Immune system diseases

As sickle cell disease is increasing in Australia, paediatricians and other health care providers need to be aware of the broad range of complications that can occur in this condition. Although the complications of splenic sequestration and chest crises are well recognised, the infrequent but equally dramatic complication of hyperhaemolysis is less well appreciated. Here, we report a case of hyperhaemolysis in a Victorian paediatric patient.11 Clinical recordA 12-year-old boy with sickle cell disease (homozygous haemoglobin S) presented in July 2006 with abdominal pain and fever — symptoms of a vaso-occlusive crisis. His usual baseline haemoglobin level ranged from 65 g/L to 75 g/L. He was thriving, but had a history of numerous vaso-occlusive crises. His past management included repeated transfusions with Rhesus and Kell phenotypically matched, leukocyte-depleted (LD) red cells. During this admission, he was managed with intravenous (IV) fluids, IV analgesia, antibiotics and a transfusion of 1 unit of phenoytpically matched, crossmatch compatible, LD red cells. His pain gradually resolved and he was discharged home. Twenty-four hours after discharge (7 days after the transfusion), he re-presented with marked lethargy, jaundice, tachycardia, and no increase in splenic size. His haemoglobin level was 45 g/L and reticulocyte count was increased, at 444 × 109/L (reference range, 20–200 × 109/L). He received a transfusion of a further 2 units of red cells (about 500 mL). However, he remained pale after the transfusion and his haemoglobin level had further decreased to 39 g/L. He also developed profuse haemoglobinuria. Based on his estimated blood volume of 2350 mL, the total transfusion of 750 mL during the two admissions would equate to an increase in haemoglobin of 55 g/L, so the observed drop in haemoglobin level was consistent with haemolysis of both recipient and donor red cells. No red cell alloantibodies or autoantibodies were detected. A presumptive diagnosis of sickle cell hyperhaemolysis syndrome was made. Further transfusions were avoided, and the patient was treated with IV immunoglobulin (IVIG) (1 g/kg) and high-dose IV steroids (methylprednisolone, 20 mg/kg/day). IV mannitol and hyperhydration were commenced to avoid free haemoglobinaemia-associated renal damage. The patient recovered after 1 week and was discharged, with a haemoglobin level of 71 g/L. Six months later, the patient experienced a further episode of marked haemolysis that occurred after a red cell transfusion for vaso-occlusive crisis. He presented to hospital 5 days after the transfusion with a 48-hour history of increasing pain, increased jaundice and discoloured urine. His bilirubin level was 129 μmol/L (reference range, < 10 μmol/L) (unconjugated, 125 μmol/L; conjugated, 4 μmol/L), which was greater than a previous measurement of 77 μmol/L. Again, no red cell alloantibodies or autoantibodies were detected, and his reticulocyte count was elevated, at 303 × 109/L. His haemoglobin level continued to fall after admission, reaching 24 g/L after 24 hours. He was managed with further IVIG and high-dose steroids. In view of his ongoing marked, symptomatic anaemia after 3 days of this treatment, he was transfused with 250 mL of phenotypically matched red cells, without complication, and was discharged 2 days later with a haemoglobin level of 71 g/L. He did not re-present with further haemolysis. Follow-up is ongoing, with management as clinically indicated. This was a prolonged and dramatic event for the child and his family. Placing him on a regular transfusion program was discussed, but the risks of repeated transfusions and the possibility, although small, of another hyperhaemolysis event were considered to outweigh the benefits of maintaining a higher haemoglobin level in a child who was thriving. If a regular transfusion program were to be considered again in the future, it would be prudent to assess the risks and benefits of exchange transfusion. Treatment with erythropoietin was also considered but deemed unnecessary at this time. Pretransfusion steroid treatment was considered an appropriate addition to the future management of this patient. DiscussionSickle cell disease is increasing in incidence in Australia due to immigration patterns involving increasing numbers of people from regions where the disease is common, such as Africa.1 Although hyperhaemolysis in sickle cell disease has been recognised for more than 20 years, this case highlights it as an uncommon but potentially life-threatening complication, involving destruction of both donor and recipient red cells after red cell transfusion.2-5 Haemolysis can be rapid and profound. Onset is usually within 7 days after transfusion and is characterised by severe intravascular haemolysis, haemoglobinuria, and anaemia to levels of haemoglobin lower than pretransfusion levels. Reticulocytopenia may be present. Hyperhaemolysis has also been reported in patients with β thalassaemia and myelofibrosis.6,7 Recurrent hyperhaemolysis is unusual in children, with few available data pertaining to this phenomenon in the paediatric population. The information provided by patients in whom recurrence occurs is particularly valuable. Human leukocyte antigen antibodies were not tested in the patient described here, nor were his haemoglobin S levels followed during these episodes. Measurement of these parameters in other affected patients would add to the body of data and knowledge on hyperhaemolysis. The exact mechanisms responsible for hyperhaemolysis are not fully understood. High-performance liquid chromatography analysis of urine in a patient with haemoglobinuria after red cell tranfusion demonstrates both donor and recipient haemoglobin.8 In typical haemolytic transfusion reactions, alloimmune mechanisms are responsible, with the development of red cell antibodies in the patient against antigens present on donor red cells. The antigens most commonly implicated are those of the Rhesus, Kell, Kidd, Duffy and MNSs blood group systems. Haemolytic reactions due to alloimmunisation are associated with haemolysis of donor red cells only, and laboratory testing usually leads to identification of the causative red cell antibodies. Suggested mechanisms for hyperhaemolysis include cytokine-mediated haemolysis or uncontrolled macrophage activation.9-11 Recommended treatment of hyperhaemolysis includes avoidance of transfusion where possible and immune modulation with steroids and IVIG.3,5,8 The mechanism of action of steroids and immunoglobulin has not been fully elucidated, but these treatments have been demonstrated to be effective in a number of patients. Repeated exposure to red cells after recovery may lead to recurrence of hyperhaemolysis, as seen in this case. Erythropoietin may be used in an attempt to reduce the need for further exposure to transfused red cells.3 Prompt referral for expert management is essential. Hyperhaemolysis is an uncommon but potentially fatal complication of sickle cell disease. Recognition of this unusual complication is important for medical staff who manage patients with sickle cell disease in Australia.

