but more often produces symptoms of acute rhinoconjunctivitis. Occupational asthma secondary to LA results from inhalation of airborne latex protein-bearing particles. This explains why cases of asthma caused by LA are almost only seen in people with occupational exposure. Contact with latex proteins via the mucosal route, such as occurs during surgical or dental procedures, is most likely to result in systemic allergic reactions such as bronchospasm, hypotension and shock. Rubber glove use may also lead to problems with hand dermatitis, which may be due to chronic irritation or may be secondary to delayed type hypersensitivity reactions to preservative agents in the rubber. Both types of dermatitis are more common than LA. Diagnosis. Diagnosis of LA depends on a high level of suspicion in the correct clinical setting. Confirmation is sought by performing skin prick tests and/or in-vitro assays for specific IgE. However, there is still no uniformly satisfactory diagnostic test reagent available. Several manufacturers have produced extracts for skin testing and in-vitro reagents, but these lack the high degree of efficiency desirable for a diagnostic test. The major allergens of latex have been identified, and many are now cloned and sequenced. Hopefully this will lead to the development of improved diagnostic assays and new immunotherapy vaccines in the future.1 Clinically important cross-reactivity exists between latex and various plant-derived foods, including nuts, kiwifruit, avocado, banana, potato and tomato. This is due to structural and biological similarities between the various protein allergens. Fact or fiction — true or false? People with latex allergy must avoid all rubber products (T/F) False. The greatest risk to a person with latex allergy is contact with “dipped” rubber products (eg, gloves, condoms, balloons). Some hard or black rubber products may not pose a risk. Patients should seek specialist advice on which products to avoid. Management. Keeping sensitised individuals safe from allergic reactions on exposure to latex proteins depends on making a correct diagnosis, notifying relevant medical and dental personnel of the allergy, and being prepared to treat an acute reaction. People with LA should wear a MedicAlert bracelet (Australia MedicAlert Foundation, Adelaide, SA) and, if necessary, carry an adrenaline auto-injector. Education about the possibility of cross-reacting allergens and advice about alternative, safe, non-latex products (including polyurethane condoms) are important. Small studies of immunotherapy for LA have shown encouraging results, but further work needs to be done before this strategy can be recommended.1 Workplace measures. With the correct measures in place, there is no reason why a health care worker sensitised to LA cannot work in health care facilities. Sensitised individuals should wear non-latex gloves. If others working in the facility continue to use latex gloves, these should be powder-free with a low protein content. Universal adoption in the workplace of low-protein, non-powdered gloves and avoidance of latex gloves in non-clinical areas (eg, for kitchen and cleaning personnel) can dramatically reduce exposure and risk of sensitisation.3 Workers should be educated about the early manifestations of LA and the need for early consultation with an appropriate specialist if LA is suspected. Good hand-care education is essential in workplaces where there is frequent washing and gloving. Evidence is emerging that continuing avoidance may reduce sensitisation to LA, at least in some individuals.

Constance H Katelaris MB BS, PhD, FRACP

Anaphylaxis is a serious, rapid-onset, allergic reaction that may cause death. Severe anaphylaxis is characterised by life-threatening upper airway obstruction, bronchospasm and/or hypotension. Anaphylaxis in children is most often caused by food. Bronchospasm is a common symptom, and there is usually a background of atopy and asthma. Venom- and drug-induced anaphylaxis are more common in adults, in whom hypotension is more likely to occur. Diagnosis can be difficult, with skin features being absent in up to 20% of people. Anaphylaxis must be considered as a differential diagnosis for any acute-onset respiratory distress, bronchospasm, hypotension or cardiac arrest. The cornerstones of initial management are putting the patient in the supine position, administering intramuscular adrenaline into the lateral thigh, resuscitation with intravenous fluid, support of the airway and ventilation, and giving supplementary oxygen. If the response to initial management is inadequate, intravenous infusion of adrenaline should be commenced. Use of vasopressors should be considered if hypotension persists. The patient should be observed for at least 4 hours after symptom resolution and referred to an allergist to assist with diagnosis, allergen avoidance measures, risk assessment, preparation of an action plan and education on the use of self-injectable adrenaline. Provision of a MedicAlert bracelet should also be arranged.

Simon G A Brown PhD, FACEM · Raymond J Mullins PhD, FRACP · Michael S Gold MD, FRACP

Insects that commonly cause anaphylaxis in Australia are honeybees, jack jumper ants and wasps. Honeybee (Apis mellifera) sting is the most common cause of sting anaphylaxis in most areas of Australia, except where jack jumper ants (Myrmecia pilosula) occur (in native woodland areas in southern and eastern Australia). In some regions of Australia, “European wasps” (Vespula spp) and “paper wasps” (including Polistes and Ropalidia spp) make significant contributions. Who is at highest risk of anaphylaxis to stings and bites? People at highest risk of severe anaphylaxis after a sting are those aged over 35 years (Level II) and those who have had a previous severe reaction (Level II) (see case scenario Box).1,2 Do sting reactions always get worse? Sting hypersensitivity may persist for decades, but reactions to individual stings are highly unpredictable. Individual sensitivity and the amount of venom may vary, and each sting has the capacity to resensitise. Prospective sting studies have shown that the probability of the next sting giving no reaction or a lesser reaction than the presenting reaction is about 80% for Vespula wasps, 50% for honeybees and 30% for jack jumper ants.1-3 Evidence-based practice tip When a definite diagnosis of rapid-onset, systemic sting allergy has been made and the responsible insect identified, insect venom immunotherapy is highly effective at reducing the risk of anaphylaxis to future stings (Level II).* * NHMRC levels of evidence. What are some common pitfalls in practice? Doctors should be aware that: In some patients with sting anaphylaxis, rash may not be observed or may be very transient.4 Over the 60–90 minutes after the sting, many patients with sting anaphylaxis require more adrenaline (as judged by titrated continuous infusion4) than the amount provided by use of one EpiPen syringe.4 Although honeybee venom immunotherapy (VIT) provides significant protection against life-threatening stings, the protection appears to be less complete than that conferred by VIT for Vespula spp and the jack jumper ant.2,3 Case scenario* A 60-year-old farmer was stung on the neck while driving a truck. After parking, he removed a stinger and found a dying bee. Within 5 minutes he experienced flushing, sweating, fading vision and momentary loss of consciousness. He was too confused to call an ambulance on his mobile phone, but managed to stumble out of the vehicle and lie on the ground, where he was found by a passing motorist 10 minutes later. An ambulance was called. Paramedics arrived 20 minutes after the sting event and noted the man was wearing a MedicAlert bracelet. He was arousable, showed no respiratory distress or rash, and had a regular pulse rate of 55 beats/min and systolic blood pressure of 80 mmHg. The patient had brief expiratory wheeze and a blood oxygen saturation level of 88%. His condition improved with horizontal posture and with administration of oxygen, intramuscular adrenaline (0.5 mg injected into the lateral thigh) and nebulised salbutamol. On arrival at a hospital emergency department 30 minutes later, he received another intramuscular injection of adrenaline (0.3 mg), and 2 L normal saline was given intravenously over 20 minutes. A transient urticaria was noted. After another 4 hours’ observation, the patient was discharged with a prescription for an automated adrenaline syringe (EpiPen), an emergency anaphylaxis action plan, and an appointment arranged to visit an allergy clinic. The man had tolerated bee stings on multiple occasions up to the age of 53 years, when, for the first time, he developed flushing and mild wheezing 15 minutes after a sting. At that time, he was provided with an EpiPen. Five years later, he experienced an uneventful bee sting and decided not to renew the EpiPen. Intercurrent problems included mild chronic airflow obstruction, a history of smoking (until 30 years of age) and borderline hypertension (treated with a thiazide). Specialist allergy assessment 1 month after discharge demonstrated serum-specific IgE to honeybee venom at 10 kU/L and a positive skin test to the venom at 0.01 μg/mL (intradermal). Based on sighting the insect, the presence of a stinger and demonstration of high-level specific IgE to honeybee venom, the recent events were attributed to allergy to honeybee sting. The patient’s respiratory and cardiac comorbidities may also have contributed to the severity of the reaction (Level IV). Because of his occupation, the presence of comorbidities, the severe, hypotensive anaphylaxis after the latest sting, and the slow trend to higher failure rates once venom immunotherapy is discontinued,2 the patient was trained in using an EpiPen device and advised to carry one at all times and to undergo honeybee venom immunotherapy indefinitely. He was also given contact numbers for emergency services (dial 000 in Australia, or 112 from a mobile phone anywhere in the world) and advised how to minimise exposure. * This is a fictional case scenario based on similar real-life cases.

