Immune system diseases

A child with atopy produces IgE antibodies after exposure to common environmental allergens. The atopic diseases (eczema, asthma and rhinoconjunctivitis) are clinical syndromes each defined by a group of symptoms and signs. Not all children with atopy will have atopic disease or develop symptoms after exposure to an allergen. Both genetic and environmental factors determine the development of atopic disease. The presence of specific IgE antibodies to environmental allergens is determined with skin prick or radioallergosorbent testing in children with atopy. Test results should be interpreted in the context of the clinical history and further investigations (eg, allergen avoidance or challenge). Management of atopic disease is frequently symptomatic, but it is important to avoid identified allergen triggers. Immunotherapy may be considered in selected school-age children with severe rhinoconjunctivitis. Preventing atopic disease in high-risk infants and hindering progression of disease in children with established disease are the areas of active research.

Michael S Gold MD, FCP, FRACP · Andrew S Kemp PhD, FRACP

CorrectionRe: “Prescribing of amino acid formula”, by Andrew S Kemp in the 15 November 2004 issue of the Journal (Med J Aust 2004; 181: 574-575). The author’s position and address were omitted. Dr Kemp is Professor of Paediatric Allergy, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145. andrewk5ATchw.edu.au The html and pdf versions of his letter published in the eMJA were corrected on 21 December 2004.

Andrew S Kemp

Allergic rhinitis (AR) is one of the most prevalent medical conditions. It has significant effects on quality of life and can have considerable socioeconomic effects. The traditional classification of perennial and seasonal rhinitis does not distinguish between provoking factors, nor does it indicate the most appropriate treatment. A more useful classification is based on symptoms, which may be intermittent or persistent, and vary widely in severity. The goal of management is to achieve optimal symptom control. Therapeutic options include allergen avoidance, pharmacotherapy and immunotherapy. Antihistamines and intranasal corticosteroids (INCS) have become the cornerstones of therapy. A variety of effective treatments are available for consumers to self-select, without the advice of a doctor or pharmacist. INCS are widely recognised as the most effective pharmacotherapy for AR, in both adults and children. The efficacy of various preparations is similar, but those with low systemic bioavailability are preferred for children and for patients who are also receiving inhaled, topical or systemic corticosteroids.

Ronald S Walls DPhil, FRACP, FRCPA · Robert J Heddle PhD, FRACP, FRCPA · Mimi L K Tang MBBS, PhD, FRACP, FRCPA · Ben J Basger MSc, BPharm, DipHPharm · Graham O Solley MBBS FACP · Guan T Yeo FRACGP, MBBS

We report two elderly women who presented with hypertensive crisis and acute pulmonary oedema, which responded poorly to antihypertensive therapy. The patients were later diagnosed as having hepatitis C virus-related cryoglobulinaemia. Acute pulmonary oedema is a well-known complication of severe hypertension,1 but, to our knowledge, has never been reported in association with mixed cryoglobulinaemia. We report two patients with severe hypertension who presented with pulmonary oedema which was not controlled until cryoglobulinaemia was diagnosed and treated with plasmapheresis and methylprednisolone. Clinical recordsPatient 1Presentation: A 66-year-old woman presented to our emergency department in late February (winter) with severe dyspnoea of 2 hours’ duration. She had a 10-year history of hypertension, and had had a stroke 3 months before, but had recovered. Over the previous month, her blood pressure had been over 210/120 mmHg, and she had intermittent dyspnoea, orthopnoea and leg oedema. On examination, she was orthopnoeic, with blood pressure of 218/124 mmHg, regular pulse of 126 bpm, and respiratory rate of 36 breaths per minute. She had engorged jugular veins, bilateral chest crackles, hyperpigmentation of the legs and marked bipedal pitting oedema. A chest radiograph showed diffuse haziness over both lungs. Electrocardiography (ECG) showed inverted T waves in leads V4 to V6. Oxygen saturation was 77% while breathing 100% O2 (reference range [RR], 95%–100%). Initial management: The patient was intubated and mechanically ventilated. Her central venous pressure was 13 cmH2O (RR, 3–11 cmH2O), and pulmonary wedge pressure was 19 mmHg (RR, 6–12mmHg). She was treated with intravenous glyceryl trinitrate and diuretics, but over the next 48 hours her blood pressure fluctuated between 300/130 mmHg and 200/90 mmHg, and pulmonary oedema persisted. After 2 days, the patient was extubated. Over the next 24 hours, she developed massive bilateral pleural effusions and numerous petechiae over the legs. Echocardiography revealed a normal left ventricular (LV) ejection fraction (72%) and diastolic dysfunction. Radionuclide angiography confirmed these findings. Laboratory tests showed hypoalbuminaemia, proteinuria (daily protein loss, 9.3 g), haematuria with granular casts, impaired renal function, anaemia and thrombocytopenia (Box 1). Nephrotic syndrome was diagnosed. Further tests revealed a decreased serum concentration of complement components C3 and particularly C4, and markedly raised concentration of rheumatoid factor. However, tests were negative for antinuclear (ANA), anti-double-strand-DNA (anti-ds-DNA), antiglomerulo-basement-membrane and antineutrophil-cytoplasmic antibodies. A cryoglobulin test was positive (Box 2). Immunofixation electrophoresis of the cryoprecipitates showed monoclonal IgM/kappa and polyclonal IgG. A test for hepatitis C virus antibodies (anti-HCV) was then performed and was positive. Diagnosis: On Day 27 of admission, the patient was diagnosed with type II mixed cryoglobulinaemia associated with HCV infection. At that time, her blood pressure was still fluctuating between 230/130 mmHg and 180/100 mmHg, and pulmonary oedema and massive pleural effusions persisted, despite vigorous antihypertensive therapy with frusemide, intravenous glyceryl trinitrate, an α-adrenergic blocker and angiotensin-converting enzyme inhibitors. Repeated thoracocentesis was required to release massive effusions (initially transudative, but later haemorrhagic). Renal biopsy revealed diffuse glomerulonephritis with crescent formation. Management: Plasmapheresis was started on Day 27, along with pulse therapy of intravenous methylprednisolone (500 mg daily for 3 days). After five courses of plasmapheresis in 12 days, the hypertension and pulmonary oedema were controlled. The patient was discharged from hospital on Day 57 of admission. At discharge, serum creatinine level was 141 μmol/L (reference range [RR], 53–106 μmol/L), and she was taking prednisolone (25 mg), diltiazem (180 mg), spironolactone (75 mg) and doxazosin (8 mg) per day. Patient 2Presentation: In February, 2 years after Patient 1, a 77-year-old woman presented to our emergency department with a 1-day history of severe dyspnoea and orthopnoea. She had had hypertension for 3 years. On several occasions during the previous month, her blood pressure had risen to 200/120 mmHg. On examination, she was stuporous, with blood pressure of 200/110 mmHg, regular pulse of 112 bpm, and respiratory rate of 36 breaths per minute. She had engorged jugular veins, bilateral chest crackles, hepatomegaly, ascites and bipedal oedema. A chest radiograph showed bilateral diffuse haziness, and ECG showed a generalised low QRS complex. Blood gas analysis showed pH, 7.43 (RR, 7.35–7.45); Paco2, 3.9 kPa (RR, 4.7–5.3 kPa) and Pao2, 11.2 kPa (RR, 12.7–13.3 kPa) while breathing oxygen through a mask. Initial management: The patient was intubated and mechanically ventilated. Central venous pressure was 12 cmH2O. Echocardiography revealed concentric LV hypertrophy, normal LV ejection fraction, but impaired LV diastolic function. Blood pressure fell to 170–200/90–100 mmHg in 2 days, after diuretic and nitroprusside therapy, but pulmonary oedema and respiratory failure did not decrease, even after haemodialysis. She had massive ascites, bilateral pleural effusions, hypoalbuminaemia, proteinuria (daily protein loss, 3.5 g), haematuria, poor renal function, anaemia and thrombocytopenia (Box 1). Nephrotic syndrome was diagnosed. Levels of both C3 and C4 were markedly low. ANA and anti-ds-DNA antibodies were negative, but rheumatoid-factor titre was markedly high. Cryoglobulin tests on Days 14 and 16 of admission were positive. Immunofixation electrophoresis of serum cryoprecipitates showed polyclonal IgG. HCV tests were negative for anti-HCV antibody but positive for serum HCV RNA. Diagnosis: The diagnosis of type III mixed cryoglobulinaemia associated with HCV infection was thus established on Day 16 of admission. At that time, the patient was still being mechanically ventilated and needed repeated thoracocentesis (effusions were initially yellow, but later became haemorrhagic). Computed tomography of the head showed multiple ischaemic infarcts. Management: Plasmapheresis and methylprednisolone pulse therapy (1 g intravenously daily for 3 days) were started on Day 17 of admission. The patient was extubated the next day and discharged from hospital 2 weeks later, after two courses of plasmapheresis. Serum creatinine level at discharge was 291.5 μmol/L. DiscussionHypertensive crisis with rapid-onset pulmonary oedema has been associated with coronary artery disease,2 renal artery stenosis3,4 and phaeochromocytoma,5 but a search of English-language articles in PubMed revealed no previous reports of an association with mixed cryoglobulinaemia. The latter is characterised by the presence of cold-precipitable cryoglobulins in serum. Underlying diseases include autoimmune and infectious diseases, especially hepatitis C.6-9 “Mixed” indicates that the cryoglobulins in these patients contain either monoclonal plus polyclonal immunoglobulins (type II cryoglobulinaemia), or polyclonal immunoglobulins (type III cryoglobulinaemia).7 In hepatitis C, cryoglobulins usually contain anti-HCV antibody, HCV RNA and IgM rheumatoid factor (ie, anti-IgG autoantibody).9 Cryoglobulins often trigger the formation of immune complexes, leading to immune-complex-type vasculitis, and produce cutaneous, vasomotor, renal and neurological symptoms.7-9 In our patients, factors precipitating the acute pulmonary oedema included hypertensive crisis, renal insufficiency and probably coronary insufficiency. The hypertensive crisis and pulmonary oedema had abrupt onset, progressed rapidly to respiratory failure, were accompanied by nephrotic syndrome, and responded poorly to antihypertensive and diuretic therapy. Our patients had had moderate hypertension for 3–10 years before their blood pressure suddenly rose markedly 2 to 3 months before the development of pulmonary oedema. Hypertension has been found in 37% of patients with cryoglobulinaemia.6 When the underlying disease of cryoglobulinaemia (eg, hepatitis C) flares up, levels of cryoglobulins (which contain HCV-RNA) increase, resulting in higher levels of circulating immune complexes, acute vasculitis and raised blood viscosity. These factors all precipitate the abrupt rise in blood pressure and pulmonary oedema, and explain the failure of conventional antihypertensive agents. Treating cryoglobulinaemia in our patients decreased renal vasculitis and ischaemia, fluid overload, and ultimately hypertension and pulmonary oedema. Coronary vasculitis, found at autopsy in 22% of patients with mixed cryoglobulinaemia,6 could contribute to pulmonary oedema. However, both our patients had a normal LV ejection fraction, suggesting that neither had significant coronary vasculitis. In both patients, acute pulmonary oedema developed in winter. Whether cold weather worsens hypertension by precipitating more cryoglobulins and increasing viscosity awaits further observation. In our patients, the initial features that led to the suspicion of vasculitis were petechiae, proteinuria and haematuria. Further testing revealed decreased complement levels (especially C4). These and other manifestations, including oedema, ascites, recurrent pleural effusions, cerebral infarction and glomerulonephritis, were caused by circulating cold-precipitable immune complexes and resulting vasculitis.6-9 Chronic HCV infection stimulates B-cell clones to proliferate and produce cryoprecipitable IgM antibody with rheumatoid-factor activity10 — an important laboratory index of HCV-related mixed cryoglobulinaemia. However, Patient 2 was negative for anti-HCV antibody, possibly because the sensitivity of the anti-HCV immunoassay, although high, is still suboptimal,11 or because the anti-HCV antibodies were concentrated in cryoprecipitates, and therefore not detectable by the serum assay.7 In both patients, the refractory hypertension and pulmonary oedema responded to plasmapheresis and methylprednisolone therapy. Conventional treatment of mixed cryoglobulinaemia aims to reduce circulating immune complexes through immunosuppression and plasmapheresis.8 Although immunosuppressive therapy alone could ameliorate vasculitis,12 plasmapheresis has shown hypotensive effect in immune-complex nephritis, including mixed cryoglobulinaemia.13 It also reduces plasma viscosity and improves perfusion of the affected organs,14 thus helping in patients with hypertension, encephalopathy or severe renal impairment. Neither patient had a history of blood transfusion, surgery, intravenous drug use or tattooing. They probably acquired HCV infection through non-sterile injections or acupuncture in local clinics, the most common source of HCV infection in Taiwan.15,16 With the increasing prevalence of hepatitis C,17 knowledge of its extrahepatic manifestations is important. Our two patients illustrate the association with mixed cryoglobulinaemia presenting with hypertensive crisis and acute pulmonary oedema. 1 Blood test results before diagnosis of cryoglobulinaemia Test Patient 1 Patient 2 Reference range Serum albumin (g/L) 24 24 32–45 Serum urea nitrogen (mmol/L) 13.9 36.8 2.9–8.2 Serum creatinine (μmol/L) 230 412 53–106 Haemoglobin (g/L) 59 98 120–160 Platelet count (× 109/L) 105 69 150–450 Complement 3 (g/L) 0.62 0.30 0.79–1.19 Complement 4 (g/L) 0.02 0.07 0.17–0.37 Rheumatoid factor 1:10 240 > 1:20 480 < 1:40 2 Cryoglobulin test Cryoglobulin particles float in the serum and precipitate at the bottom of the test tube at 4°C. The particles dissolve on rewarming of serum to body temperature.