Ian C Stokes BSc(Hons), BM BS · Peter A Downie MB BS, FRACP · Erica M Wood MB BS, FRACP, FRCPA · Donald K Bowden MB BD, FRACP · Paul T Monagle MB BS, FRACP, FRCPA · Chris D Barnes MB BS, FRACP, FRCPA

To the Editor: A 69-year-old Indigenous Australian man, with no known Caucasian ancestry, presented in 2008 with a 7-week history of depigmentation of the face and neck, which was initially intensely pruritic and erythematous. He had neither a personal history nor family history of vitiligo, but a 2 mm thick, Clark level III, superficially spreading melanoma had been widely excised from his right lateral calf in 2001; results of a right inguinal sentinel node biopsy had been negative. In 2005, multiple small local recurrences on the right lower leg had been surgically removed. Two years later, further histologically confirmed local cutaneous and subcutaneous recurrences were excised, but new lesions continued to develop. His medical history included type 2 diabetes mellitus, hypertension, atrial fibrillation and coronary artery bypass grafting. He had no family history of melanoma. The onset of facial inflammation and depigmentation over a few days in 2008 was associated with complete regression of some leg lesions and partial regression of others. The facial inflammation settled spontaneously within a week. Computed tomography of the abdomen and pelvis at this time did not show any distant disease. The patient was unconcerned by the depigmentation and declined treatment. Over the following 5 months, the extent of his head and neck depigmentation increased (Box, A) and he developed more melanomas on his right lower leg, including one with a depigmented rim (Box, B). Positron emission tomography identified several areas of focally increased metabolism corresponding to the right lower leg lesions, but no evidence of disease elsewhere. The leg lesions have demonstrated only slow progression, and the patient continues to have 6-monthly follow-up at our department, as well as ongoing local review. Cutaneous melanoma is rare in Indigenous Australians, with only two reported cases of acral lesions.1,2 In melanoma, immunogenic factors may play a key role in disease course. Antibodies that cross-react with antigens on melanocytes and melanoma cells, such as tyrosinase, tyrosinase-related-protein-1 and tyrosinase-related-protein-2, can lead to both vitiligo-like autoimmune depigmentation and tumour regression.3 T-cell-mediated responses to melanoma antigens, such as MART-1 (melanoma antigen recognised by T-cells-1), are also enhanced in melanoma patients with depigmentation,3 which has been reported in approximately 3% of patients with stages III and IV melanoma.4 Vitiligo is a positive prognostic factor and has been reported in association with tumour regression distant from the depigmentation.4 In conclusion, this case of vitiligo-like depigmentation, affecting both the head and neck and a cutaneous metastasis, highlights the immune responsive potential of metastatic melanoma. Vitiligo-like depigmentation associated with melanoma in a 69-year-old Indigenous Australian man A: Extensive depigmentation of the face and neck 5 months after the onset of vitiligo. B: Depigmentation around the largest subcutaneous metastasis on the right lower leg.