Robert J Heddle PhD, FRACP, FRCPA

Australian researchers are at the forefront of allergy prevention and treatment Allergic diseases increased dramatically throughout the 20th century, a change that has been described as an “epidemic”.1,2 To mark the launch of the the MJA Practice Essentials — Allergy series in this issue, we review some aspects of the Australian response. The incidence of allergic disease in Australia is one of the highest in the world. Between 1993 and 2002, the Australian arm of the International Study of Asthma and Allergies in Childhood demonstrated increases in the 12-month prevalence of rhinitis (from 9.7% to 12.7%) and eczema (from 11.1% to 17.2%), but a fall in asthma prevalence (from 27.2% to 20.0%).3 The reasons why asthma prevalence almost doubled between 1984 and 1994,4 but then fell,3 remain unclear. Food allergy and anaphylaxis are also increasing.5,6 The emergence of new food allergy-related disorders, such as the eosinophilic enteropathies (inflammatory disorders of the gastrointestinal tract with significant eosinophilic infiltration),7 and the unabated increase in demand for hypoallergenic formulae in infants8 and injectable adrenaline for people at risk of anaphylaxis indicate that the epidemic has not subsided. One popular explanation for the epidemic is the “hygiene hypothesis”, which postulates that lack of recurrent early exposure to infections and bacterial products (such as endotoxin) may promote an allergic response to environmental allergens.9 Australian researchers have been at the forefront in demonstrating that potentially allergic infants have an imbalance between allergy-promoting (TH2) and non-allergy-promoting (TH1) cytokines.10,11 It has been proposed that this imbalance, combined with early allergen exposure, promotes the development of allergic disease. However, the simplistic TH1/TH2 paradigm that forms the basis for the hygiene hypothesis can be challenged.12 The role of allergen exposure has been explored in Australian studies that have demonstrated an association between asthma incidence and levels of exposure to fungal13 and house dust mite allergens14 and the triggering of acute asthma attacks by submicronic pollen particles released after rain (so-called “thunderstorm asthma”).15 Despite the associations between allergen exposure and disease prevalence and severity, it has been difficult to demonstrate a clinical benefit from a reduction in exposure to inhaled allergens such as house dust mite allergen in the Australian environment.16 As the response to allergen minimisation is often incomplete and pharmacological therapies are not curative, the prospect of permanently modulating the immune response is attractive. Injectable allergen immunotherapy has been shown to reduce the severity of allergic respiratory disease and the onset of new sensitisations,17,18 but is not acceptable to young children and poses a small (but definite) risk of adverse allergic reactions. Immunotherapy substantially reduces the risk of anaphylaxis to stinging insects. For example, the Australian Jack Jumper ant is a major cause of severe allergy in many parts of Australia, and immunotherapy has proved effective in combating serious reactions to its sting.19 The ant is a uniquely Australian problem and the market for such a vaccine is relatively small, so funding is problematic. However, in view of the seriousness of anaphylaxis in susceptible people, making ant venom immunotherapy available to the at-risk population should be a major priority. Future challenges include reducing the risk of adverse reactions to immunotherapy (eg, by using modified or peptide-derived allergens20) and making immunotherapy more acceptable to younger patients (eg, by sublingual or oral administration).21 The ultimate goal is to understand the reasons for the epidemic of allergic disease and develop preventive strategies. While breastfeeding of infants22 and preventing children from being exposed to cigarette smoke have a role in reducing allergic disease, it is unclear whether benefits extend beyond childhood. Modification of atopic eczema by dietary supplementation with probiotics (supplements containing live bacteria given with the aim of altering the gut flora) has shown promising results,23 and research is continuing in this area. Based on the possible role of early dust mite allergen exposure and the proinflammatory impact of arachidonic acid metabolites (derived from ingested fatty acids), a study of asthma prevention by dietary supplementation with omega-3 fatty acids and house dust mite allergen avoidance from birth was commenced in 1999. The study showed that neither intervention achieved a significant reduction in asthma or eczema at 5 years.24 Allergic disease has a negative impact on quality of life.25 Excluding visual conditions and deafness, asthma, hayfever and “allergy” comprised three of the top six most common long-term self-reported illnesses in New South Wales in 1997.26 Food allergy engenders significant anxiety regarding care in schools, risk of death and the potential need for injectable adrenaline.27 In response to these issues, the Australasian Society of Clinical Immunology and Allergy has published guidelines on allergy prevention, anaphylaxis, prescription of EpiPen (CSL Limited, Melbourne, VIC) and the care of food-allergic children in schools and preschools.28 So, what challenges remain for the future? We have some understanding of the immunological mechanisms of the allergic response and of epidemiological associations, but this is yet to be translated into proven preventive measures. We require more reliable testing for the non-IgE mediated immune responses to food observed in some patients with atopic dermatitis and the eosinophilic enteropathies. Current tests for food allergy provide reliable indicators that hypersensitivity exists, but do not necessarily prove that a food is the cause of allergic symptoms or help us predict the severity of reactions. As immunotherapy may alter the natural history of allergic disease, there is a major need for more effective and child-friendly therapy modalities. We also need to educate our doctors and patients on the impact of allergic disease and on evidence-based methods for management. We hope that the current MJA Practice Essentials — Allergy series, which addresses all the topics raised here, will achieve some of these goals.

Andrew S Kemp MB BS, PhD, FRACP · Raymond J Mullins PhD, FRACP, FRCPA · John M Weiner MB BS, FRACP, FRCPA

Allergy is defined as an immune-mediated inflammatory response to common environmental allergens that are otherwise harmless. The diagnosis of allergy is dependent on a history of symptoms on exposure to an allergen together with the detection of allergen-specific IgE. The detection of allergen-specfic IgE may be reliably performed by blood specific testing or skin prick testing. Skin prick testing is not without its attendant risks, and appropriate precautions need to be taken. A doctor should be present for safety and test interpretation. Accurate diagnosis of allergies opens up therapeutic options that are otherwise not appropriate, such as allergen immunotherapy and allergen avoidance. Allergen immunotherapy is an effective treatment for stinging insect allergy, allergic rhinitis and asthma. The most effective methods for primary prevention of allergic disease in children that can currently be recommended are breastfeeding and ceasing smoking. Emerging trends in allergen treatment include sublingual immunotherapy.

Jo A Douglass MD, FRACP · Robyn E O’Hehir FRACP, PhD, FRCPath

Although allergen injection immunotherapy (AII) has been around for nearly a century, many doctors are still not aware of the evidence for its efficacy. About 15 000 patients are treated by AII in Australia each year, with about 300 000 injections administered annually for a wide range of allergens. The 10 most commonly prescribed allergen vaccines in Australia are house dust mite; five-grass pollen mix; 12-grass pollen mix; cat; couch grass, ryegrass and plantain pollens; Alternaria mould; cockroach; and olive/privet pollen. Patients receive regular subcutaneous doses of the allergens to which they are allergic, often for 3–5 years.1 Does the treatment work, and, if so, is it cost-effective and is it safe? Does it work? To date, about 200 completed randomised controlled trials have examined the question of whether AII is an effective treatment for allergic airway disease. Based on National Health and Medical Research Council levels of evidence, AII significantly reduces symptoms and medication usage in both allergic rhinitis (Level I) and asthma (Level I), although the former is the usual indication in Australia for this intervention. Evidence-based practice tip The incidence of mild immediate reactions to allergen injection immunotherapy is reduced by pre-medication with an oral antihistamine before each injection (Level II).* * NHMRC levels of evidence. Improvements with AII are clinically as well as statistically significant. In asthma,2 the number needed to treat (NNT) (ie, number of patients treated to avoid asthma worsening in one subject) is four, the NNT to avoid increasing medication in one patient is five, and there is a significant reduction in both specific and non-specific bronchial hyper-responsiveness. Data are homogenous, and most studies are of medium to high quality. Further, AII may reduce the progression from allergic rhinitis to asthma in some children (Level II),3 and monotherapy for one specific allergen reduces the risk of development of new sensitisation to other allergens (Level II).4 Whether AII is effective for treating food allergy has not been established, but research in this area is continuing. Is it cost-effective? AII is cost-effective for treating atopic airway disease. Two large, rigorous German studies5,6 examining the pharmacoeconomics of AII for treating atopic airway disease found that there are net savings 3–6 years after starting treatment. Other research from Italy and the USA supports these findings. AII treatment is cost-effective because (a) allergen extracts are relatively cheap (about $10–15 a month in Australia); (b) the tolerance induced persists for years after treatment has stopped (Level II);7 and (c) the reduction in new asthma and prevention of additional allergen sensitisation may reduce the incidence of new disease.3,4 Is it safe? Most debate on AII centres on questions of safety and risk. Mild to moderate systemic effects (rhinitis, mild bronchospasm, urticaria) occur in one in 1500 injections, there is one severe (near-fatal) anaphylaxis per million injections, and one death per 2.5 million injections.8 An Australian general practitioner treating 10 patients with AII annually could expect one instance of a mild to moderate systemic reaction every 7 years. AII might cause one death in Australia every 8 years. Notwithstanding the tragedy of any treatment-related death, this statistic has to be compared with the rate of rare deaths associated with other treatments and balanced against the proven reduction in development of asthma in most patients. Most severe adverse events result from giving an incorrect dose, giving the wrong extract, or giving the vaccine to a patient who has unstable asthma or is taking β-blockers. As adverse reactions are not predictable, safety can be enhanced by adhering strictly to the requirement that patients remain in the clinic for a minimum of 30 minutes (ideally, 45 minutes) after each injection (even maintenance doses). This facilitates early access to medical treatment if an adverse reaction occurs. When should patients be referred? There are good reasons for referring a patient to an allergist or clinical immunologist before initiating AII: apart from obtaining a second opinion on contraindications and other safety issues, this allows the consultant to assist with management if problems arise. Medical practitioners administering AII should be aware of the data on safety and compare these with data on the adverse effects of other interventions that they prescribe, and the disease itself, to put the issue into perspective. With proper selection of patients and vaccines, attention to contraindications, provision of a suitable administration milieu, strict adherence to the recommended waiting time after giving the injection, and a team approach with a consultant, AII can be a rewarding treatment for the patient.