Li-Na Lee MD, PhD · Shyh-Chyi Lo MD · Fu-Chi Lin BS · Hon-Ping Lau MD · Jih-Shuin Jerng MD · Pan-Chyr Yang MD, PhD

To the Editor: Recent media reports have claimed numerous health benefits for A2 milk1,2 (eg, “new wave milk”, “wonder milk”). It is becoming more widely available, particularly in health food shops, and is advertised on Queensland television. We believe it is important to offer clear information about this product and cows’ milk allergy. A2 milk is produced by cows homozygous for the A2 polymorphic variant (his→pro) at amino acid 67 of the b-casein gene. A difference in degradation patterns of the A1 and A2 variants is purported to lead to differences in immunological or pharmacological effects,3-5 which we will not comment on here. Regarding cow’s milk allergy, β-casein is one of at least seven proteins in cows’ milk with allergenic significance (α-, β- and κ-casein, α- and β-lactoglobulin, lactoferrin and transferrin). One would not expect a single amino-acid difference in one protein to have a significant effect on milk allergenicity. We have found in discussion with parents of milk-allergic children, as well as from inquiries from the community to AllergySA, that there is a perception that A2 milk may be less allergenic than “normal” milk (which contains A1 and A2 b-casein). Although most proponents of A2 milk have made no explicit claims about allergenicity — and indeed some have cautioned against the use of A2 in milk-allergic individuals — there have been media reports that may have led to this perception.6 However, these reports are misleading. For example, it is quite likely that children with a previous history of cow’s milk allergy who have been found to tolerate A2 milk have in fact “grown out” of the allergy, which is the usual natural history. Others may never have had true milk allergy. We obtained a sample of pure A2 milk from A2 Dairy Marketers (Acacia Ridge, QLD) and used it for skin-prick testing of 11 consecutive milk-allergic children (Box). The tests compared A2 milk with “normal” (A1/A2) milk and cow’s milk protein extract. The mean diameter of the wheal raised by normal milk was not significantly different to that raised by A2 milk (8.2 mm for normal milk v 10.7 mm for A2 milk; P = 0.09, paired t test). No patient had a negative reaction to A2 milk when the reaction to normal milk was positive. We did not perform an oral challenge with A2 milk in these children, as many had experienced severe allergic reactions, and the predictive value of a positive skin-prick test in the presence of a clear recent history of clinical allergy is high. We therefore caution that A2 milk should not be used by those with IgE-mediated cow’s milk allergy, particularly those who have had recent severe reactions to milk. Mean wheal diameter* (mm) on skin-prick testing Patient Normal milk† A2 milk† Cow’s milk extract‡ Histamine positive control 1 12 10 8 4.5 2 11.5 12 11 5.5 3 4 8 6 15 4 8 11 10.5 3 5 12 8 6 9 6 3 5 2 9 7 7 15 7 10 8 7 7.5 5 7.5 9 6 7.5 4 3.5 10 13 25 4.5 3 11 7 9 3 5 Mean 8.2 10.7 6.1 6.8 * As wheals produced are not necessarily circular, it is standard to report diameter as the mean of two measurements taken perpendicular to each other. Results for all negative controls were 0 mm. † Normal and A2 milk were stored frozen, and aliquots thawed for testing. They do not produce wheal reactions in non-allergic individuals. ‡ Cows’ milk extract is manufactured for skin-prick allergy testing by Hollister-Stier, Wash, USA, and purchased from Richard Thomson, Sydney, NSW.

William B Smith · Deryn Thompson · Margaret Kummerow · Patrick Quinn · Michael S Gold

To the Editor: There appear to be regional differences in the prescribing of amino acid infant formula in Australia. This is possibly due to differing practices in use of this formula as a first-line treatment for cow’s milk allergy or as a strategy for preventing allergy. This has financial implications, as the cost to the Pharmaceutical Benefits Scheme (PBS) of amino acid formula is $371 per prescription, compared with $106 for hydrolysed protein formula.1 In infants at high risk of allergic disease who are unable to be completely breastfed, there is evidence that prolonged feeding with a formula based on hydrolysed cow’s milk protein rather than conventional cow’s milk formula reduces infant and childhood allergy.2,3 There is no clear evidence that amino acid formula should be substituted for extensively hydrolysed protein formula as a primary preventive strategy.3 The current PBS indication for hydrolysed protein formula is treatment of intolerance to both cow’s milk and soy protein, but not primary allergy prevention. Similarly, current PBS guidelines restrict the use of amino acid formulas to proven intolerance to cow’s milk, soy protein and protein hydrolysate. Among children who are allergic to cow’s milk, 10% or less are also sensitive to protein hydrolysate formula.4 Thus, if current guidelines were followed, one might expect nine times the use of hydrolysed protein formula compared with amino acid formula. I obtained statistics on PBS items supplied for the period January 2003 to January 2004 from the Health Insurance Commission (www.hic.gov.au/statistics/dyn_pbs/forms/pbs_tab1.shtml) for hydrolysed protein formula (item numbers 2676W and 8259Q) and synthetic amino acid formula (item numbers 3066J, 8443J, 8574G and 8575H). These showed that 8374 hydrolysed protein formula items were supplied, half the number of amino acid formula items (16 886). Numbers of amino acid formula items supplied per 1000 children aged 4 years and younger were calculated using population statistics from the Australian Bureau of Statistics census figures 2001. These are compared in the Box with numbers of paediatric physicians per 1000 children (obtained from the Royal Australasian College of Physicians 2004) and paediatric allergists (derived from the Australasian Society of Clinical Immunology and Allergy membership handbook 2003). Prescribing practice varied markedly between states and territories. The Australian Capital Territory, New South Wales and Victoria had six to seven times more amino acid formula items per 1000 children than Western Australia. This did not appear related to numbers of paediatricians or paediatric allergists, as Western Australia had a similar number of paediatricians and more paediatric allergists per 1000 children than NSW and Victoria. The differences found were unlikely to be related to variation in numbers of adult immunology/allergy specialists, who are unlikely to treat many infants aged under 2 years. Nor were they likely to be due to differing prevalence of combined milk, soy and protein hydrolysate intolerance, as the prevalence of allergic disease does not differ markedly between Australian states. For example, the prevalence of atopic eczema at age 6 years in four cities (Adelaide, Melbourne, Sydney and Perth) was very similar, ranging from 10.1% to 11.4%.5 It seems unlikely that 80% of cases of combined intolerance are being missed in Western Australia. The estimated cost to the PBS for amino acid formula for 2003–2004 of $7 107 627 was 10 times that of hydrolysed formula ($757 570). Amino acid formula prescription rates, January 2003 to January 2004, compared with numbers of paediatric physicians and allergists per 1000 children aged 4 years or younger Amino acid formula items per 1000 children Paediatric physicians per 1000 children Paediatric allergists per 1000 children Australian Capital Territory 22.3 0.79 0 New South Wales 18.8 1.02 0.033 Victoria 17.8 1.00 0.030 Tasmania 12.3 0.53 0.033 South Australia 9.3 1.01 0.067 Northern Territory 9.1 0.92 0 Queensland 5.9 0.72 0.008 Western Australia 3.3 0.99 0.049

Andrew S Kemp

To the Editor: A recent editorial1 and article2 continue to promulgate and link the unproven concepts that patients with chronic fatigue syndrome (CFS) are “deconditioned” and exercise is beneficial in treatment. The cited study by Fulcher and White3 is open to opposite conclusions, depending on their use of the outcome descriptor “better”. If the term is restricted to “much better” and “very much better”, then, as cited by Lloyd,1 16 of 29 people with CFS rated themselves as “better” after a graded exercise program, compared with only 8 of 30 in the control group who completed a flexibility treatment regimen. However, if the “better” descriptor combines “a little better”, “much better” and “very much better”, which is the interpretation used by Wallman et al,2 then the scores for the exercise versus flexibility groups are not different, being 27 of 29 and 26 of 30, respectively, agreeing with the conclusion of Wallman et al.2 Whichever interpretation is applied, any beneficial effect of the graded exercise program in people with CFS in these studies must be independent of any training effect or change in level of “conditioning”, as this was reported in one study,2 but not in the other.3 A fundamental flaw with most exercise studies in CFS is the use of submaximal or symptom-limited tests, which provide notoriously misleading data when compared with maximal exercise testing procedures.4,5 Wallman et al2 correctly identify maximal oxygen consumption as the “gold standard” measure of exercise capacity, yet such measurements were not made in the three articles they cited. When such procedures are applied, the exercise capacity of people with CFS is not significantly different from either measured or age-predicted values for healthy sedentary people.6 Wallman et al2 suggested that maximal testing procedures could favour the recruitment of “more robust or healthier” patients and provide misleading information. In the first place this is denied by the study of Sargent et al,6 in which the illness status reported by patients who completed the maximal tests was similar to that in previous CFS studies. In the second place, the maximal test protocol chosen for a given population should be designed to exclude any influence of fatigue on the metabolic measurements. This is confirmed by the results from the study cited,6 in which the metabolic measurements met the published criteria of a maximal test.4,5 In summary, patients with CFS are not “deconditioned”. Neither their muscle strength nor their exercise capacity is different from that of other sedentary members of the community (> 70%). We remain unaware of any incontrovertible evidence that the various “exercise training” programs suggested in previous articles improve either the physiological or clinical status of people with CFS.