Elizabeth M Christou · Diona L Damian · John F Thompson

Currently available, relatively safe vaccines may help tackle this serious and increasing public health problem Melanoma is a serious public health problem in many countries throughout the world, with an incidence increasing at a faster rate than that of any other cancer except lung cancer among women.1 In Europe and the United States, the incidence increased threefold between 1970 and 2000, although improved awareness meant that the mortality rate did not rise so steeply. The risk of melanoma varies greatly (around 100-fold) from region to region, with the highest risk being in Australia where, in 2003, the annual risk was 46.9 per 100 000 population, with estimated lifetime risks of one in 28 and one in 19 up to the ages of 75 and 85 years, respectively.2 With the exclusion of non-melanotic skin cancers, melanoma was the fourth most prevalent cancer in Australia, accounting for 10% of all cases, and the age-standardised risk of melanoma increased by 14% between 1993 and 2003. There are anecdotal reports of regression and even complete resolution of melanoma in patients who had developed serious febrile infections.3 Although these cases are rare and perhaps coincidental, they encouraged us to conduct epidemiological studies on the impact of prior infectious diseases and vaccinations on the risk of melanoma. We therefore established the Febrile Infections and Melanoma (FEBIM) working group in six European countries and Israel, within the Epidemiological Section of the Melanoma Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC). In an evaluation of our EORTC case–control study, the FEBIM group established that a history of severe but increasingly uncommon infections, with fever above 38.5°C, including sepsis, pneumonia, pulmonary tuberculosis and Staphylococcus aureus infection, was associated with a reduced risk of melanoma.4 Moreover, in patients with histories of severe infections, the extent of risk reduction was directly related to the number of infections. Thus those with histories of one, two to three, and four or more infections had odds ratios of 0.66, 0.63 and 0.32, respectively, and this trend was statistically significant (P = 0.004). It was also established that vaccination early in life against smallpox (with vaccinia vaccine) or tuberculosis (with BCG vaccine), or both, conferred a significant and enduring degree of protection against melanoma. Adjusted odds ratios were 0.40 (95% CI, 0.18–0.85) for BCG alone, 0.60 (95% CI, 0.36–0.99) for vaccinia alone and 0.41 (95% CI, 0.25–0.67) for both vaccines. Not only did these vaccinations afford protection against melanoma, it was subsequently established in an EORTC cohort study of patients with melanoma, that those who developed melanoma had a significantly better prognosis if they had received one or both vaccinations, or had previously had serious but uncommon infections.5 Although confirmatory studies in different settings are required, the multicentre nature of our studies, the high degree of internal consistency of the observations, and the close parallels between their retrospective and prospective arms enhance confidence in the findings. A clue as to how certain vaccinations and infections might protect against melanoma came from the finding that a patient recruited for a trial of a melanoma vaccine had an expanded population of CD8+ T cells that recognised an epitope coded for by a human endogenous retrovirus of the HERV-K family.6 These viruses entered the human germ line millions of years ago and, although no longer capable of replication, can still code for gene products. A possible role of their gene products in the development of melanoma has been the subject of recent research.7 The HERV-K-MEL peptide is expressed on the surface of most human melanomas,6 and it was therefore postulated that a major component of the observed protection by certain infections and vaccinations is the generation of populations of CD8+ T cells cross-reacting with this epitope.8 Accordingly, amino acid sequences with homologies to HERV-K-MEL were sought among pathogens and vaccines, and were found in those associated with protection, but not in those that did not confer protection. A structurally similar sequence was also found in the 17D yellow fever vaccine, suggesting that it might likewise confer protection, and this prediction was confirmed in a recent pilot study of 28 000 adults vaccinated with this vaccine; this pilot study also showed that there was a period of around 10 years between vaccination and observed protection, indicating that the induced immune response is most effective at the time of tumour initiation, which may precede clinical manifestation by several years.9 This protection seems, therefore, to result from prevention of tumour initiation rather than the killing of melanoma cells already present in the body. So, it is important to emphasise that, in contrast to their likely preventive properties, BCG and vaccinia vaccines are of little or no value in treating established melanomas.4,7 Treatment of melanoma by immune modulation is much more complex than prevention, although several approaches of greatly varying complexity hold out hope for effective immunotherapeutic strategies in the future.10 However, our FEBIM studies indicate that certain currently available and relatively well tolerated vaccines against infectious diseases are able to make a significant impact on the serious and increasing public health problem of melanoma. Although it is unlikely that smallpox vaccination will be re-introduced for this purpose, the increasing global incidence of tuberculosis, including extreme drug-resistant forms, makes an additional case for considering widespread neonatal BCG vaccination. Yellow fever vaccine is another possibility as it is cheap and safe, although its efficacy in preventing melanoma requires confirmation in more extensive studies. The currently available evidence indicates the need for further studies to determine whether modifications of vaccination programs to include strategies to reduce the risk of melanoma would be of benefit, especially in high-risk countries such as Australia.