John M Weiner MB BS, FRACP, FRCPA

To the Editor: Food, medication or insect stings are the major causes of systemic allergic reactions.1 That topical agents can mimic such reactions is not commonly appreciated. I report here a systemic allergic reaction to a topical medication (initially attributed to food). A 7-year-old boy experienced generalised urticaria and facial swelling within an hour of eating a peanut-containing slice. His father recalled applying a topical antiseptic (Medi Creme [Pharmacare]) to a graze over the boy’s right elbow at about the same time. There were no respiratory or cardiovascular symptoms, and the urticaria settled within 2 hours of taking oral promethazine. Six months later, the same cream applied to a graze over the boy’s right chest resulted in a localised 15 cm urticarial welt. Intercurrent problems included atopic dermatitis but no known food or drug hypersensitivity. The active ingredients of Medi Creme are hexamidine isethionate, chlorhexidine acetate, cetrimide and lignocaine hydrochloride. With the assistance of the manufacturer, skin prick tests using a 10% weight/volume suspension of Medi Creme or a 10% suspension of hexamidine isethionate in normal saline produced 5 mm itchy weals at 15 minutes in the patient (but not controls). By contrast, skin prick tests to the other active ingredients, inert vehicles and relevant foods (including peanut, almond, brazil nut, cashew, hazelnut, pecan, walnut, sunflower seed and sesame seed) were negative. Avoidance of hexamidine was advised. The child has eaten peanut products before and since without any adverse reaction. Hexamidine is an aromatic diamidine antiseptic (other members of the group include pentamidine and dibrompropamidine). These drugs have broad antibacterial and antifungal properties and are also used topically to treat corneal infections and some skin infections.2 In Australia, hexamidine is an ingredient of one topical local anaesthetic/antiseptic cream (Medi Creme) and one nappy rash cream, as well as some tinea treatment creams, medicated shampoos, sunscreens and cosmetic facial wipes in other countries. Adverse reactions (such as contact allergic dermatitis and photodermatitis3) are rare — only four reports of localised dermatitis have been reported to Australia’s Adverse Drug Reactions Advisory Committee (ADRAC) in the past 6 years (Dr K Mackay, Acting Director, ADRAC, Adverse Drug Reactions Unit, Therapeutic Goods Administration, personal communication). There have been more reports of systemic allergic reactions (including anaphylaxis) triggered by chlorhexidine or cetrimide,4 with one description of anaphylaxis to hexamidine after patch testing, but none with clinical use.3 Underlying dermatitis is a risk factor for sensitisation to topical agents.5 This case emphasises the importance of documenting exposure to potential allergenic triggers in the setting of a short-lived episode of urticaria (where the search for an avoidable trigger is more likely to be productive) or anaphylaxis. Exposure to stinging insects is usually obvious, whereas exposure to particular foods or medications is often poorly recalled. That topical allergens can also trigger systemic reactions should be considered.

Raymond J Mullins PhD, FRACP, FRCPA

Objective: To assess the potential for dose-reduction of prophylactic anti-D postpartum.Design: Retrospective audit of fetomaternal haemorrhage (FMH) quantitation by flow cytometry.Participants and setting: 5148 consecutive Rhesus D-negative women aged 15–45 years who had FMH estimation by flow cytometry at a central laboratory in Western Australia in the 65 months between 1 August 1999 and 31 January 2005.Main outcome measures: Quantitation of FMH volume for adequate prophylactic anti-D administration in a timely fashion.Results: 90.4% (4651/5148) of the women had an FMH volume of 1.0 mL or less of Rh D-positive red cells, and 98.5% (5072/5148) had a volume of less than 2.5 mL. Only 0.4% of cases had an FMH volume of 6.0 mL or greater (range, 6.0–92.4 mL).Conclusions: This large retrospective audit shows that a currently available dose of 250 IU (50 mg) of anti-D would have been sufficient for 98.5% of the 5148 Rh D-negative women. On the basis of this evidence, a reduction in the recommended routine postpartum dose of anti-D from 625 IU to 250 IU when flow cytometric quantitation for FMH is available should be considered. Adopting such a strategy would ensure the ongoing provision of a valuable human blood product currently in limited supply.

Bradley M Augustson FRACP, FRCPA · Elizabeth A Fong BappSc, PGradDip(MBiol), GradDip(BCom) · Dianne E Grey FAIMS, BAppSc · Janine I Davies BAppSc, PGradDip(MSc) · Wendy N Erber MD, FRCPA

A 31-year-old woman presented with a tender left axillary mass. There was no history of concurrent fevers, sweats or recent illness. She was born in Australia and had not travelled overseas recently. Examination showed a left axillary mass measuring 5 cm in diameter. There was no other lymphadenopathy, no hepatosplenomegaly, nor any breast masses. Aspiration produced 10 mL of purulent fluid. Polymorphs were seen on microscopy but no Mycobacterium spp or other organisms were grown on culture. Histological sections of an excisional biopsy showed nodules of epithelioid histiocytes and giant cells with central necrosis in fibrous stroma, consistent with necrotic granulomatous lymphadenitis (Box, A). The woman’s symptoms resolved, but the mass re-accumulated after 2 years. An autoimmune process was presumed. As the mass resolved with a trial of prednisone 25 mg daily followed by methotrexate 12.5 mg per week (as a steroid-sparing agent), no further biopsy was undertaken. After 6 months of methotrexate treatment the mass recurred. Histological sections from a repeat excisional biopsy revealed the fibrous capsule of a hydatid cyst and multiple scolices. The capsule contained a patchy mixed inflammatory infiltrate and granulomatous reaction with giant cells (Box, B). Hydatid serological testing (by indirect haemagglutination) was positive at a titre of 1 : 640. The presumed exposure was from time spent about 25 years earlier on a farm in rural New South Wales where offal was fed to working dogs. Three months after commencement of albendazole therapy, the lesion was significantly reduced in size.1 Primary axillary hydatid disease is rare, with only nine previous case reports in the literature.2,3 The causes of granulomatous lymphadenitis can be classified as infective or non-infective, and among these causes, tuberculosis is the most common aetiological agent.4 We believe this to be the first case of axillary hydatid disease presenting as necrotising granulomatous lymphadenitis. Hydatid disease should be considered in the differential diagnosis of granulomatous lymphadenitis. Histological sections of excisional biopsy of axillary mass A: First biopsy, showing a central area of necrosis (arrow) surrounded by granulomatous inflammation (haematoxylin–eosin stain, original magnification × 100). B: Second biopsy, showing the characteristic laminated membrane of a hydatid cyst with associated scolices (arrows) (haematoxylin–eosin stain, original magnification × 40).