Garry C Scroop · Richard B Burnet

To the Editor: The claim in Lloyd’s editorial1 that “the criteria for diagnosis are well accepted internationally” ignores the recent publication of the Canadian consensus guidelines for the diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome,2 which were sponsored by Health Canada and written by an international group of well published researchers. The Canadian definition of chronic fatigue syndrome (CFS) requires the concurrent presence for six months of fatigue, post-exertional fatigue, sleep dysfunction, pain (including headaches) and neurological/cognitive manifestations, as well as at least one symptom from two of autonomic, neuroendocrine and immune manifestation categories (pp 12–13). These requirements add clinical specificity to the Fukuda criteria and exclude subjects who may have chronic fatigue for other reasons, such as psychiatric disorder without multiple physical symptoms. Lloyd refers to the “recent refinements to improve reliability” in the revision of the research case definition by Reeves et al.3 The SPHERE screening instrument recommended by that article was designed for psychiatric screening in primary care. It arbitrarily classifies people with multiple physical symptoms, often severe in degree and associated with major disability, as having somatisation disorder. This is akin to subclassifying people with severe multiple sclerosis as having somatoform disorder and those with fewer and less severe symptoms as the “core” multiple sclerosis group, a finding which is not supported by the evidence. Conclusions from the article by Wallman et al4 cannot be generalised to the severely ill. Recruitment was from “notices placed in medical surgeries and by advertisements in local newspapers”. Patients with severe CFS, who can barely venture outside their homes and are often too ill to read, would be unlikely to participate. Loblay, Chair of the Royal Australasian College of Physicians Working Group for CFS Clinical Practice Guidelines, urges caution about generalising from exercise studies, which never include people with severe CFS: “All these studies involve people willing and able to participate. The people who find it makes them feel lousy drop out.”5 Lloyd asserts exercise is no longer a question (“. . . graded physical exercise should become a cornerstone of the management approach for patients with CFS”). To promote such a strong, unqualified message to busy general practitioners who may be unfamiliar with the range of severity in CFS risks serious harm to patients.

Ellie Stein · Christine Hunter

In reply: Scroop and Burnet correctly identify the vagaries of the necessarily subjective measurement of outcomes in intervention studies of chronic fatigue syndrome (CFS). Given that muscle strength, endurance and recovery are essentially normal in patients with CFS,1 rather than become too focused on the best approach to measurement of exercise capacity the key issue is whether patients benefit in terms of self-reported symptom severity or functional status. The weight of evidence indicates that graded physical exercise does provide such benefits. Whether this occurs via improvements in aerobic fitness or via the well-recognised psychological and social benefits of exercise is something of a side-issue. Stein and Hunter draw attention to the recently published Canadian consensus guidelines for the diagnosis and management of myalgic encephalomyelitis/CFS. Although this document may provide a welcome recognition for Canadian patients with the disorder, unlike the Australian guidelines,2 it is devoid of an evidence base for the recommendations. Sadly, rather than “add[ing] clinical specificity”, it is also highly likely that the modified diagnostic criteria fall into the trap of preferentially identifying patients with somatisation disorder,3 as such individuals often report large numbers of unexplained symptoms, and hence the addition of 20 or more symptoms to the diagnostic criteria may well bias towards inclusion of such patients. Stein and Hunter are incorrect in the assertion that SPHERE was designed for psychiatric screening in primary care, as the instrument arose out of our studies in CFS specifically seeking to identify clinically significant fatigue states.4 I support the recommendation about caution in generalising from existing published data regarding graded exercise to patients who are severely ill, as such patients are indeed likely to be under-represented in published studies. Nevertheless, it is noteworthy that the recommendations made in the Canadian document cited by Stein and Hunter also clearly support the notion of graded physical exercise: “Patients should gently and gradually increase their level of activity.” Thus, rather than leave the severely affected to continue to “barely venture outside their homes”, I would recommend a carefully designed graded exercise program in the home, with a goal of improving functional performance sufficiently to escape those confines.

Andrew R Lloyd

More accurate food labelling would assist consumers and the food industry alike “We . . . can . . . not be held responsible for its content or any side-effects resulting from exposure to same. Your statutory rights are not affected. May contain traces of nuts” [website disclaimer].1 Conceived as a warning for allergic consumers, born and nurtured as a statement to dissuade potential litigation, the phrase “May contain traces of . . .” now threatens to become immortal as it enters the lexicon as a proxy for a blanket disclaimer. This situation developed as a response to the problem of hidden food allergens. Immediate hypersensitivity to certain foods, with the potential for anaphylaxis and death, affects about 6% of children and 2% of adults.2 Characterised by sudden allergic symptoms on ingestion and confirmed by positive skin and/or radioallergosorbent tests, inadvertent ingestion of a food allergen may require self-injection with adrenaline using an EpiPen (self-injectable adrenaline device) and/or medical resuscitation. Food allergy causes about 25% of anaphylactic deaths in the United Kingdom.3 There is also the distressing scenario of administering and/or witnessing emergency treatment that affects everyone, including parents, friends, carers and schools. “Hidden” allergens are hidden in the sense of being unrecognisable, such as egg in a pudding. In December 2002, Food Standards Australia New Zealand introduced changes to the Food Standards Code, making it mandatory that common food allergens and products derived from those allergens be labelled on packaged foods.4 Foods that are not labelled must have ingredient information available at the consumer’s request. Food allergens that must be declared include egg, milk, peanut, tree nuts, sesame, crustaceans, fish, soy, and cereals containing gluten. There are rare sensitivities for which mandatory labelling does not apply, including anaphylaxis to certain spices5 or fruits.6 In this issue of the Journal, the article by Smith et al7 (page 219) describes the first reported Australian cases of anaphylaxis to lupin, and the authors submit that foods containing lupins, used increasingly in manufactured food products, should be subject to mandatory labelling. Follow-up strategies after anaphylaxis include assessment in a specialist clinic, immunological and food analysis, provision of an EpiPen (now listed under the Pharmaceutical Benefits Scheme), practice with an EpiPen trainer, a written anaphylaxis action plan, a personal allergen identification medallion, access to useful websites (Box), and involvement of carers and schools. Education of children as well as their carers is crucial so that teenagers can walk away from childhood with skills to help keep them safe. There are simple principles to emphasise: Always carry an EpiPen Always read food labels Ask questions about food preparation (be aware of the risk of cross-contamination) No label/no eat No EpiPen/no eat Tell friends about a serious food allergy Tell friends if feeling unwell, especially after eating. How are we to interpret the disclaimer “May contain traces of . . .”? “May contain” means the allergen is stored or processed close to the food product, and/or added to other food lines, but not purposely included in the product. We don’t know the chances of accidental contamination, which may be measurable if the same production line is used, but remote if the allergen is restricted to a separate building. The word “traces” implies extremely small amounts, but defining the allergenic potential of foods, and thus obtaining a threshold dose that triggers reactions in the majority of sensitised subjects, has proved difficult.8 While people with allergies welcomed the 2002 changes to the Food Standards Code, their diet is now more restricted because of the proliferation of these “may contain” precautionary statements. Manufacturers argue that the risks associated with cross-contamination of food ingredients “from paddock to plate”, despite good manufacturing practice, have led to the many variations of “may contain” warnings. This has reduced the already limited food choices of consumers with allergies and has led to a rise in unnecessary avoidance of many foods that may in fact be safe. Since January 2003, Australia has had more than 50 food recalls for undeclared allergens.9 While many of the recalls have involved imported products, an alarming number have related to Australian-made foods recalled as a result of consumer complaints or government testing. How can we improve the current situation? Recently published Australian guidelines recommend that allergen minimisation, rather than banning certain foods, is the appropriate strategy in schools.10 If a school “thinks” it has banned an allergen, a level of complacency may develop among teachers and childcare workers. But if one focuses on allergen minimisation, then it follows that foods that have peanut, for example, in the ingredient list should be left for consumption at home and not sold in the school canteen, but foods that are labelled “May contain traces of . . .” can be allowed at school for the non-allergic school population. We must be alert to newly recognised hidden food allergens, such as the lupins identified by Smith et al.7 Consensus protocols are being developed to determine threshold doses of food allergens,11 and, in time, these may serve as a guide to more accurate labelling. Food manufacturers, food scientists, health professionals and consumer organisations must work towards reducing the number of precautionary statements. The Australian Food and Grocery Council now facilitates an Allergen Working Group, which draws together relevant stakeholders to focus on the needs of consumers with allergies. As Australia imports and exports both food ingredients and packaged foods, steps toward uniform regulations will assist consumers and the food industry alike. In time, with a cooperative approach, we may even find a smarter way of saying “May contain traces of . . .”. Useful websites for information about food allergy Anaphylaxis Australia Inc (www.allergyfacts.org.au) Australasian Society of Clinical Immunology and Allergy (www.allergy.org.au) Food Allergy and Anaphylaxis Network (www.foodallergy.org) Food Allergy and Anaphylaxis Alliance (www.foodallergyalliance.org)

Maria Said RN · John M Weiner MBBS,FRACP, FRCPA

Clinical records Patient 1 A 42-year-old woman developed acute urticaria and angioedema, with throat tightness and cough, after a meal including a bread roll. A more severe anaphylactic reaction, including marked breathlessness requiring oxygen and adrenaline, followed ingestion of the same type of bread roll on another occasion. The only unusual ingredient in this type of bread roll is lupin bran. Skinprick tests with saline extracts of the raw lupin bran and the baked bread roll were strongly positive (Box 1). Tests for allergy to soy and peanut were negative. The patient’s history included seasonal rhinitis with positive skin tests to aeroallergens, but no previous food allergy. She was advised to avoid products containing lupin, as far as possible. She decided not to carry an EpiPen (a self-injectable adrenaline device). A subsequent mild generalised reaction followed ingestion of a specialty bread that was later found to contain lupin bran. Patient 2 A 42-year-old woman developed acute abdominal discomfort, urticaria, facial oedema, cough and shortness of breath 10–15 minutes after eating a bread roll that contained lupin bran (the same type as Patient 1). She was treated at a hospital emergency department with oxygen, salbutamol, promethazine and hydrocortisone. Skin testing was positive to a saline extract of lupin bran (Box 1). Her history included seasonal rhinitis with pollen allergy on skin testing. She was provided with an EpiPen. Patient 3 A 26-year-old woman with a Mediterranean family background had often eaten lupini (boiled/dried lupin in the form of a snack food). On one occasion, after eating commercially prepared lupini from a jar, she developed urticaria, angioedema and respiratory difficulty, requiring hospital treatment with adrenaline. She subsequently tried a small portion of home-prepared, boiled and salted lupini, and had a similar but less severe reaction. She reported experiencing urticaria and angioedema after eating a bread roll (she was unable to find out the ingredients of the roll) and after eating imported European ginger biscuits, which were subsequently noted to contain lupin flour as a labelled ingredient. Skin testing was strongly positive to a saline extract of lupin bran (Box 1). Specific IgE to lupin (12.9 kUA/L; reference range, < 0.35 kUA/L) was identified in her blood by the UniCAP test (Pharmacia Diagnostics, Uppsala, Sweden). She was provided with an EpiPen. Two of the three patients described here were atopic and thus had an increased propensity to develop food allergy, although one of them had no previous food allergies and the third had no previous allergies at all. None was allergic to peanut. None had exercised after eating the implicated foods, and none reacted to normal bread, other wheat sources, or pea. DiscussionIgE-mediated food allergy is an important cause of acute anaphylaxis1 and anaphylaxis-related death.2 The major allergenic foods are well known: peanuts and tree nuts (in people of all ages), milk and egg (mainly in children), and crustaceans and fish (mainly in adults). A variety of other foods are less commonly responsible for anaphylaxis. Peanut-allergic individuals are sometimes allergic to other foods from the legume family, such as soy. Lupin, another legume related to pea, peanut and soy, has been recognised in Europe as a cause of allergic reactions and anaphylaxis.3-5 Lupin flour in food has been reported to produce urticaria and anaphylaxis,3 and may also produce rhinitis and asthma in an occupational setting, through inhalation.6,7 Moneret-Vautrin et al reported that 44% of children allergic to peanut showed positive skinprick responses to lupin, and 7 of 8 who were challenged reacted to lupin flour.8 It seems that lupin allergy may arise by cross-reactivity in people who are already allergic to peanut, or de novo, by primary sensitisation, as in the cases reported here. Lupinus albus (of the genus Lupinus, which has about 500 members, including ornamentals) is the species most widely cultivated for food (Box 2). Dried lupini, prepared by boiling — a traditional snack in some Mediterranean countries (and, in Australia, among migrants from these areas) — have been reported to cause anaphylaxis.5 Lupin flour and bran are widely used in Europe in bread, pasta, biscuits and other baked products, confectionery, and soya substitutes. Inclusion of lupin in wheat flour was officially authorised in France in 1997. It has been identified as a target for allergy surveillance in that country.8 It was introduced in the United Kingdom in 1996 and has been recognised as a new or novel food. A form of “postmarketing surveillance”, analogous to that employed by pharmaceutical companies for new drugs, has been suggested.9 Until recently, lupin was not common in Australian foods, but lupin flour and bran are now entering into food manufacturing, where they contribute protein content, fibre, and some textural properties. Currently, lupin is not covered by mandatory labelling regulations such as are in place for peanut, soy and several other allergenic foods. It is of some concern that, despite relatively restricted use, lupin sensitisation has already become clinically apparent in Australia. According to the current requirements of Food Standards Australia New Zealand (Standard 1.2.4),10 lupin flour, as a separate ingredient or as a component of greater than 5% of a compound ingredient, must be included in the ingredient list on the product label. However, lupin is not part of the mandatory allergy warning system (Standard 1.2.3).10 We believe that it is currently justified to consider it a potentially “hidden” allergen, as bread rolls sold without labels or packaging may contain lupin bran, and indeed at least two and probably three of our patients reacted to an unlabelled food. We suggest that lupin should be considered in cases of unexplained food allergy and should be added to the list of ingredients requiring mandatory allergy warning labelling. 1 Skinprick test results* Average diameter of weal (mm)† Case 1 Case 2 Case 3 Lupin bran 9 12 9 Bread roll crust 10 ND ND Peanut 0 2 0 Pea ND 10 8 Soy 1 1 3 Wheat ND 3 3 Negative control 0 0 0 Histamine positive control 7 5 7 Aeroallergens Positive Positive Negative ND = not done. * Standard skinprick test methods were used. Standard extracts (Hollister-Stier, Wash, USA) were used for all foods except lupin. To test reactions to lupin-containing products, a crude saline extract was prepared by incubating the food in equal volumes of sterile isotonic saline for 10 minutes. This extract produced negative skin test results in 10 atopic (non-legume-allergic) and 10 non-atopic donors, ruling out non-specific irritant effects.† A weal > 3 mm diameter was taken as a positive reaction (note that not all positive reactions correlate with clinical symptoms). 2 Seeds of Lupinus albus, the lupin species most widely cultivated for food Lessons from practice Lupin, a legume, is either eaten whole as lupini or used in the form of flour or bran in food manufacturing. Lupin has the potential to cause anaphylaxis, which may occur by cross-reactivity in people with peanut allergy or may arise de novo in people with no previous food allergy. Currently, lupin may appear on the ingredient label of manufactured foods, but it may also be used as an unlabelled ingredient in some foods, such as bread rolls. Lupin allergy may be investigated by referral to an allergy specialist, and/or specific IgE blood testing (available by special request at some laboratories).