John M Grange MSc, MD · Bernd Krone MD PhD · Klaus F Kölmel MD · Giuseppe Mastrangelo MD

There is still no cure, but what advances have been made in managing this disabling condition? In its more aggravated forms diffuse scleroderma is one of the most terrible of all human ills. Like Tithonus [a Greek mythological hero who was granted immortality but not eternal youth] to “wither slowly” and like him to be “beaten down and marred and wasted” until one is literally a mummy, encased in an evershrinking, slowly contracting skin of steel, is a fate not pictured in any tragedy, ancient or modern. Sir William Osler, 18981 Scleroderma encompasses the name of a disease and a clinical sign (thickened skin) that have eluded any unifying mechanism of causation. While we still await a cure, new and significant pharmacological agents are now available that can assist in the symptomatic treatment and disease modification of this condition. The disease is uncommon, with Australian estimates of prevalence per 10 000 population ranging from 0.4–0.9 (Sydney, 1974–1988)2 to 1.47 (South Australia, 1993)3 to 2.4 (Tasmania, 2007).4 Scleroderma is classified into either localised (skin alone) disease or systemic (internal organ involvement ± skin) disease, which is known as systemic sclerosis. The principal subsets of systemic sclerosis are: diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, systemic sclerosis sine scleroderma (systemic disease with no skin involvement), environmentally induced scleroderma, overlap syndromes and pre-scleroderma. In limited disease, skin thickening is limited to the extremities distal to the elbows and knees, and the face. Diffuse disease, at its maximal extent, affects not only the skin of the distal extremities and face but also the skin over the proximal extremities and trunk. The disease has three pathological features: fibrosis with excessive collagen and other ground substance deposition; vasculopathy involving small and large vessels; and smooth muscle atrophy. In diffuse systemic sclerosis, inflammation and fibrosis predominate, whereas in limited disease, vascular changes predominate. While skin involvement (dermal inflammation and fibrosis) is associated with variable morbidity, it is the systemic manifestations, especially pulmonary and cardiac, and occasionally renal and gastrointestinal, that are responsible for much of the disease-related premature mortality. Therapy is classified as either “disease-modifying” or “symptomatic” and is tailored to the individual’s tolerance and need. Therapeutic decisions are determined by the pattern of organ involvement (vital or non-vital), underlying pathological features, and other comorbidities. General measures such as staying warm, using gloves and skin moisturisers, taking antireflux or bowel motility agents, modifying timing and volume of meals, brushing teeth regularly to prevent caries, using eye drops for sicca symptoms, and avoiding aggravating factors are important first steps in treating and managing the condition. In the early onset of systemic sclerosis, an activated immune system (Box 1) may be important in the pathogenesis of subsequent fibrotic and vascular lesions, so early disease-modifying drug therapy is aimed at suppressing the immune response. Immunosuppressive drugs such as methotrexate, cyclophosphamide and mycophenolate, often in conjunction with judicious use of corticosteroids (there is some controversy surrounding the causal association between high-dose corticosteroids and scleroderma renal crisis), intravenous gammaglobulin, and minocycline, have been used with varying measures of success. The levels of evidence for therapeutic intervention strategies are outlined in Box 2. “Heavier” immunosuppression, with or without haemopoietic stem cell rescue, is contemplated in patients with early inflammatory vital organ involvement of the lung or myocardium.6,7 Two large multicentre Phase III studies — the ASTIS (Autologous Stem cell Transplantation International Scleroderma) Trial in Europe, and the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) study in the United States — to determine the relative efficacy of haemopoietic stem cell transplantation compared with less rigorous immunosuppression are well underway. In Australia, we have performed autologous stem cell transplantation in seven patients with systemic sclerosis who had progressive vital organ involvement and in whom conventional immunosuppression had failed, and noted a dramatic, sustained, long-term remission in four of them that featured marked skin softening, stabilisation of interstitial lung disease and a three- to fourfold fall in antinuclear antibody titre (H J E, personal communication). These findings support the use of autologous stem cell transplantation as a disease-modifying modality. The use of mesenchymal stem cells (MSCs) in the treatment of arthritic disease is novel, and this approach has shown great potential because of the