Armand Borovik MB BS · David Massasso MB BS · Kathy Gibson BA(Hons), BM BCh, PhD

Objective: To test the B-cell antigen D8/17 as a marker of past rheumatic fever (RF) in a predominantly Aboriginal Australian population, and to evaluate technical modifications to allow its use in remote settings.Design and setting: Cross-sectional survey in a remote Aboriginal community, a regional tertiary referral hospital and a tertiary paediatric centre in Melbourne.Participants: 106 people, including three with acute RF, 38 with a history of past RF, 20 relatives of these people, and 45 healthy controls.Main outcome measure: D8/17 expression in B cells.Results: Blood was collected from each participant and the expression of D8/17 and CD19 in each sample was analysed by flow cytometry. The mean proportion of D8/17-positive B cells was 39.3% (SD, 11.8) in patients with previous RF, 22.5% (SD, 5.2) in first-degree relatives, 11.6% (SD, 7.2) in controls, and 83.7% (SD, 10.1) in patients with acute RF (analysis of variance test between means, P = 0.001). A cut-off of 22.1% of D8/17-positive B cells to indicate past RF yielded the highest percentage of correct results (95.4%). Delayed staining of whole blood (mean, 0.55 days; SD, 0.2) gave equivalent results to immediate staining, but the D8/17 assay on peripheral blood mononuclear cells was unreliable.Conclusions: The B-cell antigen D8/17 accurately identifies Australians with a past history of RF, and the assay is feasible in remote settings with access to facilities capable of performing D8/17 staining within half a day of sample collection.

Zinta Harrington MB BS, BA · Kumar Visvanathan PhD, FRACP · Narelle A Skinner BSc · Nigel Curtis PhD, FRACP · Bart J Currie FRACP, DTM+H · Jonathan R Carapetis PhD, FRACP

Middle lobe syndrome — recurrent atelectasis and/or bronchiectasis involving the right middle lobe and/or lingula — has, up to now, not been reported as the pulmonary manifestation of primary Sjögren’s syndrome. We describe a patient in whom lymphocytic bronchiolitis in the atelectatic lobes was proved histologically from two separate transbronchial biopsies. The atelectasis responded well to glucocorticoid treatment, suggesting that the peribronchiolar lymphocytic infiltrates may have played an important role in the development of middle lobe syndrome in this patient. Clinical record A 53-year-old woman was admitted to our hospital in 2003 with symptoms, for the past 3 days, of shortness of breath, cough, and blood-tinged sputum. Primary Sjögren’s syndrome had been diagnosed in 2002, based on the presence of xerostomia, keratoconjunctivitis sicca, anti-Ro/La antibody, and rheumatoid factor, as well as a positive Schirmer’s test and the results of sialoscintigraphy. The patient had no prior history of smoking, fever, rhinitis or pharyngitis. Physical examination was unremarkable, except for a rapid respiratory rate (20 breaths/min) and coarse crackles heard during the early inspiratory phase in the middle lung field. A complete blood count, C-reactive protein levels, erythrocyte sedimentation rate, and the results of serum biochemistry were all within normal limits. A chest x-ray revealed a vague opacity in the right lower lung that obliterated the cardiac border in the posteroanterior view, and a wedge-shaped density in the cardiac area in the lateral projection (Box, A). Sputum studies for bacteria, mycobacteria and fungi, and serological tests for Mycoplasma pneumoniae and Legionella pneumophila all gave negative results. A computed tomography (CT) scan of the chest showed inhomogeneous opacities, as well as dilated airways crowded in the medial segment of the right middle lobe and inferior segment of the lingula, without mediastinal lymphadenopathy (Box, B). A fibrobronchoscopic examination to verify central bronchial patency showed no intraluminal obstruction in the affected bronchi. Cultures of the lavaged bronchial fluid were negative for tuberculosis and other microorganisms, and no malignant cells were found in aspirated specimens. A transbronchial biopsy from the atelectatic middle lobe revealed lymphocytic bronchiolitis with a moderate degree of mononuclear cell infiltration, predominantly by lymphocytes, in the terminal bronchiolar walls and adjacent interstitial areas, and no granuloma formation (Box, C). A diagnosis of middle lobe syndrome secondary to Sjögren’s syndrome was made and the patient was initially treated with methylprednisolone (125 mg/day for 4 days), followed by prednisolone (20 mg/day). The glucocorticoid dose was tapered off as the atelectatic lesions resolved. A repeat CT scan performed 1 year later showed that the atelectatic lesions had almost completely disappeared with this treatment (Box, D). Subsequently, the prednisolone dose was ceased. In 2005, atelectasis developed once again in the lingula. Malignancy and infection were excluded after extensive studies, including cytological examination, virus isolation, and bacterial and mycobacterial cultures from the endobronchial aspirates. Pulmonary tissue, obtained from the atelectatic lingula by biopsy, again showed evidence of lymphocytic bronchiolitis. With the use of medium-dose prednisolone (20 mg daily), the atelectasis gradually resolved. At the time of writing, there has been no further relapse in this patient. DiscussionMiddle lobe syndrome is a disorder of recurrent or fixed atelectasis involving the right middle lobe and/or lingula.1-3 It can result from either extraluminal or intraluminal bronchial obstruction, but also may develop in the presence of a patent lobar bronchus without identifiable obstruction.1-3 Inflammatory processes and defects in the bronchial anatomy and collateral ventilation have been designated as the non-obstructive causes of middle lobe syndrome.1-3 Middle lobe syndrome is commonly associated with many underlying lung conditions, such as neoplasms, asthma, broncholithiasis, microbial infections, granulomatous disorders, mucous plugging, or foreign body aspiration.1,2 It has, up to now, not been reported in patients with primary Sjögren’s syndrome, although similar radiological findings have been described in a patient with systemic lupus erythematosus with suspected secondary Sjögren’s syndrome.4 Primary Sjögren’s syndrome is a chronic inflammatory autoimmune disease characterised by lymphocytic infiltrations in the involved organs. This disorder predominantly affects the salivary and lacrimal glands, but can also involve internal organs resulting in many extraglandular complications.5 A wide spectrum of pulmonary manifestations has been described, including xerotrachea, obstructive airway disease, interstitial lung disease, and lymphoproliferative disease.6 With pulmonary involvement in primary Sjögren’s syndrome, the inflammation can be focal and predominantly cellular, with lymphocytes infiltrating the small airway walls.7,8 Local bronchial or bronchiolar lymphocyte infiltrates and inflammatory cell products may lead to impairment of tracheobronchial mucociliary clearance.8,9 In our patient, lymphocytic infiltrations in the terminal bronchioles were found in the atelectasis of the right middle lobe and lingula. The atelectatic and bronchiectatic lesions seen on the chest CT scan resolved after immunosuppressive drug treatment. Lymphocytic bronchiolitis with underlying bronchiectasis has also been described in patients with non-obstructive middle lobe syndrome. Our findings suggest that the peribronchiolar lymphocytic infiltrates may have been involved in the pathogenesis of the middle lobe syndrome in our patient. Lymphocytic bronchiolitis is common in primary Sjögren’s syndrome, but pulmonary atelectasis, as in our patient, is fairly rare.6,10,11 Therefore, mechanisms other than impaired mucociliary function and lymphocytic bronchiolitis may also have contributed to the development of this disorder. The right middle lobe bronchus is at higher risk of obstruction from inflammatory processes, as it has a relatively narrow diameter and an angular attachment to the intermediate bronchus. Compared with other areas of the lung, the middle lobe and lingula have a large ratio of pleural to non-pleural surface because of the presence of deep fissures, which are effective barriers to the collateral ventilation.,3 These anatomical features may thus predispose to the formation and persistence of atelectasis. Immunosuppressive drugs, either azathioprine alone or in combination with prednisolone, are effective in treating the pulmonary complications of primary Sjögren’s syndrome.7 In our patient, the lymphocytic bronchiolitis-associated atelectasis resolved after prednisolone therapy, but relapsed when the drug was ceased. Therefore, we think that immunosuppressive drugs, such as glucocorticoids, should be considered in this unusual pulmonary complication of primary Sjögren’s syndrome. Tapering of the dose must be gradual to avoid disease recurrence, and a long follow-up period is necessary. Box A A: Lateral chest radiograph showing a wedge-shaped dense area (arrows) with the apex pointing to the hilum. Box B B: Computed tomography scan of the lung showing atelectasis and bronchiectasis in the medial segment of the right middle lobe (arrow) and the inferior segment of the lingula (arrowhead). No pulmonary fibrosis or space-occupying lesion was observed elsewhere. Box C C: Lung tissue from a transbronchial biopsy revealing lymphocytic infiltrations in the terminal bronchiole (arrow) and adjacent interstitial area (arrowhead) (haematoxylin?eosin stain, original magnification, × 100). Box D D: Computed tomography (CT) scan performed 1 year after the first CT scan, showing almost complete resolution of the atelectatic lesions (arrow and arrowheads).