William B Smith FRACP, FRCPA, PhD · David Gillis FRACP, FRCPA · Frank E Kette FRACP, FRCPA, PhD

Graded physical exercise is no panacea, but is beneficial Much remains unknown about the enigmatic clinical disorder chronic fatigue syndrome (CFS). Apart from clear evidence implicating certain infections as a trigger, and reproducible evidence of increased rates of comorbid depression, the aetiology remains obscure.1 Similarly, despite numerous tantalising hypotheses of pathogenesis, including immunological, neuroendocrine and metabolic disturbances, all remain unproven.1 On the positive side, the criteria for diagnosis are well accepted internationally,2 and have been the subject of recent refinements to improve reliability.3 The disorder is well recognised, and about 0.5% of patients attending general practice are identified as having CFS.4 What, then, of treatment for a disorder with so many unknowns? About 40 controlled trials of treatment interventions for patients with CFS have been published to date.1,5 The most striking features of these studies are, firstly, that no curative treatment has been found, and secondly, there has been a remarkable lack of benefit demonstrated from any of the broad array of antiviral, immunological, hormonal, antidepressant and other treatments evaluated. The sole exception lies in the relief of symptoms and improvement in functional capacity provided by programs incorporating graded physical exercise. Several studies have incorporated physical exercise as a component of cognitive–behavioural therapy (CBT). The CBT approach in treatment for patients with CFS is based upon the premise that cognitive attributions and behavioural patterns act as perpetuating factors for symptoms. In particular, given that the cardinal phenomenon of fatigue in CFS is characterised by a marked and prolonged exacerbation of symptoms following minor physical activity, patients may reach the conclusion that it is best to avoid exercise. Thus, patients may develop an understandable cognitive attribution that exercise is harmful in the short term (as symptoms are worsened) and detrimental in the longer term. This leads to altered behaviour in the form of reduced physical activity with consequent deconditioning. Similarly, as sleep typically takes on a characteristic unrefreshing quality, and fatigue is dominant in the symptom complex, patients may consider that increased sleep holds promise for symptom relief and for rapid recovery. This attribution commonly leads to a behavioural pattern of phase-shifted sleep (late night to late morning) and frequent daytime naps. Accordingly, the CBT approach generally seeks to alter these cognitive attributions and modify the associated behavioural patterns. Having established CBT as a beneficial treatment approach, subsequent studies have sought to identify the “active” components of the CBT package. In this regard, graded physical exercise therapy has been found in several studies to be significantly better than comparators such as relaxation therapy, notably in reducing symptom severity and gaining improved function.6-8 In particular, Fulcher and White6 reported that 16 of the 29 patients who completed exercise treatment rated themselves as “much” or “very much” better, compared with eight of the 30 patients in the “flexibility” control group. Similarly, Powell et al7 found that 84% of a selected patient group had significantly improved functional capacity and reduced fatigue 12 months after graded exercise therapy when compared with standard medical care. The report by Wallman et al (page 444) adds to this evidence with a systematic and well-controlled evaluation of graded exercise versus relaxation over 12 weeks.9 Importantly, these authors have incorporated the notion of “pacing” into the exercise program. This concept recognises that individual patients with CFS differ significantly from each other in the amount of physical activity they can achieve before symptoms become exacerbated. In addition, this “threshold” beyond which symptoms worsen may vary over time. Hence, the graded exercise program allowed patients who experienced worsened symptoms to temporarily reduce exercise duration and then to resume once symptoms subsided. Their findings are noteworthy in that multiple parameters of exercise performance, such as resting systolic blood pressure and work capacity, were improved in the active group, indicating that the reconditioning component of the program was indeed effective. In addition, measures of mood and cognitive performance also showed improvement. Interestingly, the proportion of patients who rated themselves as significantly better was not different in the two groups. Unfortunately, no commonly used measure of disability (such as the SF-36)10 was included as a primary outcome measure, as would be typical in studies of chronic medical illness. In addition, the durability of the effects was not examined after the completion of the intervention. Finally, although “pacing” was an important component of the exercise intervention, this approach was not formally evaluated against “unpaced” exercise. Nevertheless, one can safely conclude from these studies that graded physical exercise should become a cornerstone of the management approach for patients with CFS. When applied astutely, including via “pacing”, it may not be realistic to anticipate cure, but it is realistic to expect that patients will feel better and will improve their functional capacity. In combination with appropriate interventions to improve sleep hygiene and to treat any comorbid mood disturbance,11 patients with CFS managed in this way often achieve a substantially better quality of life while awaiting recovery.

Andrew R Lloyd MB BS, MD, FRACP

Objective: To investigate whether 12 weeks of graded exercise with pacing would improve specific physiological, psychological and cognitive functions in people with chronic fatigue syndrome (CFS).Design: Randomised controlled trial.Setting: Human performance laboratory at the University of Western Australia.Participants: 61 patients aged between 16 and 74 years diagnosed with CFS.Interventions: Either graded exercise with pacing (32 patients) or relaxation/flexibility therapy (29 patients) performed twice a day over 12 weeks.Main outcome measures: Changes in any of the physiological, psychological or cognitive variables assessed.Results: Following the graded exercise intervention, scores were improved for resting systolic blood pressure (P = 0.018), work capacity (W·kg-1) (P = 0.019), net blood lactate production (P = 0.036), depression (P = 0.027) and performance on a modified Stroop Colour Word test (P = 0.029). Rating of perceived exertion scores, associated with an exercise test, was lower after graded exercise (P = 0.013). No such changes were observed in the relaxation/flexibility condition, which served as an attention-placebo control.Conclusions: Graded exercise was associated with improvements in physical work capacity, as well as in specific psychological and cognitive variables. Improvements may be associated with the abandonment of avoidance behaviours.

Karen E Wallman BSc(Hons), BEd, PhD · Alan R Morton DipPE, MSc, EdD · Carmel Goodman MD, MB BCh · Robert Grove PhD · Andrew M Guilfoyle PhD

Francisco J Ruiz-Ruiz,* Fernando J Ruiz-Laiglesia,† Juan I Perez-Calvo,‡ Carmen B Torrubia-Perez§ * Home Doctor; †,‡ Associate Professor of Medicine; § Staff Doctor, Servicio de Medicina Interna “B”, Hospital Clínico Universitario “Lozano Blesa”, Avenida San Juan Bosco 15, Zaragoza 50009, Spain. fjruiz1ATterra.es To the Editor: Sarcoid arthritis is often underdiagnosed because it may mimic reactive or rheumatoid arthritis. We report a case which was initially misdiagnosed. A 38-year-old white woman was admitted to hospital because of pain and swelling of her hands and feet. Two years earlier, she had been admitted because of joint pain and erythematous, painful round lesions on her shins. A chest x-ray at that time was normal. She was diagnosed with reactive polyarthritis based on positive serological tests for Rickettsia conorii and Coxiella burnettii. Doxycycline and indomethacin were given and her condition improved. Three days before the current admission her fingers, wrists and ankles had become painful and swollen. There was tenderness and swelling of the metacarpophalangeal, wrist and ankle joints. She was afebrile. Chest x-rays showed an enlarged left hilum. Computed tomography (CT) of the chest (Box) showed lymphadenopathy in the mediastinum and both hila. Her erythrocyte sedimentation rate was 104 mm/h (normal, 3–12 mm/h). Laboratory test results were normal, except for an elevated serum level of angiotensin-converting-enzyme (ACE). A mediastinoscopy was performed, and specimens obtained for biopsy revealed sarcoidosis. Prednisone (30 mg/day) was prescribed and she was discharged 7 days later with no symptoms. “Sarcoid arthritis” is a sarcoid process whose main or unique manifestation is joint disease. Some of its characteristics are seasonal clustering (typically in spring), higher incidence among non-smoking patients, and the presence of the human leukocyte antigen DQ2 (DQB1*0201) and DR3 (DRB1*0301) haplotypes. It occurs slightly more frequently in women. The median age of affected patients is 40 years. The process affects mainly ankle and knee joints symmetrically. Acute sarcoid arthritis is a self-limiting joint disease with a benign prognosis, but some patients can develop chronic sarcoidosis of the lungs, specially those who suffer recurrent episodes of arthritis.1,2 In our patient, the first episode, with associated erythema nodosum, was misdiagnosed as a reactive arthritis as there were false positive serological test results for Rickettsia and Coxiella secondary to an immune polyclonal response. In the second episode, the patient had mediastinal and hilar lymphadenopathy and an elevated ACE level. Although sarcoid arthritis is very often associated with lymphadenopathy and erythema nodosum (Löfgren syndrome), we should keep in mind other forms of joint involvement in sarcoidosis.3 Doctors should consider sarcoid arthritis in the differential diagnosis of seronegative arthritis. Chest x-ray and ACE assay are useful in identifying sarcoidosis. Computed tomography scan showing mediastinal and hilar lymphadenopathy

Francisco J Ruiz-Ruiz · Fernando J Ruiz-Laiglesia · Juan I Perez-Calvo · Carmen B Torrubia-Perez