ease of isolation, rapid growth and extensive culture expansion of MSCs suitable for therapeutic use. In diseases such as scleroderma where there is excessive mesenchymal overactivity, MSCs are an ideal candidate cell type for tissue regeneration and repair of damaged structures. Trials of therapeutic uses of MSCs are currently in progress.8 Therapies directed toward modification of established fibrosis have been uniformly disappointing. D-penicillamine, previously the gold standard of scleroderma therapy, has fallen into disrepute after a US multicentre study showed no outcome difference between very low dose and usual dose D-penicillamine therapy.9 However, occasionally patients will exhibit resolution of skin fibrosis with little or no therapeutic intervention. Pulmonary arterial hypertension is a relatively common complication of systemic sclerosis and is caused by pulmonary arterial narrowing and thickening leading to increased pulmonary vascular resistance and arterial pressures (> 25 mmHg). As early diagnosis and treatment can have a profound effect on outcome, it is extremely important to screen patients for this condition. The gold-standard screening procedure is right heart catheterisation. There is level I evidence5 of efficacy of three categories of medications for pulmonary arterial hypertension: endothelin receptor antagonists, prostanoids, and phosphodiesterase inhibitors. These may be used as a single agent or in combination, with combined epoprostenol and sildenafil being more efficacious than combined bosentan and sildenafil. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been found to favourably modify the outcome of the vascular pathological features of scleroderma renal crisis. Symptomatic therapies for microvascular hyperreactivity, upper and lower gastrointestinal dysmotility, and musculoskeletal symptoms are outlined in Box 2. Promising new approaches include the use of a protein tyrosine kinase inhibitor, imatinib mesylate (Glivec, Novartis), that interferes with the signalling of platelet-derived growth factor and transforming growth factor-β, two pivotal mediators of the fibrotic process of systemic sclerosis. However, no biological agent has shown definitive evidence of efficacy thus far. Overall, despite the obvious absence of a cure, progress is being made in the understanding and management of this chronic and disabling rheumatic condition. 1 Pathophysiology of systemic sclerosis, with possible sites for therapeutic intervention Rational therapy would be designed to (1) prevent endothelial cell damage; (2) alter communication between mononuclear cells; (3) prevent mononuclear cell stimulation of fibroblasts; (4) prevent mast cell degranulation; (5) block fibroblast production or extrusion of procollagen; or (6) increase solubilisation of preformed collagen. Diagram courtesy of Professor Thomas Medsger, University of Pittsburgh. 2 Therapeutic intervention strategies for systemic sclerosis, with levels of evidence* Organ-specific features† Therapy (level of evidence) Cardiovascular (> 95%) (i) Microvascular (> 95%) Raynaud’s syndrome (> 95%) Efficacious: calcium channel blockers (II); topical glyceryl trinitrate (I); prazosin (I); intravenous iloprost (I); losartan (I); endothelin receptor antagonists; phosphodiesterase-5 inhibitors Disappointing: cisaprost; oral iloprost Promising: autologous progenitor cell implantation (II); protein tyrosine kinase ± Rho‑kinase inhibitors Digital ulcers Efficacious: as above; statins (I); bosentan (I); sildenafil (I) (ii) Macrovascular Myocardium (5%) Efficacious: immunosuppressives (III) Pericardium Efficacious: corticosteroids ± immunosuppressives Skin/adnexae (> 95%) Sclerosis Efficacious: cyclosporin (?II); tacrolimus (?II); cyclophosphamide (III) Disappointing: methotrexate (I) Promising: intravenous gammaglobulin (III) Respiratory (40%) Interstitial lung disease‡ Efficacious: cyclophosphamide (II) Promising: azathioprine (remission) (I) Pulmonary arterial hypertension Efficacious: bosentan (I); sildenafil (I); epoprostenol (I); treprostinil (I) Promising: beraprost (II) Aspiration pneumonitis None Gastrointestinal (75%–90%) Upper Efficacious: proton-pump inhibitors; histamine H2-receptor antagonists Lower Efficacious: domperidone (II); erythromycin (II); cisapride (II); octreotide (II) Renal (10%–15%) Hypertensive renal crisis Efficacious: angiotensin-converting enzyme inhibitors (II) * United States Preventive Services Task Force levels of evidence:5 I = at least one randomised controlled trial; II = well designed trial(s) without randomisation, or well designed case–control or cohort studies, or multiple time series with/without intervention; III = opinions of respected experts based on clinical experience; ?II = probably level II, but uncertain. † Percentages represent prevalence among all patients with systemic sclerosis. ‡ Non-specific interstitial pneumonitis, usual interstitial pneumonitis, bibasilar pulmonary fibrosis.