Horng-An Chen MD · Shinn-Liang Lai MD · Wei-Kang Kwang MD · Juhn-Cherng Liu MD · Chun-Hsiung Chen MD · De-Feng Huang MD

Australia’s effective monitoring system shows that serious reactions are rare Australia has achieved very high levels of vaccination coverage in the past 10 years, with 91% of children fully vaccinated at 12 months of age and 92.1% at 2 years.1 Consequently, rates of vaccine-preventable diseases are very low. As the incidence of vaccine-preventable diseases declines, the safety and side effects of vaccines gain prominence, and an increasingly important role of health care professionals is to communicate the benefits and risks of vaccination to parents.2 Worries about vaccines date back more than 200 years, when Jenner’s introduction of cowpox vaccine prompted cartoons in the satirical magazine Punch depicting vaccine recipients turning into cows. More recently, unproven and unjustified concerns about pertussis vaccine3 and measles–mumps–rubella vaccine4 have resulted in falls in vaccination uptake in the United Kingdom, and the needless deaths of children.3,4 Vaccine constituents, such as preservatives, stabilisers, adjuvants and biological growth media used in vaccine production, are necessary to ensure the efficacy, stability and safety of vaccines, but can also contribute to consumer concerns.5 A recent review concluded that the amounts of aluminium, formaldehyde, antibiotics and yeast proteins in vaccines have not been found to be harmful to humans and animals in exposure studies.5 Currently, if providers have concerns about constituents of vaccines, they can consult the excellent booklet Myths and realities.6 In addition, the National Centre for Immunisation Research and Surveillance (NCIRS) website (<http://www.ncirs. usyd.edu.au>) has a fact sheet relating to thiomersal: <http://www.ncirs.usyd.edu.au/facts/f-thiomersal.html>. The US Centers for Disease Control and Prevention have fact sheets on vaccine components at <http://www.cdc.gov/node.do/id/0900f3ec8006587f>. The article by Eldred et al7 in this issue of the Journal is an important overview of vaccine components and constituents of vaccines in use in Australia, and is an important reference for vaccine providers to answer consumer concerns and questions. Serious adverse events following vaccination are rare, and the risk of morbidity associated with these adverse events is generally far less than the risk from catching a vaccine-preventable disease. Nevertheless, it is extremely important to have in place adequate surveillance for adverse events associated with vaccines. Both the public and health care professionals need to feel confident of vaccine safety. Australia has had local reporting mechanisms for many years, but only since 2000 has there been a national reporting system.8 Under the current system, which was driven by the dynamism of John McEwen, former Principal Medical Adviser of the Therapeutic Goods Administration (TGA), all adverse reports are coordinated by the Australian Adverse Drug Reactions Unit (ADRU) of the TGA. Adverse events associated with vaccines can be reported to ADRU by health care professionals or the public by telephone (02 6232 8386) or by prepaid reporting form (“blue card”) or online at <http://tga.gov.au/adr/bluecard.htm>. The data are further analysed by NCIRS and regularly reported in Communicable diseases intelligence.9-11 The data are extremely reassuring: serious adverse events are rare. Between 2000 and 2004, only seven of 5128 adverse events reported following vaccination were reported as having persisted and resulted in sequelae.9-11 Furthermore, the reporting of an adverse event following vaccination implies an association in timing with vaccine administration, but does not necessarily mean the vaccine caused the reported adverse event. Australia has an effective system for monitoring vaccine safety. In future, privacy laws permitting, it is hoped to link Australia’s database of immunisations, the Australian Childhood Immunisation Register, with hospital admissions to be able to look actively at questions regarding the safety of specific vaccines. It is vital that parents and providers are fully informed about the risk of vaccines and of the diseases they prevent. Australia’s monitoring system will continue to gather the data for informed decision-making.

Nicholas Wood MB BS, DCH, FRACP · David Isaacs MB BChir, MD, MRCP, FRACP, FRCPCH

Vaccination remains a vital strategy in the prevention of infectious disease. Commercial vaccine formulations contain a range of additives or manufacturing residuals, which may contribute to patient concerns about vaccine safety. Primary health care professionals are well placed to address patient concerns about vaccine safety. We describe the key constituents present in vaccines, discuss issues related to safety and acceptability of these constituents, and provide a table highlighting constituents of commercially available vaccines in Australia.

Barbara E Eldred BPharm · Angela J Dean BPharm, PhD · Treasure M McGuire BPharm, BSc, PhD · Allan L Nash BPharm

Andrew S Kemp Professor, Allergy Immunology and Infectious Diseases, The Children’s Hospital at Westmead, Locked Bag 4001,Westmead, NSW 2145. andrewk5ATchw.edu.au To the Editor: Publicity such as that on the recently televised “Sunday” show (Channel 9) entitled “When food can be fatal” (http://sunday.ninemsn.com.au/sunday/cover_stories/transcript_1770.asp), which contained statements that “30 in every 1000 [3%] children in Australia are at risk of a severe allergic reaction [anaphylaxis] to a food”, and a reference to a “tsunami of children” with serious allergies, provokes understandable concern and anxiety. Some perspective on this issue is required. To determine the risk, it is essential to study a population-based cohort. Allergies to peanuts or tree-nuts are the most common cause of severe childhood food anaphylaxis and death.1 What is the risk for Australian children of peanut-induced anaphylaxis that is likely to require adrenaline? Of a population-based cohort of 456 Tasmanian children aged 7–8 years, none reacted to a peanut skin-prick test.2 In the Australian Childhood Asthma Prevention Study (CAPS),3 a high-risk cohort, 4.9% of 3 year olds were prick-test positive to peanut (unpublished data) using a liberal cut-off of ≥ 2 mm (for clinical testing the usual cut-off is ≥ 3 mm). Perhaps the most helpful information comes from a population-based study of 13 971 preschool children in the United Kingdom who were followed from birth to 6 years of age. Forty-nine (0.35%) children had an allergic reaction to peanut, of whom only two (0.014%) had what was described as anaphylaxis.4 Thirty-six of the children underwent formal peanut challenge, 23 reacted and three had reactions for which adrenaline was given. Combining these three with the previous two gives a severe reaction rate requiring adrenaline of 0.036%. This suggests that, of the 49 children in the UK study who had an allergic reaction to peanut, only 10% were at risk of a severe reaction requiring adrenaline. Only a third to a half of children with a positive peanut skin test will react if exposed.5 Applying these considerations to Australian children indicates that the proportion at risk of a severe peanut reaction is only 0.25% (4.9% × 1/2 × 5/49) even in a high-risk cohort such as the CAPS. This would be substantially lower in a population-based cohort. For the cohort of 7–8-year-old Tasmanian children referred to above, the risk would be much less than 0.2%, considering none of 500 children was prick-test positive to peanut allergen. There has been a substantial increase in childhood food allergy in recent decades;5 however, sensationalist statements and inaccurate figures are unlikely to be helpful in developing appropriate responses. The Australasian Society of Clinical Immunology and Allergy recently published guidelines for the prevention of food anaphylactic reactions,6 and has other useful information for patients and medical practitioners on its website (http://www.allergy.org.au/).