John M Weiner Allergist, Department of Respiratory Medicine, St Vincent’s Hospital, Fitzroy, VIC 3065. jmweinerATallergynet.com.au To the Editor: Any doubts that many Australian doctors are prescribing inhaled fluticasone for asthma at inappropriately high doses are dispelled by the three reports in the 3 March issue of the Journal.1-3 Fluticasone has a flat dose–response curve for efficacy and a steep dose–response curve for adverse effects;1 individuals with asthma are receiving high doses of inhaled fluticasone;2 and there is a potential for the effects to be lethal.3 Each of these reports restricted its advice to negative recommendations about drug treatment (DON’T overtreat, BACK-titrate), but this is the right time to also promote positive recommendations about asthma management. All individuals with persistent asthma requiring daily therapy should have either skin testing or in-vitro testing to determine the presence of specific IgE antibodies to inhalant allergens.4 This might allow the option of allergen avoidance. In some studies, dust mite reduction was found to ameliorate asthma symptoms in sensitised individuals (National Health and Medical Research Council Level II evidence), although those findings are not supported by a meta-analysis. Repeated low-dose exposure to cat allergen in cat-allergic individuals with asthma leads to increased non-specific bronchial hyperreactivity (Level II evidence).5 Allergen desensitisation in carefully selected cases with consultant supervision can lead to a significant reduction in medication requirement, and reduced specific bronchial hyperreactivity (Level I evidence).6 Treatment of concomitant rhinitis can itself lead to easier asthma control. A checklist of the “A,B,C...” of asthma triggers does not take long and often yields useful tertiary prevention strategies: Allergy (seasonality, dust, pets), Bronchial infection, Cold air/exercise, Drugs, Emotion/stress, Food and food additives, Gastro-oesophageal reflux, Hormones and pregnancy, Irritants including cigarette smoke, and the Job. Inhaled anti-inflammatory treatment using cromolyns or corticosteroids, with or without consideration of oral montelukast, remains the cornerstone of asthma control when the disease is frequent or persistent. However, the search for allergic and other triggers by healthcare workers, individuals with asthma, and their carers can instil into the entire group a culture of prevention, which naturally leads to a brake on overtreatment. Such a culture is firmly entrenched in continental Europe and the United States. In Australia, there has been outstanding research into the epidemiology and immunology of asthma, but it’s at the coalface where the individual with asthma gets advice. A diligent search for triggers, with appropriate management, should start at the first consultation, as the pen (or mouse) is poised to prescribe.

John M Weiner

Previous recommendations for preventing allergic disease need to be critically re-examined A marked increase in allergic disease has occurred over the past century. For example, between 1992 and 1997, the prevalence of asthma increased by 26% and skin-prick sensitivity to house dust mite (HDM) increased by 63% in Australian children.1 In determining the causes of this increase it is important to distinguish between primary and secondary causes of allergic disease. Primary causes are those considered to induce allergic disease in a non-sensitised person, while secondary causes are those that trigger symptoms in people who are already sensitised. Primary prevention strategies are aimed at reducing sensitisation. In the early 1980s it was considered that a clean environment, avoidance of pets, the provision of synthetic "allergy free" bedding (rather than feather bedding) and prolonged breastfeeding were all important in primary prevention. But recent epidemiological studies have challenged these beliefs. There is evidence that a clean environment in early life may actually promote rather than inhibit the development of allergy. The "hygiene hypothesis" is based on epidemiological studies comparing the prevalence of allergic disease in "clean" and "dirty" environments. For example, children growing up in East Germany before the fall of the Berlin Wall had a lower prevalence of allergic disease than children in West Germany, despite having more exposure to pollution and infection.1 These results have been confirmed in similar comparative studies. Other relevant studies supporting the "hygiene hypothesis" have demonstrated fewer allergies in children from large families, in younger siblings, in children exposed earlier to day-care centres, and in children growing up on farms in Europe. Prevention programs for allergic disease have recommended avoidance of pets, particularly cats. However, recent studies showing either less asthma or less sensitisation among children exposed to cats in infancy have challenged this view.2,3 Exposure to cats in infancy does not appear to increase the risk of developing asthma. With regard to sensitisation, the evidence is conflicting, with some studies suggesting decreased sensitisation following cat exposure in infancy and others indicating the reverse. Cat exposure is associated with increased environmental levels of bacterial endotoxin. There is a hypothesis that endotoxin derived from pets may play a role in the prevention of allergy, as endotoxin can induce immune deviation away from "allergic" TH2 responses. The common belief that feather bedding promotes and synthetic bedding prevents allergic disease is now in doubt. This belief arose because of purported allergy to feathers or accumulation of HDM allergen in feather products. In fact, feather pillows contain up to eightfold lower levels of HDM allergen and accumulate this allergen more slowly than synthetic pillows. Children using a feather quilt are less likely to be sensitised to HDM.4 Prospective studies show that use of feather bedding in early childhood is associated with reduced asthma5 and use of synthetic bedding with increased asthma6 in later childhood. Studies of bedding are potentially complicated by selection bias: children with asthma may preferentially use synthetic rather than feather bedding, because of the widely held belief that synthetic bedding is less harmful. It is widely believed that breastfeeding should be recommended for primary prevention of allergic disease. Exclusive breastfeeding beyond four months of age reduces the development of atopic disease in early life,7 but the long-term benefits are now in question. One study has suggested that breastfeeding increases both asthma and allergen sensitisation in adult life;8 however, the fact that the breastfeeding was not necessarily exclusive may be a possible confounder. Another study demonstrated a protective effect of breastfeeding in early life but increased asthma in older children.10 A parental history of allergy is the most important risk factor for childhood allergy. What, then, are we to recommend to parents? Firstly, it is not possible to guarantee that any steps taken will prevent allergic disease. It seems reasonable to recommend exclusive breastfeeding for at least four months to increase the chance of reducing allergic disease in early childhood. It is not clear that the benefits extend to later life. Currently, it is not possible to provide firm recommendations on allergen reduction measures. Local environmental factors are important for HDM replication, and the benefits or otherwise of measures to reduce HDM exposure in infancy need to be demonstrated in the local environment. An Australian study of the effect of HDM reduction measures in infancy is in progress and the results are awaited with interest. Feather pillows or Doonas do not need to be avoided and may in fact be more beneficial than synthetic bedding. Once a child is sensitised, there may be a role for effective HDM encasing on any type of bedding, although again not all studies agree on this issue. Avoidance of household pets is not likely to prevent the development of allergic disease and cannot be recommended as a prophylactic measure. Nevertheless, it is advisable for clinically sensitive patients. It is clear that we need to critically re-examine the previous recommendations given to parents.

Andrew S Kemp FRACP PhD

To the Editor: The working group responsible for the recent chronic fatigue syndrome (CFS) guidelines needs to be congratulated for producing a sensible and well balanced document in a most controversial area.1 Larkins and Molesworth have contributed a somewhat predictable response.2 Some sufferers of CFS can be characterised by their capacity to react strongly to the suggestion that psychological factors may be involved in the pathogenesis of their condition.3 From the perspective of the consultation-liaison psychiatrist, their response can be written with the comments on physical and psychological issues substituted for one another. Hence it can read (1) there is no current evidence that the syndrome has a specific physical origin, and (2) there is evidence that a range of psychological issues occur in people with CFS, although it remains unclear whether these changes are primary or secondary. The mental health movement has worked hard in recent times to reduce the stigma associated with psychiatric conditions. The sufferers of chronic physical illness now accept the importance of looking after their emotional health as well as their physical well-being. Enlightened CFS sufferers and support groups accept the links between physical and psychological morbidity and do not mindlessly exclude the latter. There is ample evidence that cognitive–behavioural strategies and graded exercise programs assist those with CFS, and psychiatrists are skilled in providing these treatments.4

James D Hundertmark

To the Editor: The process of destigmatising chronic fatigue syndrome (CFS) is not advanced by either limiting enquiry to "acceptable" sciences or increasing the stigma already experienced by people with other neuropsychiatric disorders. Contrary to its intent, and in contrast to the recently published Royal Australasian College of Physicians (RACP) guidelines,1 the recent statement by the immediate past president of the RACP and the Chairman of the ME/Chronic Fatigue Syndrome Association of Australia2 is in danger of increasing the stigma for both people with CFS and people with other common mental disorders. Unfortunately, key propositions in their letter ("There is no evidence that the illness is primarily psychological in origin") are clearly at variance with the tone of the guidelines (see Box 1.5, p. S31; Box 1.7, p. S32; and, "Management" summary, p. S38). Their letter reinforces the classical "dualistic" and rather simplistic "biological" approach (eg, "There is significant evidence of a range of biological abnormalities occurring in people with CFS"). Unwittingly, it colludes with community-based beliefs that mental health problems are "not health",3 and often imaginary or under the voluntary control of the patient.4 There is no doubt that people with CFS share many experiences with people with other neuropsychiatric disorders. They both have daily experiences where their credibility is challenged, their disability is minimised and their needs for appropriate medical management are not met. Australian research and best practice have been recognised internationally for emphasising the integration of psychological, psychiatric and biological factors and respect for the experiences of persons with these debilitating disorders.5 Unfortunately, the major advances captured in the guidelines may now be undermined if the RACP is perceived to be backing away from supporting appropriate psychological assessment and provision of effective "psychological" treatments (such as cognitive–behavioural therapy and physical rehabilitation approaches). Similar equivocation has left clinical guideline processes in the United Kingdom in disarray.6 As demonstrated recently, prolonged fatigue syndromes are common in the Australian community, and the vast majority of those who seek healthcare services have concurrent depression or anxiety.7 Real progress towards destigmatisation, meaningful research progress and improved health services for people with CFS will only occur when the field is mature enough to deal with the clear relevance of psychological factors. Instead of rejecting "psychological factors" and associated treatments, relevant professional and consumer bodies should now join with the broader community movement towards increased community awareness of common neuropsychiatric disorders, genuine understanding of their (genetic, "biological", psychosocial and personal) causes and provision of effective (pharmacological and psychological) treatments.8

Ian B Hickie

To the Editor: In the recent letter from Larkins and Molesworth1 various statements are made on which I would like to comment. From time to time everyone becomes physically or mentally exhausted, whether or not it is related to activity. For some people this exhaustion becomes disabling. They deserve understanding and sympathy. We must do everything we possibly can to assist them to recover and to try to find possible causes. Larkins and Molesworth acknowledge that chronic fatigue syndrome is a serious, disabling illness. When does ordinary exhaustion become disabling? I would agree that at this stage there is no clinical evidence that the condition is primarily psychological. Nor is there evidence that it is primarily physical. There may be a mixture. What is the "significant evidence" of a range of biological abnormalities occurring in people with CFS? What are these biological abnormalities and what physiological evidence is there for each one of these abnormalities to produce fatigue? Larkins and Molesworth state that treatment plans should be "within the capabilities of the patient": is there evidence to indicate that stimulating each patient to do just that little more each day will do harm? It was stated that scientific evidence of the aetiology, pathology and treatment is grossly deficient. It is in fact absent. There is no evidence at all. Research is certainly required. One of the problems is that, as soon as a medical advisor informs a patient that investigations have shown no serious abnormality, the patient often goes away and says to himself or herself or family that the "doctor said there is nothing the matter with me and that it is all in my head". Nothing could be further from the truth. Something is the matter and it is up to us to find it out.