Helen J Englert MB BS, PhD, FRACP · Nicholas Manolios MB BS, PhD, FRACP

To the Editor: Italiano and colleagues described a 49-year-old woman with prolonged vaccine viraemia, associated with hepatitis, streptococcal toxic shock syndrome and poststreptococcal reactive arthritis following routine varicella vaccination.1 The woman, initially seronegative for varicella zoster virus (VZV), was stated to be immunocompetent, possibly because she was previously well and produced varicella IgG following vaccination. It is not clear whether other aspects of her immune status were investigated. Although VZV IgG was detected after vaccination, indicating appropriate adaptive immune activation, this does not necessarily exclude a defect in the innate immune system. Natural killer (NK) cells, which comprise 10%–15% of total lymphocytes, are part of the innate immune system and play an important role in the suppression of VZV replication via direct cell killing and production of γ-interferon.2,3 A smaller population of lymphocytes, known as NKT cells, which express both NK cell surface markers and T-cell receptors, also appear be important in controlling VZV infection in humans.2 The role of these cells in the immune response to varicella vaccine is unclear. In children, NK cell cytotoxicity increased after wild-type VZV infection but not after vaccine administration.4 However, disseminated life-threatening VZV infection was observed after varicella vaccination in a child with NKT cell deficiency.2 Primary isolated deficiencies and functional defects in NK function have been reported in children and adolescents with severe, life-threatening wild-type VZV infection.5 Some of these patients were previously well and came to medical attention only after VZV exposure. It is not clear how many had prior varicella vaccination, but at least one patient had previously received VZV vaccine with no adverse consequences and developed disseminated disease only with the wild-type virus. Acquired defects in NK immunity have also been reported. Severe transient depressions of NK and CD8 cell numbers and NK cell function have been documented in children at the time of severe VZV infection, with return of immune competence following convalescence.3 This phenomenon may be due to initial CD8 and NK cell exhaustion or redistribution of these cells from the circulation into inflamed peripheral tissue under the influence of chemokines.3 It has been suggested that an NK cell defect should be considered in unexplained severe herpesvirus infections.5 It would therefore be of interest to determine NK cell number and function and NKT cell number in the patient reported by Italiano and colleagues.

Sam S Mehr · Andrew S Kemp

To the Editor: We report a case of reactive arthritis with an unusual cause in a previously well 47-year-old male landscape gardener. The patient presented with acute onset of left ankle arthritis. He had a 10-day history of a productive cough associated with mild fever, back pain and arthralgias. His temperature was 37.7°C and occasional crackles were audible at the lung bases. His left ankle was tender, with decreased range of movement. The provisional diagnosis was atypical pneumonia with reactive arthritis. A chest x-ray was normal. Laboratory tests showed an elevated white cell count of 11.93 × 109/L (reference range [RR], 4–11 × 109/L), with a C-reactive protein level of 326 mg/L (RR, < 3 mg/L). Arthrocentesis showed increased white cells but was negative for crystals and bacteria. Serological tests were positive for Chlamydia psittaci (IgM, IgA and IgG were all elevated and increased during illness), and the patient was also positive for human leukocyte antigen (HLA)-B27. He was initially treated with meloxicam for the arthritis. Oral prednisone was added when his joint symptoms became more disabling. Weaning of prednisone was attempted, but symptoms recurred. Sulfasalazine was subsequently added. Symptoms took about 8 weeks to resolve. Sufferers of psittacosis are infected by inhaling the obligatory intracellular bacterium, Chlamydia psittaci, from the faeces of infected birds in soil or grass. As a landscape gardener, our patient was at risk. Clinical presentations of psittacosis vary considerably, but patients usually present with flu-like and respiratory symptoms.1 Reactive arthritis is unusual, being more commonly associated with pathogens such as Salmonella, Shigella, Campylobacter and Yersinia spp.2 Although reactive arthritis usually involves asymmetrical large joint oligoarthropathies, patients with Chlamydia psittaci infection usually have a polyarticular pattern.3 HLA-B27 has a high association with spondyloarthropathies, including reactive arthritis. Contact with infected birds is often not obvious, making the diagnosis challenging. Microimmunofluorescence (showing a fourfold increase in antibodies or IgG titre greater than 16) has become available for diagnosis. Differential diagnosis of reactive arthritis includes other causes of arthritis such as sepsis and crystal deposition. Management of Chlamydia psittaci reactive arthritis includes early use of the antibiotics doxycycline or erythromycin, or possibly ceftriaxone.4 Anti-inflammatory drugs are the mainstay for symptomatic treatment of all reactive arthropathies. Intra-articular steroid injections may be helpful. There is conflicting evidence regarding the benefit of systemic corticosteroids. Sulfasalazine may be a helpful adjunct.5 For gardeners, preventive measures include the use of masks, gloves and lawnmower catchers.