Andrew S Kemp

It may be difficult for patients to distinguish current concepts of immune function from other, non-conventional explanations of illness Each year, as many as 50%–70% of adults and children with allergic disease consult alternative practitioners.1-3 Some will undergo unproven diagnostic “allergy testing” as used by some alternative (and some conventionally trained) medical practitioners. The potential for adverse outcomes from using unproven diagnostic techniques is not only insidious but also potentially more serious than the more commonly debated issues surrounding costs,1 or the risks and benefits of alternative therapies such as naturopathy, chiropractic, acupuncture, homoeopathy or so-called “allergy elimination therapy”.4,5 Particular concerns arise when “positive test results” are followed by advice to restrict diet, a practice that our combined clinical experience tells us occurs not infrequently, regardless of the presenting problem — even in cases of asthma, allergic rhinitis or recurrent infection in which food allergy is not considered to play a pathogenic role. Such advice may unnecessarily delay more appropriate therapy and sometimes impair nutrition and growth.6 It is not difficult to understand why patients with allergic disease seek help where they can find it. Most people affected by allergic disease are young adults, or parents of young children with eczema, food allergy or allergic respiratory disease — groups that may find concepts of chronicity, and palliation rather than cure, unattractive. Parents of young children may be attracted to non-invasive (“no needles”) allergy testing. Furthermore, the field of allergy and immunology is a non-organ-based specialty, making it difficult for some patients to distinguish current concepts of immune function (or dysfunction) from other, non-conventional explanations of illness. Blurring the meaning of “allergy” to refer to any perceived response to an environmental agent, and use of the term “impaired immunity” interchangeably with “fatigue” (in the media as well as among some alternative practitioners), is conducive to blending concepts of immunology, neurology and spirituality to explain the pathogenesis of disease by some non-conventional philosophies.7 Factors that may contribute to the uptake of unproven diagnostic and therapeutic techniques include congruence with patients’ own philosophies about the pathogenesis of some disorders, a desire for autonomy, long waiting lists for specialty allergy services (and the lack of any publicly-funded clinics in some states, such as Tasmania and Queensland), advice from friends and family, internet-derived information (and misinformation) and uncritical media attention.1-3 Some of the non-conventional “allergy” tests in current use arose in the early 20th century, when allergy practice was essentially empirical.8 At that time, without mechanistic explanations or reliable tests to confirm an immune origin, disorders with a similar phenotype (eg, allergic and non-allergic urticaria) and some non-specific symptoms (eg, migraines, fatigue) were attributed to allergy, if skin tests were positive, or to “allergic toxaemia”, if results were negative.9 Cytotoxic food testing (“Bryans’ test”, and the ALCAT variant — whereby a patient’s leucocyte morphology is assessed after incubation with food extracts) was one, now considered unconventional, technique to arise from a search for more “reliable” tests to explain these phenomena.9 This test continues to be used today, despite evidence that results are not reproducible, are different when duplicate samples are analysed blindly, do not correlate with those from conventional testing, and “diagnose” food hypersensitivity in people with conditions in which food allergy is not considered to play a pathogenic role.10 In the meantime, modern allergy practice relies on understanding the biological mechanisms underlying allergic disorders and the correlation of symptoms with standardised tests to detect allergen-specific IgE.11 Reliable allergy testing increases diagnostic accuracy and facilitates the identification of avoidable inhaled or ingested triggers.12 Advances in scientific understanding have also facilitated the development of medications to block specific inflammatory pathways and novel approaches to immunotherapy.11 By contrast, many non-conventional diagnostic techniques are used without published evidence of clinical utility, and those subjected to formal evaluation have produced uniformly negative results. For example, in a blinded study, iridology practitioners were unable to distinguish healthy from diseased individuals and gave different diagnoses using iris photographs from the same patients taken minutes apart.13 Furthermore, the theoretical basis for iridology — that disease is reflected in iris patterns — is undermined by the use of iris patterns as biometric identification markers because they are considered to be unchanging and unique to individuals, differing even between genetically identical twins. Kinesiology (muscle testing) has been shown, in controlled studies, to be no more accurate than guessing.14 Vega (electrodiagnostic) testing, whereby skin electrical resistance is measured with food extracts present in the same circuit, was unable to distinguish between healthy and allergic individuals, or between control and allergen extracts, and yielded results that did not correlate with conventional test results.15 Rigorous study of other non-conventional methods such as IgG food antibody testing, food immune complexes and sublingual provocation/neutralisation have provided similarly negative results. (These and other techniques are reviewed in more detail at <http://www.allergy.org.au/pospapers/unorthodox.htm>.) In light of the evidence, how can we, as doctors, best serve our patients? First, we need to understand our patients’ belief systems and understand conventional and non-conventional approaches to diagnosis and treatment of allergies. Second, when assessing polysymptomatic patients with normal clinical and laboratory findings, we need to resist the temptation to label medically unexplained illness as “allergic disease”, and should question an allergy diagnosis made by the patient or based on unproven diagnostic techniques. By doing so, we may be able to help our patients to direct their efforts into more productive areas, and minimise unnecessary expenditure resulting from the use of unproven diagnostic techniques. We may also then be able to reconcile concepts of patient autonomy with the medical principle of primum non nocere (first, do no harm) and reduce the possibility that patients may inadvertently harm themselves or their children by pursuing unproven diagnostic techniques.

Raymond J Mullins PhD, FRACP FRCPA · Robert J Heddle PhD, FRACP, FRCPA · Pete Smith PhD, FRACP, FRCPA

The cytokine, tumour necrosis factor-alpha (TNF-α) plays a key role in the pathogenesis of many chronic inflammatory and rheumatic diseases, in particular, Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Controlled trials have shown that the TNF inhibitors (etanercept, infliximab and adalimumab) significantly reduce symptoms and signs, improve function and quality of life, and reduce radiologically evident damage in patients with rheumatoid diseases. For reasons that are not entirely clear, etanercept does not work in Crohn’s disease. Injection site and intravenous reactions and increased risk of infection (in particular, reactivation of tuberculosis) are associated with the use of these agents. Increased risk of lymphoproliferative disease, the development of lupus-like syndromes and demyelination, including optic neuritis and reactivation of multiple sclerosis, are under evaluation in long-term follow-up studies. The TNF inhibitors are expensive (about $18 000 per year), and in some patients need to be given continuously to maintain benefit, even in the presence of other immunosuppressive therapy.

Peter T Nash MB BS, FRACP · Timothy H J Florin MB BS, FRACP

Christopher M MacIsaac,* Mark A Page,† Beverley-Ann Biggs,‡ Kumar Visvanathan§ * Associate Intensivist, † Registrar, ‡ Associate Professor, The Royal Melbourne Hospital, Grattan Street, Melbourne, VIC 3050; § Senior Research Fellow, Murdoch Children’s Research Institute, Melbourne, VIC. Christopher.macisaacATmh.org.au To the Editor: We report a recent case of toxic shock syndrome associated with menstruation which illustrates that this syndrome still occurs, even when tampons are used appropriately. A potential diagnostic test for the syndrome is also discussed. An 18-year-old woman presented with a 1-day history of fever, chills and severe back pain, with no other focal symptoms. On examination, she was febrile with a blood pressure of 75/40 mmHg, and had begun vomiting. She was treated empirically with intravenous ceftriaxone and flucloxacillin and resuscitated with intravenous fluids. Over several hours, the back pain resolved, and a widespread erythrodermic rash developed, centred mainly on the trunk. Further questioning revealed that the patient had removed a tampon shortly before presentation, as she had just ceased menstruating. Renal ultrasound examination, chest x-ray and blood cultures were non-diagnostic. She was treated with intravenous antibiotics for 4 days and discharged home with a further 10-day course of oral amoxycillin and clavulanic acid. At outpatient follow-up 3 weeks after admission, she reported desquamation of the skin of her palms and soles. Toxic shock syndrome was first described in 1978,1 and a strong association with Staphylococcus aureus, menstruation and tampon use was established in 1980.2 Toxic shock syndrome toxin-1 (TSST-1), a protein secreted by S. aureus, was the first of many toxins associated with the syndrome to be identified. The term “superantigen” was adopted to describe the ability of these toxins to cause a remarkable expansion of T lymphocytes displaying specific β chain variable regions of the T-cell antigen receptor. Superantigens bypass normal antigen presentation and can stimulate over 20% of all T cells, whereas a conventional antigen stimulates only in the order of 1 in 10 000 T cells. The signature feature of superantigen activity is the expansion of lymphocyte populations bearing the particular Vβ chains that bind the superantigen. In the case of TSST-1, this is Vβ2.3 Our patient consented to blood being sampled to investigate the Vβ profile of her T cells at follow-up. This investigation was part of a broader study on superantigens in sepsis that was approved by the Ethics Committee of the Royal Melbourne Hospital. The blood was stained with monoclonal antibodies against 24 Vβ families4 and analysed by flow cytometry. This showed a massive expansion of Vβ2 cells, which accounted for 28% of all CD4 lymphocytes (Box). Currently, there is no diagnostic test for toxic shock syndrome. Toxin production from cultured organisms can be established in vitro by some laboratories, but does not confirm toxin production in vivo. Detection of a “skewed” Vβ repertoire is a potential diagnostic test. Clearly, the sensitivity and specificity of the assay would need to be established before general application. To date, we have found skewed Vβ T-cell profiles in six independent cases of toxic shock syndrome. This patient had used tampons appropriately, including replacing tampons at least every 4 hours and not using them overnight, but nevertheless developed a life-threatening disease. The incidence of toxic shock syndrome peaked in the United States in 1980 and has since fallen substantially, as a result of factors including changed tampon absorbency. However, the incidence may be now increasing.5 Our case serves to remind us all to be vigilant for toxic shock syndrome in association with menstruation, and to consider the diagnosis in all patients with severe sepsis. Vβ profile of the T-cell antigen receptor of CD4 lymphocytes in a patient with toxic shock syndrome Vβ profile of CD4 cells from a patient 21 days after onset of toxic shock syndrome compared with the mean profile from 11 adult intensive-care patients with no evidence of infection. Note the massive expansion of cells carrying Vβ 2, for which toxic shock syndrome toxin-1 has known affinity.