Donald D Beard

In reply: We thank the writers for their comments on the CFS guidelines1 and our joint letter about these guidelines.2 Hundertmark remarks on the interplay between physical and psychological factors in morbidity associated with CFS. We trust that our letter in no way contradicts this. Similarly, the inferences that Hickie drew from our letter are not supported by the text of the letter. Far from undermining the guidelines, our letter had the full support of the convenor of the working party responsible for the guidelines. As clearly discussed in the guidelines, in the absence of specific diagnostic tests it is likely that a range of factors may contribute to the pathogenesis of CFS. Assumption of a primarily "psychological" pathogenesis is as unjustified as assumption of a primary "physical" basis. There are "abnormal" test results in many people with CFS, including abnormalities of the hypothalamic–pituitary–adrenal axis and some abnormalities of immune function. As stated, it is controversial whether such abnormalities are primary or secondary. While cognitive–behavioural therapy with graded exercise is effective in some patients, the guidelines outline the deficiencies of the evidence which "significantly limit the generalisability of the findings". As the guidelines indicate, and as is supported by our letter, treatment should be designed in partnership with the patient, and tailored according to the patient's capacity and response. Finally, as implied by Beard's letter, we restate the need for further research into the aetiology, pathology and treatment of CFS. We believe that effective progress in the management of this complex and mysterious illness will be best achieved by positive and cooperative rather than adversarial relationships between those suffering from the condition and the doctors and researchers attempting to help them.

Richard G Larkins · Simon R Molesworth

A 39-year-old man was investigated for three episodes of facial swelling following dental procedures performed between 1999 and 2001. On two occasions the patient was hospitalised and given intravenous antibiotic treatment for cellulitis. The facial swelling was ipsilateral to the dental procedure, unresponsive to antihistamines and not associated with urticaria, laryngeal oedema or bronchospasm. It occurred within about 12 hours of the procedure and resolved over several days. The patient reported a history of rash after penicillin exposure but no prior reactions to local anaesthetic agents. Full blood count, serum complement C3 and C4 levels, C-1-esterase inhibitor level and function were all within the normal range. An antinuclear antibody test was negative, IgE levels were not raised and no latex-specific IgE was detected. Skinprick, intradermal and subcutaneous testing with normal saline, the amide anaesthetics lignocaine and citanest, and the ester anaesthetic procaine showed no evidence of an immediate type 1 allergic reaction. However, two days later the patient reported that a raised area of skin had appeared. Subcutaneous injection with lignocaine resulted in a localised raised erythematous rash 48 hours after injection. A less intense reaction occurred with citanest, and no reaction was detected with procaine or normal saline alone. Histopathology of the skin biopsy from the lignocaine challenge site is shown in Boxes 1 and 2. DiscussionLocal anaesthetics can be classified into ester-type agents (eg, procaine, benzocaine) and amide-type agents (eg, lignocaine, bupivacaine, mepivacaine). Although allergic reactions to local anaesthetic agents are uncommon, both type 1 reactions (via an IgE-mediated mechanism) and delayed-type hypersensitivity (DTH) reactions have been described.1-5 This patient demonstrated a DTH reaction to two agents from the amide class of anaesthetics. Presumably, sensitisation to lignocaine had occurred at the time of previous procedures using the agent. Cross-reactivity with another amide-type local anaesthetic is the most likely explanation for the less intense reaction seen with citanest. Although DTH reactions to local anaesthetics are rare, this case highlights the fact that DTH reactions should be considered in the differential diagnosis of local reactions after procedures using local anaesthesia. This may avoid unnecessary investigations, misdiagnoses and inappropriate treatment. 1: Lignocaine challenge site (skin biopsy; haematoxylin and eosin stain) A dense dermal lymphocytic infiltrate was present around vessels (arrow), with focal spread into the papillary dermis. (Skin from the procaine challenge site showed no such infiltrates.) 2: Lignocaine challenge site (skin biopsy; immunoperoxidase stain) The infiltrating lymphocytes showed strong staining for CD3 surface antigens, typical of a delayed-type hypersensitivity reaction. (Staining for CD4, CD8 and CD4 surface antigens was also positive.)

Louise A Evans MB BS PhD · Judy Pointing RN · Edward J Wills MD FRCPA · Stephen Adelstein MB BCh FRACP FRCPA PhD · John Michalopoulos BDS(Hons)

To the Editor: Reactions to insect bites are unpleasant and can be dangerous.1 Kumar2 commented that people who react to mosquito bites with local itching and inflammation appeared less likely to develop malaria than those with no reaction. In a later personal communication, he gave me unpublished data showing an inverse linear relationship between the severity of the reaction to mosquito bites and the incidence of clinical malaria. Ross River virus infection is endemic in all Australian states. A specific serological test is available to confirm suspicious clinical illnesses. Some people have serological signs of past infection without any history of clinical disease. With Kumar's findings in mind, I asked people with a past history of clinical Ross River virus infection, proven by serology, whether they reacted to mosquito bites. All seven asked said that they had had no reaction. Their main complaint was the noise made by predatory mosquitoes. I then asked patients who were in the same age range and general social class, who lived in the same area and were attending clinics with other diseases, whether they had had any clinical illness diagnosed as Ross River virus infection. Of the 18 asked, none had had the clinical disease or serological tests for the disease. All 18 had moderate to severe reactions and itching with mosquito bites. The Box shows these results Fisher's exact test gives the probability of this finding as 0.0000003. These observations have not explored all aspects of the problem, so this level of probability may be optimistic, but, even so, it makes pointless any further informal collection of data. These findings justify a formal epidemiological study, including antibody titres. It should include those who react to mosquito bites and those who do not, and those with and without a past history of the clinical illness. This informal study suggests that reactions to mosquito bites protect against Ross River virus infection, and parallels Kumar's findings in malaria. There may be behavioural and biological explanations for this finding. People who itch with mosquito bites may take greater precautions to avoid them. Conversely, people who do not itch may spend more time outdoors and be more likely to be bitten. Biologically, reactions to bites may be examples of a generalised protective effect of local reactions against insect-borne diseases. The inflammatory reaction with itching may be a factor in defence against infection3 by limiting or destroying injected parasites and viruses locally or through a more vigorous generalised response that prevents disease or limits infection to a subclinical level. Investigation of local inflammatory response might provide clues to effective prevention and treatment. Reactions to mosquito bites among people with and without evidence of Ross River virus (RRV) disease No reaction Moderate to severe reaction Past RRV disease 7 0 No past RRV disease 0 18

Alan E Dugdale

To the Editor: Cyanocobalamin and hydroxycobalamin are synthetically derived preparations of vitamin B12. Allergy to vitamin B12 injection is infrequent, but may be serious. We describe a patient with allergy to hydroxycobalamin, without cross-reaction to cyanocobalamin. Our patient was a 45-year-old woman with vitamin B12 deficiency. She had positive antiparietal cell antibodies and normal results of Schilling's test after addition of intrinsic factor. Otherwise she was in good health, with no other evidence of autoimmune disease. Her allergy commenced after an intramuscular injection of hydroxycobalamin, with onset of mild generalised pruritus. Subsequent monthly 1 mg injections of hydroxycobalamin were followed by incrementally worsening pruritus, and then frank urticaria. The last of nine injections was followed by urticaria, bronchospasm and oropharyngeal angioedema, which responded to administration of adrenalin. The patient underwent skinprick and intradermal testing with hydroxycobalamin and cyanocobalamin. Wheal-and-flare reactions occurred with injection of dilutions of hydroxycobalamin, suggesting an IgE-mediated response. No reactions were evident with dilutions of cyanocobalamin (Box). Subsequently, the patient had no reaction to a challenge of subcutaneously administered cyanocobalamin 0.1 mL (100 μg), and then intramuscularly administered cyanocobalamin 0.5 mL (500 μg). Her macrocytic anaemia resolved with ongoing monthly injections. After one year of treatment, the patient described an episode of delayed urticaria after a routine cyanocobalamin injection. The skinprick and intradermal tests were repeated, with negative reactions to cyanocobalamin, and wheal-and-flare reactions to hydroxycobalamin. She has since tolerated monthly intramuscular cyanocobalamin for over 12 months. Vitamin B12 allergy is rare, but has been reported.1-3 Positive results of basophil histamine release assay and skin testing suggest an IgE-mediated mechanism.2 Desensitisation is therefore theoretically possible; however, anaphylaxis during desensitisation has occurred.3 In Australia, both hydroxycobalamin (Neo-cytamen, David Bull) and cyanocobalamin (Cytamen, David Bull) are available. The excipients of each preparation are identical — sodium chloride, glacial acetic acid, and sterile water. Although the risk of severe allergy is low, adequate facilities for resuscitation should be available when parenteral vitamin B12 is administered. One approach to dealing with vitamin B12 allergy is to use the alternative compound after skin testing to exclude cross-reactivity. If cross-reactivity occurs, then desensitisation may be considered. Alternatively, oral administration of vitamin B12 may also be used.4 Results of skinprick and intradermal testing with hydroxycobalamin and cyanocobalamin* Dilution Saline (negative control) Morphine (positive control) Hydroxycobalamin Cyano-cobalamin Skinprick 1 : 1000 Negative Positive Positive Negative Intradermal 1 : 100 Negative Positive Positive Negative Intradermal 1 : 10 Negative Positive Positive Negative * A positive reaction was a wheal greater than that of the positive control.

David Heyworth-Smith · Patrick G Hogan

Allergy falls squarely into the class of common disorders caused by interaction between a genetic predisposition and an environmental stimulus. Genetic approaches are revolutionising the treatment of many primary immunodeficiencies, which are caused by single gene defects, but are unlikely to be of therapeutic value in the short term for multifactorial allergic disorders such as asthma, rhinitis and eczema. Nevertheless, advances have been made in our understanding and management of these disorders, which together are among the five most common conditions for which people consult their general practitioners. Prevention. It is unclear why the incidence of atopic diseases, particularly asthma, is rising so sharply in First World countries. Atopic diseases are associated with the persistence beyond infancy of a strong interleukin-4 (IL-4) dominant response by T cells that favour IgE synthesis and inflammation (TH2, or type 2 helper T cells). The "hygiene hypothesis" attributes this persistence to changes in infant diets (such as sterile water), early and increased use of antibiotics within the first year of life with consequent changes in gut bacterial flora, and reduced incidence of bacterial infections because of cleaner homes, smaller families and use of cleaner and more supervised childcare. The data support the view that a less affluent or rural lifestyle is protective.1 Mechanistically, the hypothesis postulates that a "clean lifestyle" is associated with decreased stimulation of the innate immune system because of less exposure to immunostimulatory DNA sequences (CpG motifs) ubiquitous in environmental bacteria. Vaccine adjuvants and DNA vaccines are under investigation that include these bacterial CpG motifs and drive an immune interferon (IFN-γ) dominant cytokine response by type 1 helper T cells (TH1), thereby inhibiting the allergic phenotype. These approaches and other forms of novel allergen-specific immunotherapy may play a preventive role in the future. Diagnosis. Diagnosis of allergy is now more precise, with better standardisation of allergen extracts and increasing use of monoclonal antibodies prepared from recombinant allergen proteins. Commercial diagnostic kits using recombinant antigens should become available within the next five years, particularly for conditions such as latex allergy, for which current tests have low diagnostic sensitivity and specificity.2 The causative mutations have been identified for most of the catastrophic sex-linked and autosomal primary immunodeficiencies, such as adenosine deaminase deficiency and severe combined immunodeficiencies, and prenatal diagnosis of these conditions is now available. Intervention. Some primary immunological disorders resulting from single gene defects can be corrected by gene therapy, largely because the treatment (which would be hazardous if attempted in vivo) can be undertaken ex vivo on cells from the patient's marrow or blood.3 This therapy is available in specialist centres only. Pharmacotherapy for atopic disorders has advanced over the past five years.4 Long-acting β-agonists for symptom control have been extremely effective additions to the treatment regimens for moderate and severe asthma, and exercise-induced asthma. The leukotriene-receptor antagonists are the first new class of asthma drugs for 25 years. Although their role in asthma is still not fully defined, they may be valuable in other allergic and immunological disorders, such as rhinitis, nasal polyposis and urticaria. Once-daily topical corticosteroid preparations are now available for use in rhinitis, asthma and eczema, providing increased topical potency, low systemic bioavailability and improved compliance. Allergic inflammatory processes involve multiple cytokines, decreasing the usefulness of antagonists to single cytokines, such as IL-4 and IL-5, or the anti-Th2 cytokine IL-12. IL-10 therapies were initially unsuccessful, but increasing evidence suggests this cytokine is important in effective immunotherapy, possibly by inducing antigen-specific tolerance (anergy) and by promoting a switch from IgE to IgG4 synthesis. Strategies focusing on IL-10 are likely to increase over the next five years. More recently, a monoclonal antibody directed against IgE has been developed for human use. This agent has potential for treating patients with multiple sensitivities, who benefit little from conventional allergen-specific immunotherapy. Clinical trials demonstrate that it attenuates both early and late asthmatic responses after allergen challenge. However, it is likely to be expensive. Anti-IgE treatments may play an adjunctive role in enhancing safety during rapid updosing of allergen immunotherapy. Allergen-specific immunotherapy may modify the natural course of allergic disorders, or even prevent their occurrence, and is attracting a resurgence of interest, particularly for bee-venom, pollen, cat and latex allergy. Research on vaccines containing the allergenic sites that react with T cells, but not IgE-binding sites (to minimise anaphylactic side effects), should result in new specific immunotherapy products within the next five years.5 Nevertheless, the strong environmental influence in atopic disorders suggests that public health intervention strategies are needed in addition to pharmacotherapy. The real advances of the next decade should come from creative combinations of molecular biology, immunology, pharmacology, genomics and proteomics, and allow us to manage allergic and immunological disorders more effectively and safely.