Peter N Gonski · Bobby Chan

Twenty-five patients living in a tick-endemic region of Sydney, New South Wales developed red meat allergy after experiencing large local reactions to tick bites. This represents a potentially novel cross-reaction between an arthropod and a food protein. Clinical recordsBetween 2003 and 2007, 25 patients (seven men, 18 women; mean age [range], 29.9 [21–63] years) presented to our allergy practice in Sydney, New South Wales with a history of an allergic reaction to red meat. All 25 patients reported a clinical reaction (one or more of: urticaria, angioedema, respiratory distress, syncope) after ingesting red meat. Ten of the 25 patients (40%) reported a delayed onset of symptoms, as defined by manifestations occurring more than 4 hours after ingestion. Seventeen of the 25 patients (68%) had severe reactions, characterised by cardiorespiratory involvement (one or more of: tongue swelling, throat constriction, shortness of breath, wheeze). Beef was the most commonly implicated red meat, followed by lamb, pork and game; 11 individuals reported reactions to more than one type of red meat. All patients lived in the northern beaches region of Sydney, which is endemically infested with several tick species. Twenty-four of the 25 patients gave a history of large local reactions to tick bites, defined as the rapid or delayed onset of a painful, pruritic lesion greater than 50 mm in diameter that persisted for at least 1 week.1 They all stated that the organism responsible for their local reaction was a hard-bodied tick, based on the presence of an armoured shell (scutulum). They also provided an estimate of the tick’s size, which ranged from 3 to 10 mm, and recalled the shape as resembling that of a human fingernail. No patient reported a history of large local or generalised reactions to other bites or stings, such as those from honeybees, wasps or mosquitoes. The remaining patient did not report any reactions, despite having incurred multiple tick bites. In all but one case, tick exposure preceded the development of the meat allergy by 1 to 6 months. One patient’s onset of meat allergy preceded the tick bite by 6 months. Patients’ IgE-mediated responses to red meat were confirmed by skin-prick test and/or fluoroenzyme immunoassay (ImmunoCAP, Phadia, Uppsala, Sweden). All patients had a positive result for at least one type of red meat; 22/25 (88%) had a positive reaction to more than one type (Box 1). There was no correlation between the wheal size on skin-prick testing or the amount of specific IgE detected by fluoroenzyme immunoassay and either the severity of the response to red meat ingestion or the size of the local reaction to the tick bite. The records of 29 patients (10 men, 19 women; mean age [range], 34.1 [17–71] years) with confirmed IgE-mediated responses to foods other than red meat, attending the same practice and residing in the same region, were examined as a retrospective control. The control group comprised patients with reactions to a spectrum of foods, most commonly seafood, peanut, tree nut and soybean. All 29 patients had reported a history of tick bites without subsequent reaction. These findings suggest that, in our patient population, the overwhelming majority of cases of the relatively rare condition of red meat allergy were preceded by sensitisation to tick bites. DiscussionBased on our experience of 25 patients, we suggest a novel association between tick bite reactions and red meat allergy. We speculate that individuals are sensitised to tick salivary proteins that are cross-reactive with proteins found in various red meats. Cross-reactivity between milk and beef,2 and between animal epithelia and meat,3,4 has been previously described, suggesting mechanisms of secondary sensitisation to meat. The association with reactions to tick salivary proteins may represent another such example. Anaphylactic and large local reactions to tick bites are IgE-mediated responses to tick salivary proteins.1 We infer that the species of hard-bodied tick most likely to be responsible for these local reactions is Ixodes holocyclus, commonly known as the paralysis tick (Box 2). I. holocyclus is not only the major species of