Christopher M MacIsaac · Mark A Page · Beverley-Ann Biggs · Kumar Visvanathan

Patrick M Schlievert Professor, Microbiology, University of Minnesota, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA. patsATlenti.med.umn.edu Comment: As noted by MacIsaac et al above, my colleagues and I recently reported an increase in the incidence of staphylococcal toxic shock syndrome (TSS) in Minneapolis–St Paul in the United States, from 0.8 per 100 000 (in January 2000) to 3.4 per 100 000 (in December 2003).1 We noted that physicians across the United States were reporting TSS cases in increasing frequency. There are two major categories of staphylococcal TSS, menstrual and non-menstrual.2,3 Menstrual TSS is defined as occurring during menstruation or within the 2 days preceding its onset or the 2 days following its cessation; the illness is primarily, but not exclusively, associated with tampon use. Menstrual TSS is nearly always caused by the superantigen exotoxin, TSS toxin-1 (TSST-1).4 Superantigens significantly overactivate the human immune system to release cytokines that cause the clinical features of TSS (interleukin-1β [endogenous pyrogen]; tumor necrosis factor-α and β [capillary leak]; and interferon-γ and interleukin-2 [rash]).5 Non-menstrual TSS may occur in anyone, young or old, male or female, and today commonly follows superinfection of the upper respiratory tract after viral infection. Non-menstrual TSS is caused by TSST-1 (50%) or by staphylococcal enterotoxin B or C (together nearly 50%). The important question is what accounts for the fourfold rise in TSS that was reported in our 2004 study? We proposed several hypotheses. First, the increase in incidence partly results from the emergence of three strains of methicillin-resistant Staphylococcus aureus (MRSA), at least two of which are emerging worldwide. These strains are termed (by Centers for Disease Control [CDC] nomenclature) USA 1100 (TSST-1 positive), USA 400 (SEB/SEC, Panton–Valentine leukocidin [PVL] positive), and USA 300 (positive for an unknown superantigen as well as PVL). In our studies, USA 1100 strains currently comprise 20% of submitted isolates, compared with none before the year 2000. These isolates may produce 10 to 100 times more TSST-1 in vitro than their methicillin-sensitive S. aureus counterparts matched by pulsed-field gel electrophoresis profile. Thus, these organisms rapidly produce high levels of TSST-1, leading to TSS even when lower-absorbency tampons are used. In addition, the USA 400 and USA 300 strains are also emerging and are associated with increases in non-menstrual TSS. These latter isolates also produce more superantigens than their methicillin-susceptible counterparts. Secondly, in our 2004 study, physicians who submitted cultures to our laboratory defined cases of TSS based on patient presentation and the presence of an S. aureus strain producing one of the three causative exotoxins. Our TSS definition is likely to be broader than the strict CDC definition. Finally, we also noted that it is possible that women are beginning to menstruate and to use tampons at earlier ages. In addition, teenagers are bombarded with media advice that TSS is no longer a problem; failure to recognise the illness may lead to it becoming more severe before presentation. These lifestyle and awareness changes, combined with the emergence of high-toxin-producing strains and the expanded definition of TSS, may account for the observed increase in TSS. The increase does not appear to be caused by changes in tampon composition or absorbency.

Patrick M Schlievert

Objective: To report the outcome of gene therapy in an infant with X-linked severe combined immunodeficiency (SCID-X1), which typically causes a lack of T and natural killer (NK) cells.Design and setting: Ex-vivo culture and gene transfer procedures were performed at The Children’s Hospital at Westmead, Sydney, NSW, in March 2002. Follow-up to March 2005 (36 months) is available.Patient: A 9-month-old male infant with confirmed SCID-X1 (including complete absence of T cells) with an NK+ phenotype (a less common variant of SCID-X1), and no HLA-identical sibling donor available for conventional bone marrow transplantation.Procedure: CD34+ haemopoietic progenitor cells were isolated from harvested bone marrow and cultured with cytokines to stimulate cellular replication. Cells were then genetically modified by exposure to a retrovirus vector encoding human γc (the common γ chain of several interleukin receptors; mutations affecting the γc gene cause SCID-X1). Gene-modified cells (equivalent to 1.3 × 106 CD34+/γc+ cells/kg) were returned to the infant via a central line.Results: T cells were observed in peripheral blood 75 days after treatment, and levels increased rapidly to 0.46 × 109 CD3+ cells/L at 5 months. Within 2 weeks of the appearance of T cells, there was a distinct clinical improvement, with early weight gain and clearance of rotavirus from the gut. However, T-cell levels did not reach the reference range, and immune reconstitution remained incomplete. The infant failed to thrive and developed weakness, hypertonia and hyperreflexia in the legs, possibly the result of immune dysregulation. He went on to receive a bone marrow transplant from a matched unrelated donor 26 months after gene therapy.Conclusions: This is the first occasion that gene therapy has been used to treat a genetic disease in Australia. Only partial immunological reconstitution was achieved, most likely because of the relatively low dose of gene-corrected CD34+ cells re-infused, although viral infection during the early phase of T-cell reconstitution and the infant’s NK+ phenotype may also have exerted an effect.

Samantha L Ginn BSc(Hons), PhD · Julie A Curtin PhD, FRACP · Christine M Smyth MSc, PhD · Margot Latham BSc · Sharon C Cunningham BSc(Hons), PhD · Maolin Zheng BSc(Hons), MSc · Linda Hobson BPharm(Hons) · Peter B Rowe MD, FRACP · Ian E Alexander PhD, FRACP · Belinda Kramer BSc(Hons), MSc · Melanie Wong PhD, FRACP · Alyson Kakakios FRACP · Geoffrey B McCowage FRACP · Debbie Watson BSc(Hons) · Stephen I Alexander FRACP · Alain Fischer MD, PhD · Marina Cavazzana-Calvo PhD · Salima Hacein-Bey-Abina PhD

A family history of allergy and asthma identifies children at high risk of allergic disease. Dietary restrictions in pregnancy are not recommended. Avoiding inhalant allergens during pregnancy has not been shown to reduce allergic disease, and is not recommended. Breastfeeding should be recommended because of other beneficial effects, but if breast feeding is not possible, a hydrolysed formula is recommended (rather than conventional cow’s milk formulas) in high-risk infants only. Maternal dietary restrictions during breastfeeding are not recommended. Soy formulas and other formulas (eg, goat’s milk) are not recommended for reducing food allergy risk. Complementary foods (including normal cow’s milk formulas) should be delayed until a child is aged at least 4–6 months, but a preventive effect from this measure has only been demonstrated in high-risk infants. There is no evidence that an elimination diet after age 4–6 months has a protective effect, although this needs additional investigation. Further research is needed to determine the relationship between house dust mite exposure at an early age and the development of sensitisation and disease; no recommendation can yet be made about avoidance measures for preventing allergic disease. No recommendations can be made about exposure to pets in early life and the development of allergic disease. If a family already has pets it is not necessary to remove them, unless the child develops evidence of pet allergy (as assessed by an allergy specialist). Women should be advised not to smoke while pregnant, and parents should be advised not to smoke. No recommendations can be made on the use of probiotic supplements (or other microbial agents) for preventing allergic disease at this time. Immunotherapy may be considered as a treatment option for children with allergic rhinitis, and may prevent the subsequent development of asthma.