Robyn E O'Hehir FRACP, PhD, FRCP

The "jack jumper" ant (Myrmecia pilosula) is a major cause of anaphylaxis in Tasmania. We describe four deaths attributed to stings by this ant between 1980 and 1999. All victims were men aged 40 years or over with significant comorbidities; two were taking angiotensin-converting enzyme inhibitors, which may increase risk of severe anaphylaxis. Three victims had known ant-sting allergy, but only one carried adrenaline, which he did not use. Another believed he was protected by previous attempts at hyposensitisation with whole ant-body extract. There is potential to prevent deaths by careful education of people with known allergy, prescribing of adrenaline for auto-injection and development of an effective hyposensitisation therapy. Simon G A Brown, Qi-Xuan Wu, G Robert H Kelsall, Robert J Heddle and Brian A Baldo MJA 2001; 175: 644-647 Clinical records - Discussion - Acknowledgements - References - Authors' details Of 89 described species of bull ants (genus Myrmecia), 88 are found only in Australia.1 Stings are frequent, and allergy is common, especially to Myrmecia pilosula in Tasmania,2 rural Victoria,3 the Adelaide Hills of South Australia and southern New South Wales. Peptide allergens thought to account for most M. pilosula IgE-specific reactions have been identified, cloned and named Myr p I, II4-9 and III. Stings by M. pilosula caused 21%-25% of the 324 cases of anaphylaxis treated with adrenaline in the Royal Hobart Hospital Emergency Department between 1990 and 1998, compared with 13% caused by honeybee stings (Brown, unpublished data). M. pilosula is well known to local people, and recognisable by its size and coloration (Box 1A). It moves in short jerks and jumps, leading to the names "jumper ant", "hopper ant", "jumping jack", and "jack jumper". Nests are defended aggressively and range from a single hole to large mounds a meter in diameter with multiple entrances, typically surrounded by a scattering of fine gravel. Another less common but well-recognised local bull ant is the "inchman" (Box 1B). Our field trips in Tasmania have revealed this ant to comprise one species, identified as Myrmecia forficata by CSIRO (the Commonwealth Scientific and Industrial Research Organisation) Entomology, Canberra. Other species are seldom encountered and unlikely to be a common cause of stings. We present clinical details of four deaths attributed to M. pilosula stings between 1980 and 1999 in southern Tasmania (population, 223 00010). Cases were identified from a manual search of diagnoses in the hospital's forensic register. Immunological methods are shown in Box 2. The study was approved by the Royal Hobart Hospital Ethics Committee. Clinical records Patient 1 In 1989, a 49-year-old man woodcutting in bush told his companions he had been stung by a jack jumper ant. Because of known allergy to these stings, he took two antihistamine tablets. He was left alone for 15-20 minutes and was dead when his companions returned. Past history included hypertension treated with enalapril. Autopsy revealed cardiomegaly, acute on chronic pulmonary congestion and "unusually fluid blood". The pathologist discounted ant-sting anaphylaxis as "exceedingly rare". Tissue from a suspected forearm bite was negative for snake venoms (Dr Struan Sutherland, Medical Consultant, Commonwealth Serum Laboratories, Melbourne, VIC, personal communication). Tests for serum tryptase and venom-specific IgE were not available in Australia at that time. Patient 2 In 1995, a 62-year-old man was thought to have been stung by a jack jumper ant while fishing. He subsequently developed tongue and lip swelling and breathlessness. When a paramedic arrived 20-30 minutes later, he was in cardiac arrest. Resuscitation was unsuccessful. Past history and allergies were not recorded. Autopsy revealed severe oedema of lips and tongue, oedema of the upper airways, extreme lung congestion, diffuse severe atherosclerosis with occlusions of 50%-75%, and marked hypertensive left ventricular hypertrophy. Toxicological screening revealed a blood alcohol level of 0.21 g/100 mL and no other drugs or substances. Serum tryptase level in blood taken three days after death was 2.73 µg/L (reference range [RR], < 2 µg/L). IgE specific to M. pilosula venom was detected by IgE antibody-binding studies (uptake of radioactive label, 15.2%). Reactivity to other venoms was not tested. Patient 3 In 1995, a 40-year-old man reported being stung by a "bull ant" (a term commonly used by local people, including some medical practitioners, when referring to M. pilosula) outside his home in a beachside suburb of Hobart. He injected himself with promethazine (50 mg) and continued to drink alcohol. Some time later, he was noted to be slurring his words and to fall over when going to the bedroom. The precise timeframe was difficult to determine from available records. He was found dead in bed in the early hours of the morning. Past history included obstructive sleep apnoea and progressively worsening systemic allergic reactions to "bull ants", for which he was prescribed intramuscular antihistamine and an adrenaline puffer. The medical records did not mention whether "bull ant" referred to M. forficata or M. pilosula. He was known to be a heavy alcohol user and was also prescribed diazepam and fluoxetine. Autopsy results were unremarkable apart from a fatty liver. Toxicological screening revealed a blood alcohol level of 0.22 g/100 mL and non-toxic concentrations of diazepam and fluoxetine. Serum tryptase level in blood taken three days after death was 2.72 µg/L (RR, < 2 µg/L). Tests for venom-specific IgE revealed high radioactive label uptakes for M. pilosula (31.7%) and the other Myrmecia species tested (M. tarsata, 42.1%; M. simillima, 39.8%; M. pyriformis, 39.6%; M. gulosa, 37.0%; and M. nigrocincta, 24.5%). Patient 4 In 1999, a 65-year-old man working in his backyard in Hobart complained that he had just been stung on the knee by a jack jumper ant, feeling immediately unwell, itchy and short of breath. An ambulance was called, and he collapsed. A paramedic crew arrived five minutes later, when he was found to be deeply cyanosed with no palpable pulses. He had a generalised urticarial rash and was making an occasional respiratory effort without any movement of air. Cardiopulmonary resuscitation was commenced, but bag-valve-mask ventilation was ineffective. Electrocardiogram demonstrated idioventricular rhythm. Paramedics administered a total of 13 mg of adrenaline, but at no stage was a pulse detected. On arrival in hospital 50 minutes after the arrest, laryngoscopy revealed marked laryngeal oedema and a gum-elastic bougie was required to achieve intubation. Resuscitation attempts were ceased shortly thereafter. Past history included allergy to M. pilosula, with unconsciousness on several occasions. Fifteen years earlier, hyposensitisation was attempted with crushed whole-ant preparation. Since then he had been stung once, with what his family recalled to be a less severe reaction, leading him to believe he was protected from further stings. He also had a history of atrioseptal defect repair, chronic atrial fibrillation and impaired left ventricular function. Medications at time of presentation included warfarin, digoxin, bumetanide, carvedilol and fosinopril. Autopsy revealed considerable oedema of the larynx, aryepiglottic folds and adjacent pharyngeal tissues. The lower airways were clear, indicating that aspiration had not occurred. There was no significant coronary artery disease, but there was marked dilatation of the tricuspid and mitral valves and all cardiac chambers. Serum tryptase level in blood taken four hours after termination of resuscitation was 51.6 µg/L (RR, < 12 µg/L). IgE specific to the venoms of M. pilosula and honeybee was detected (radioactive label uptakes, 10.1% and 2.7%, respectively). IgE uptakes to three synthetic venom peptides, Myr p I-III, were 0.4%, 3.2% and 1.0%, respectively. No significant IgE reactivity with European wasp or other Myrmecia venoms was detected. Results of inhibition and immunoblot studies are shown in Box 3. Discussion It has been argued that deaths caused by sting anaphylaxis are under-reported because of lack of circumstantial evidence and the frequent absence of diagnostic postmortem features.15-17 This may be compounded by lack of awareness, as suggested by our first case. IgE specific for M. pilosula venom was detected in the three patient sera tested. In Patient 3, binding of IgE to all tested venoms probably represented true immunological cross-reactivity, as the patient was unlikely to have been exposed to all these ant species, which are found in geographically disparate areas. Cross-reactivity between different Myrmecia venoms is well recognised7 and may lead to anaphylaxis after the sting of a species not previously encountered, which should be made clear to patients. Consequently, the third death may have been caused by the inchman ant, M. forficata, rather than the jack jumper, M. pilosula. Postmortem findings supported anaphylaxis as a cause of death in all patients except Patient 3. In about half the deaths caused by anaphylaxis, no cause of death is evident at autopsy.17 In Patient 3, the apparent long interval between the sting and death, along with the significant comorbidities, raises the possibility that death was caused by a combination of moderately severe anaphylaxis, intoxication (alcohol, benzodiazepine and antihistamine) and obstructive sleep apnoea. Although the median time from sting to cardiac arrest in fatal cases is 15 minutes, significant delays of several hours may occur.18,19 Serum mast-cell tryptase level was markedly raised in Patient 4, but only marginally raised in the other two patients tested. The reference range for the technique used in 1995 was < 2 µg/L,11 and levels do not increase after death.20 Baseline tryptase levels are raised in some people with sting allergy because of underlying mastocytosis.21 Using 10 µg/L as the cut-off level, postmortem serum tryptase level has 86% sensitivity and 88% specificity for predicting death caused by anaphylaxis.22 Tryptase level is not raised in many anaphylaxis cases, despite raised histamine levels,23 and tryptase may not enter the circulation until 30 minutes after exposure, peaking 1-2 hours after exposure if the circulation remains intact.24 Tryptase half-life is two hours with an intact circulation, increasing to four days after death.24 In Patient 4, the clear-cut reactivity of IgE antibodies with whole venom was not replicated with synthetic peptides. While whole venom produced 80%-90% inhibition of IgE binding, synthetic peptides at much higher concentrations produced only 35% inhibition. Immunoblotting results suggested that the peptide components separated by gel electrophoresis also had low reactivity to IgE in this patient's serum. A review of serum from 273 people allergic to M. pilosula venom reveals that, of those with positive reactions to whole venom, 19% show little or no reactivity with Myr p I or Myr p II. Immunoblotting with some of these sera demonstrated four previously unidentified IgE-binding bands with molecular weights 11.7, 16.9, 25 and 43.5 kDa (Wu and Baldo, unpublished data). These findings have significant implications for immunotherapy. In the absence of further data on interactions with T-cell epitopes, it cannot be assumed that these synthetic peptides will be effective substitutes for native venom immunotherapy. Notably, we did not identify deaths of young healthy individuals. This repeats the pattern observed for bee and wasp sting allergy,15,19 and is consistent with the observation that adult males tend to have more severe reactions to bee stings.25 All victims in this series were men aged 40 or over with significant comorbidities. Two of the patients used angiotensin-converting enzyme (ACE) inhibitors, combined with a β-blocker in one case. These drugs may have contributed to the deaths or may simply have been a marker of underlying conditions that determined outcome. ACE is a kininase; inhibitors of this enzyme can trigger severe anaphylaxis in patients undergoing venom immunotherapy,26 possibly because of decreased breakdown of vasodilator kinins activated during anaphylaxis or compromise of compensatory activation of the renin-angiotensin system.27 In addition, β-blockers may both impair the endogenous adrenergic stress response and counteract and imbalance the effect of exogenous adrenaline. Interestingly, patients with severe venom allergy have reduced activity of the renin-angiotensin system, despite normal kininase activity.28 Drugs that selectively inhibit the angiotensin II-1 (AT1) receptor, such as losartan, may have less deleterious effects than ACE inhibitors. In patients undergoing haemodialysis, losartan may be associated with a lower incidence of anaphylactoid reactions than kininase inhibitors,29 but no data are available on anaphylactic reactions to external allergens. Three of the victims had previously sought medical attention for ant-sting allergy. In contrast, larger (and probably more representative) studies of sting-allergy deaths show that a minority of victims have a previous history of systemic sting allergy.16,19 Despite the known histories of sting allergy, only one of the victims had been prescribed adrenaline, which was not used. Another patient believed he was protected by previous immunotherapy with crushed whole ant-body extract. This technique has been shown to be no better than placebo in the only rigorously conducted trials available — for bee and wasp sting allergy30,31 — and is no longer available for the treatment of jack jumper venom allergy. The optimal duration of immunotherapy is also unknown — indefinite continuation has been recommended for those with a history of severe reactions, such as Patient 4.32 These cases illustrate that the severity of reactions in allergic individuals can be unpredictable. There is potential to prevent deaths by careful patient counselling, prescribing of adrenaline for auto-injection and development of an effective hyposensitisation therapy. Currently available synthetic allergens may not reproduce enough of the immunological activity of M. pilosula venom to produce hyposensitisation. Therefore, we are currently conducting a trial of hyposensitisation therapy using native M. pilosula venom. Acknowledgements The authors thank Dr Catherine Morgan (Emergency Medicine Department, Royal Hobart Hospital) for her assistance with the manual search of the hospital forensic medical register. This work was supported by a grant from the Royal Hobart Hospital Research Foundation. References Ogata K, Taylor RW. Ants of the genus Myrmecia Fabricus: a preliminary review and key to the named species (Hymenoptera: Formicidae: Myrmeciinae). J Nat Hist 1991; 25: 1623-1673. Clarke PS. The natural history of sensitivity to jack jumper ants (Hymenoptera formicidae Myrmecia pilosula) in Tasmania. Med J Aust 1986; 145: 564-566. Douglas R, Weiner J, Abrahamson M, O'Hehir R. Prevalence of severe ant venom allergy in southeastern Australia. J Allergy Clin Immunol 1998; 101: 129-131. Ford SA, Baldo BA, Weiner J, Sutherland S. Identification of jack-jumper ant (Myrmecia pilosula) venom allergens. Clin Exp Allergy 1991; 21: 167-171. Donovan GR, Baldo BA, Sutherland S. Molecular cloning and characterization of a major allergen (Myr p I) from the venom of the Australian jumper ant, Myrmecia pilosula. Biochim Biophys Acta 1993; 1171: 272-280. Donovan GR, Street MD, Tetaz T, et al. Expression of jumper ant (Myrmecia pilosula) venom allergens: post-translational processing of allergen gene products. Biochem Mol Biol Int 1996; 39: 877-885. Street MD, Donovan GR, Baldo BA, Sutherland S. Immediate allergic reactions to Myrmecia ant stings: immunochemical analysis of Myrmecia venoms. Clin Exp Allergy 1994; 24: 590-597. Street MD, Donovan GR, Baldo BA. Molecular cloning and characterization of the major allergen Myr p II from the venom of the jumper ant Myrmecia pilosula: Myr p I and Myr p II share a common protein leader sequence. Biochim Biophys Acta 1996; 1305: 87-97. Donovan GR, Street MD, Baldo BA. Separation of jumper ant (Myrmecia pilosula) venom allergens: a novel group of highly basic proteins. Electrophoresis 1995; 16: 804-810. Australian Bureau of Statistics. 1996 Census of Population and Housing. Basic Community Profiles State of Tasmania (Greater Hobart and Southern Statistical Divisions). Data summaries available online [Cited 2001 Nov 04]. Available at <http://www.abs.gov.au/ausstats> Enander I, Matsson P, Nystrand J, et al. A new radioimmunoassay for human mast cell tryptase using monoclonal antibodies. J Immunol Methods 1991; 138: 39-46. Fisher MM, Baldo BA. Mast cell tryptase in anaesthetic anaphylactoid reactions. Br J Anaesth 1998; 80: 26-29. Donovan GR, Street MD, Baldo BA, et al. Identification of an IgE-binding determinant of the major allergen Myr p I from the venom of the Australian jumper ant Myrmecia pilosula. Biochim Biophys Acta 1994; 1204: 48-52. Tovey ER, Ford SA, Baldo BA. Enhanced immunodetection of blotted house dust mite protein allergens on nitrocellulose following blocking with Tween 20. Electrophoresis 1989; 10: 243-249. Harvey P, Sperber S, Kette F, et al. Bee-sting mortality in Australia. Med J Aust 1984; 140: 209-211. Mosbech H. Death caused by wasp and bee stings in Denmark 1960-1980. Allergy 1983; 38: 195-200. Pumphrey RS, Roberts IS. Postmortem findings after fatal anaphylactic reactions. J Clin Pathol 2000; 53: 273-276. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30: 1144-1150. Sasvary T, Muller U. Fatalities from insect stings in Switzerland 1978 to 1987. Schweiz Med Wochenschr 1994; 124: 1887-1894. Yunginger JW, Nelson DR, Squillace DL. Laboratory investigation of deaths due to anaphylaxis. J Forensic Sci 1991; 36: 857-865. Ludolph-Hauser D, Rueff F, Fries C, et al. Constitutively raised serum concentrations of mast-cell tryptase and severe anaphylactic reactions to Hymenoptera stings. Lancet 2001; 357: 361-362. Edston E, van Hage-Hamsten M. Beta-tryptase measurements post-mortem in anaphylactic deaths and in controls. Forensic Sci Int 1998; 93: 135-142. Lin RY, Schwartz LB, Curry A, et al. Histamine and tryptase levels in patients with acute allergic reactions: An emergency department-based study. J Allergy Clin Immunol 2000; 106 (1 Pt 1): 65-71. Schwartz LB, Yunginger JW, Miller J, et al. Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest 1989; 83: 1551-1555. Roberts-Thomson PJ, Harvey P, Sperber S, et al. Bee sting anaphylaxis in an urban population of South Australia. Asian Pac J Allergy Immunol 1985; 3: 161-164. Tunon-de-Lara JM, Villanueva P, Marcos M, Taytard A. ACE inhibitors and anaphylactoid reactions during venom immunotherapy. Lancet 1992; 340: 908. van der Linden PW, Struyvenberg A, Kraaijenhagen RJ, et al. Anaphylactic shock after insect-sting challenge in 138 persons with a previous insect-sting reaction [see comments]. Ann Intern Med 1993; 118: 161-168. Hermann K, von Tschirschnitz M, Ebner von Eschenbacj C, Ring J. Histamine, tryptase, norepinephrine, angiotensinogen, angiotensin-converting enzyme, angiotensin I and II in plasma of patients with hymenoptera venom anaphylaxis. Int Arch Allergy Immunol 1994; 104: 379-384. Saracho R, Martin-Malo A, Martinez I, et al. Evaluation of the Losartan in Hemodialysis (ELHE) Study. Kidney Int 1998; 68 Suppl: S125-S129. Hunt KJ, Valentine MD, Sobotka AK, et al. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med 1978; 299: 157-161. Muller U, Thurnheer U, Patrizzi R, et al. Immunotherapy in bee sting hypersensitivity. Bee venom versus wholebody extract. Allergy 1979; 34: 369-378. Golden DBK, Kwiterovich KA, Kagey-Sobotka A, Lichtenstein LM. Discontinuing venom immunotherapy: Extended observations. J Allergy Clin Immunol 1998; 101: 298-305. (Received 26 Jun, accepted 15 Oct, 2001) Authors' details Department of Emergency Medicine, Royal Hobart Hospital, Hobart, TAS. Simon G A Brown, FACEM, Director. Molecular Immunology Unit, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, NSW. Qi-Xuan Wu, MB BS, MMed, Research Assistant. Office of the State Forensic Pathologist, Royal Hobart Hospital, Hobart, TAS. G Robert H Kelsall, FRCPA, Director of Forensic Pathology. Department of Immunology, Allergy and Arthritis, Flinders Medical Centre, Adelaide, SA. Robert J Heddle, FRACP, PhD, Director of Allergy. Research Laboratory, NSL Health Limited, Melbourne, VIC. Brian A Baldo, PhD, Research Director. Reprints will not be available from the authors. Correspondence: Dr Simon G A Brown, Department of Emergency Medicine, Royal Hobart Hospital, GPO Box 1061L, Hobart, TAS 7001. Simon. BrownATutas.edu.au Make a comment 1: Common bull ants (genus, Myrmecia) of Tasmania A B A: The "jack jumper" ant (Myrmecia pilosula) is 10-12 mm long and jet black, except for yellow or orange mandibles and leg tips. B: The "inchman" ant (Myrmecia forficata) is 15-20 mm long with a purple-brown body and black abdomen. Although other Myrmecia species appear similar, M. forficata appears to be the only such species found in appreciable numbers in southern Tasmania. Back to text 2: Immunological methods Immunological studies were performed at the Molecular Immunology Unit of the Kolling Institute of Medical Research, Sydney, NSW, during each forensic investigation. Serum tryptase levels: Tryptase released from mast cells was measured in postmortem serum by radioimmunoassay (reference range, < 2 µg/L in 1995; and < 12 µg/L in 1999, because of reagent changes).11,12 IgE antibody-binding studies: Patient IgE specific for venom was measured by incubating patient serum with venom-coated nitrocellulose discs. IgE that bound to the discs was measured using 125I-labelled anti-IgE, and results expressed as percentage uptake of the radioactive label. Uptake > 2% was considered positive.7 Inhibition studies: The specificity of patient IgE for synthetic venom peptides was investigated as described previously.7,13 Patient serum was pre-incubated with whole venom or synthetic venom peptides to neutralise specific IgE. Remaining venom-specific IgE was then measured by uptake to venom-coated discs as described above, and compared with levels in serum that was not pre-incubated. Percentage inhibition of IgE due to the venom or peptide was calculated. Immunoblot: To investigate specificity of patient IgE further, venom components separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) were transferred to nitrocellulose and then probed with patient serum. Binding of patient IgE to venom components in the gel was detected using 125I-labelled anti-IgE and autoradiography.5,14 Back to text 3: Inhibition and immunoblot studies in Patient 4 Inhibition of IgE binding by Myrmecia pilosula whole venom and synthetic venom peptides Whole M. pilosula venom was a potent inhibitor of IgE binding. Of the purified peptides, only Myr p II caused significant inhibition, which was markedly less than that produced by whole venom. Immunoblot studies (not shown) No binding of patient IgE to venom components separated by SDS-PAGE and transferred to nitrocellulose was identified initially by autoradiography. However, after 2 weeks of film exposure, bands previously noted to represent Myr p II9 became visible. No binding to other bands was apparent. Interpretation These findings suggest that the synthetic peptides and separated venom components do not account for the total allergenic activity of M. pilosula venom, as represented by IgE binding. Back to text

Simon G A Brown · Qi-Xuan Wu · G Robert H Kelsall FRCPA · Robert J Heddle · Brian A Baldo