Susan L Prescott BMedSci, PhD, FRACP · Mimi LK Tang PhD, FRACP FRCPA

Allergic bronchopulmonary aspergillosis (ABPA) is an uncommon condition which may complicate asthma and cystic fibrosis; it is seldom considered life-threatening. We report a well 8-year-old boy with cystic fibrosis and normal lung function who progressed to respiratory failure over several days, attributable to ABPA. He recovered with non-invasive ventilation and oral corticosteroid and antifungal medications, regaining normal lung function within 2 months. To our knowledge, such an acute severe presentation of ABPA in a previously well child has not been reported before. Clinical record An 8-year-old boy with pancreatic insufficient, homozygous ΔF508 cystic fibrosis (CF) was transferred from a district hospital with a 7-day history of progressive cough, wheeze and tachypnoea, despite 4 days of broad-spectrum antibacterial therapy (intravenous flucloxacillin and cefotaxime with oral roxithromycin), frequent nebulised salbutamol, oral prednisone (2 mg/kg/day) and chest physiotherapy. There were no other systemic symptoms such as rash, myalgia, arthralgia, diarrhoea or headaches. Initial sputum cultures isolated only normal respiratory flora. The provisional diagnosis was an atypical lower respiratory tract infection, attributed to a viral infection or Mycoplasma pneumoniae. Cystic fibrosis had been diagnosed at newborn screening. His height and weight had tracked along the 10th percentile. Lung function had been normal. Previous sputum cultures had grown Staphylococcus aureus but never Pseudomonas aeruginosa or Burkholderia cepacia. He had not previously wheezed. On arrival, he was mildly dyspnoeic on supplemental mask oxygen at 6 L/minute with a blood oxygen saturation (Spo2) of 94%. He was tachypnoeic (44 breaths per minute), tachycardic (112 beats per minute), afebrile and normotensive. He had bilateral expiratory wheeze with basal crackles. Within 24 hours of transfer, our patient’s condition deteriorated, and he required more frequent nebulised salbutamol and developed signs of respiratory fatigue. At this point an arterial blood gas analysis in 12 L of mask oxygen showed: pH, 7.3; partial pressure of oxygen (Po2), 58 mmHg; partial pressure of carbon dioxide (Pco2), 62.7 mmHg; bicarbonate (Hco3) level, 30 mmol/L; and base excess, 2.7. He was transferred to the paediatric intensive care unit (PICU) for respiratory support with mask continuous positive airway pressure (CPAP). Subcutaneous emphysema developed over the chest wall and neck during the first 48 hours of his PICU admission. A full blood count showed leukocytosis (19.6 × 109/L), and his initial mycoplasma complement fixation test titre was low (< 4). The mycoplasma IgM test result was subsequently negative. Immunofluorescence and culture of nasopharyngeal secretions to isolate a viral pathogen were negative. Total serum IgE titre was 1664 IU (normal range, 0–180 IU) and the skin prick test was positive for Aspergillus fumigatus. The provisional diagnosis was changed to allergic bronchopulmonary aspergillosis (ABPA). Prednisone therapy was continued, and antifungal treatment with oral itraconazole (100 mg twice daily) was added to his therapy. His respiratory status gradually improved and he was weaned off the nasal mask CPAP after 5 days, avoiding endotracheal intubation. He had clinically apparent subcutaneous emphysema, a small pneumomediastinum, but no pneumothoraces during his PICU stay. The chest radiograph before discharge from PICU (Box 1) showed increased perihilar opacities and left lower lobe infiltrates with resolution of the pneumomediastinum and subcutaneous emphysema. His improving spirometry measurements with treatment are shown in Box 2. He was discharged on Day 13 of admission with marked improvement in symptoms and an FEV1 (forced expiratory volume in 1 second) 66% of predicted. A provisional diagnosis of ABPA was confirmed by the significantly elevated serum IgE titre, positive skinprick tests for aspergillus, positive IgG aspergillus precipitins (× 4) and clinical findings consistent with the diagnostic criteria outlined in Box 3.1-5 He received decreasing doses of oral corticosteroids over 3.5 months, as well as oral itraconazole. Within 2 months, his spirometry results had returned to normal. Predictably, he became transiently cushingoid, developed mild untreated hypertension (maximum recorded blood pressure, 116/84 mmHg), and gained 4 kg in weight, but had no glycosuria. He was weaned from corticosteroids and itraconazole, and the side effects resolved within 3 months of discontinuing corticosteroids. Ten months later, he remains well, with normal lung function. DiscussionAlllergic bronchopulmonary aspergillosis (ABPA) is an uncommon condition that can complicate asthma and cystic fibrosis (CF),6,7 and is seldom considered life-threatening.7 The rapid deterioration in the condition of our previously well patient highlights the spectrum of disease severity that can occur in ABPA, and is a reminder that not all deteriorations in respiratory function in patients with CF are attributable to Pseudomonas aeruginosa or Burkholderia cepacia.7,8 Furthermore, this patient’s prompt clinical response to systemic corticosteroids with a return to normal lung function within 2 months suggests that his prognosis will not be adversely affected.9 The presence of Aspergillus species in the sputum cultures of patients with CF has been reported in up to 57% of patients,9 yet the prevalence of ABPA is reported to be between 2% and 14%.1,6 The diagnostic criteria are listed in Box 3. ABPA is a hypersensitivity reaction to the inhalation of aspergillus spores manifesting as chronic wheeze, pulmonary infiltrates and systemic immune activation.5 This results in elevated IgE, IgG and IgA titres.9 Interestingly, although aspergillus grows in the bronchial mucus, this is not an invasive disease.3-5,9 The exact mechanism by which bronchial wall damage evolves and how this gives rise to bronchiectasis and fibrosis is poorly understood.10 Aspergillus fumigatus infection often occurs months before a clinical diagnosis of ABPA is considered. Moreover, as about 40%–50% of school-aged patients with CF have aspergillus in their sputum, comparatively few develop ABPA.3 The reasons for this are not clear, but presumably relate to genetic predisposition, host defences and environmental exposure to aspergillus. Most children with CF who develop ABPA have relatively mild symptoms, respond to treatment over weeks and can often avoid hospital admission altogether.7 Patients with ABPA complicating CF more commonly follow a course of gradually worsening lung function (because of progression of their CF related bronchiectasis) with recurring relapses of ABPA, particularly in summer and autumn, when spore levels in the environment are at their highest.9,10 Treatment of ABPA has centred on the use of systemic corticosteroids for periods of 2–6 months, reducing from doses of 1.0 mg/kg/day of prednisone.4 The adjunctive use of oral antifungals has been advocated for the treatment of ABPA complicating CF11,12 and asthma.6 The response can be dramatic, as in our patient (Box 2). Itraconazole in combination with inhaled corticosteroids was recently shown to be useful for reducing eosinophilic airway inflammation, reducing systemic immune activation and reducing severe exacerbations over a period of 16 weeks in adults with ABPA complicating asthma.13 The use of itraconazole in children is less well studied. However, a recent case series of patients aged 9 to 33 years with CF and ABPA, treated with inhaled budesonide (800–1600 μg/day) and itraconazole (400–600 mg/day), showed a high prevalence of biochemical adrenal insufficiency on adrenocorticotropin testing. This was attributed to an increased systemic budesonide concentration through a reduced or inhibited metabolism (potentially caused by itraconazole), leading to inhibited steroidogenesis.14 This reminds us to use caution when treating patients who take inhaled steroids with courses of itraconazole for exacerbations of ABPA. In conclusion, we are unable to find another case report in which a previously well child with ABPA presented with severe acute respiratory failure. This case highlights the importance of considering a diagnosis of ABPA in highly unusual presentations which may complicate cystic fibrosis. 1 Chest x-ray 3 days after admission to intensive care Shows hyperinflated lung fields, perihilar inflammatory changes, emergence of an interstitial infiltrate in the left lower lobe and a small right-sided pleural effusion. 2 Relationship between IgE levels and FEV1 (forced expiratory volume in one second) before, during and after admission Inverse relationship between IgE levels and FEV1 over time (non-linear scale), showing the drop in lung function at the peak of the disease. 3 Classic case criteria for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis1-5 Clinical deterioration (increased cough, wheezing, exercise intolerance, increased sputum, decrease in pulmonary function) Immediate cutaneous reactivity to aspergillus or presence of serum IgE from A. fumigatus Total serum IgE concentration >1000 IU/L Precipitating antibodies to A. fumigatus or serum IgG from A. fumigatus Abnormal chest x-ray (infiltrates, mucus plugging, or a change from earlier films) Adapted from the ABPA Consensus Conference of the Cystic Fibrosis Foundation4

Emma Skowronski BMedSci · Dominic A Fitzgerald PhD, FRACP

Allergy. Your questions answered. Helen E Smith, Anthony J Frew. Edinburgh: Churchill Livingstone, 2003 (220 pp). ISBN 0 4430 7291 4. This is a compact paperback that will be of interest to primary care physicians, nurses and patients. Despite its size, it covers a broad range of allergic disorders and related topics. The authors are suitably qualified to present a resource such as this. Helen Smith is a reader in primary care medicine at the University of Southampton, and Anthony Frew is an eminent professor of allergy and respiratory medicine in the same institution. The question-and-answer format used throughout the book ensures that it provides a succinct, authoritative opinion on all aspects of allergic disease. Its layout ensures ready access to any topic, with an excellent list of chapter and topic headings as well as an easy-to-use index. There is a list of questions, which are numbered for easy reference. Within each chapter there are highlighted points, clear diagrams and a list of frequently asked patient questions at the end of each section. The material covered in this volume is relevant and up-to-date, and the authors clearly differentiate between factual material and proven therapies, on the one hand, and unproven techniques and therapies on the other. The chapter dealing with unproven diagnostic techniques and therapies is particularly well presented. The authors present a straightforward, honest appraisal of the deficiencies of many of the so-called alternative techniques used by non-medical practitioners in the pursuit of the patient with allergic disease. As with most books written in the Northern Hemisphere, sections on seasonal allergy are of limited use to an Australian audience because of the differences in our pollen seasons. The appendix of useful organisations with website addresses is also of limited use because of the predominantly local nature of this information, although two Australian organisations do rate a mention. There are a number of other international organisations listed in this section. At first glance the suggested retail price of almost $66 appears to be expensive for such a small paperback edition. In fact, this is a beautifully presented and easily accessible textbook on allergic disease, and it will have appeal both as an interesting read and as a reference book for those who desire a working knowledge of the subject. Constance H KatelarisAssociate Professor Department of Clinical Immunology and Allergy Westmead Hospital, NSW Order this book

Constance H Katelaris