tick found in the northern beaches region of Sydney that affects humans, but is also the species responsible for hypersensitivity reactions in humans.5 However, a skin-prick solution comprising paralysis tick antigens has not been standardised, and an in-house preparation carries a risk not only of anaphylaxis, but also of introduction of tick-borne disease; hence, there is currently no reliable, safe method of detecting IgE antibodies against I. holocyclus. It is intriguing that none of our patients who developed red meat allergy had an anaphylactic reaction to tick bite. It is possible that different allergens are involved in IgE-mediated local reactions and anaphylaxis, and that the allergens involved in local reactions are also found in red meat proteins, or, alternatively, that the inoculated allergens are processed differently in different individuals. There may be poorer inactivation of allergens by mast cells at the local site in some individuals, resulting in a more prolonged immunological stimulus.6 Bovine serum albumin has been identified as a major allergen responsible for a number of cases of meat allergy.7 More recently, IgE antibody to galactose-α-1,3-galactose has been identified as a cause of anaphylaxis and delayed immune reactions to red meat.8 This molecule is also present in recombinant mouse-derived monoclonal antibodies, such as cetuximab, and a number of invertebrates, such as amoebae and worms.9 It remains to be determined whether such homologous allergens exist in tick saliva. An alternative explanation is simply that the transfer of animal allergens by the tick occurs in genetically predisposed individuals. Bandicoots, possums and dogs, rather than cattle, are recipients of bites from the I. holocyclus species of tick, and it is therefore possible that there are allergens with a high level of homology found within bandicoot, possum and various ingestible red meat proteins. Also, the possibility of cutaneous exposure as a route of sensitisation to food allergens has been postulated as a mechanism for the development of peanut allergy.10 To determine the true prevalence of this cross-reactivity, a prospective study could examine consecutive patients who are bitten by ticks (with and without adverse reactions) for the subsequent development of red meat allergy. A standardised in-vitro assay for specific IgE against tick salivary allergens would need to be developed and incorporated into each participant’s evaluation. Further studies are required to characterise these allergens with immunoblotting and inhibition studies. 1 Skin-prick test and fluoroenzyme immunoassay results for patients with clinical reactions to red meat Patient Skin-prick test Fluoroenzyme immunoassay Beef Pork Lamb Game* Beef Pork Mutton 1 + − + nd + + − 2 + nd nd nd nd nd nd 3 nd nd nd nd + + + 4 + − + nd + + + 5 + nd nd nd nd nd nd 6 + + nd + nd nd nd 7 nd + nd nd nd nd nd 8 nd nd + nd + nd + 9 + + + + nd nd nd 10 + + + nd nd nd nd 11 + + + nd nd nd nd 12 + + + nd nd nd nd 13 + + + nd nd nd nd 14 nd nd nd nd + + + 15 + + + + + + + 16 + − + nd nd nd nd 17 + + nd + nd nd nd 18 nd nd nd nd + + nd 19 + + + nd − − − 20 + − + nd − − − 21 + + + nd nd nd nd 22 + nd + nd nd nd nd 23 + + + nd − nd − 24 + − + nd nd nd nd 25 nd + nd + + + + * Game refers to meat from wild animals, including kangaroo, venison and rabbit. + = positive result. − = negative result. nd = not done. 2 Developmental stages of Ixodes holocyclus Left to right: larva; nymph during engorgement; and adult female during engorgment. Image courtesy of Dr Bernard Hudson

Sheryl A Van Nunen MB BS, FRACP · Kate S O’Connor MB BS · Lesley R Clarke BSc, GradCertDiet · Richard X Boyle MB BS, FRACGP · Suran L Fernando PhD, FRACP, FRCPA

Clinical record A 47-year-old woman — an Australian resident of North Indian origin — was referred to our outpatient clinic. She had a 4-year history of lethargy on a background of primary hypothyroidism that was diagnosed 2 years earlier. She reported weakness, myalgia, poor concentration and chronic diarrhoea, which had been attributed to irritable bowel syndrome after a colonoscopy found no abnormalities. Given her racial origin, coeliac disease had not previously been considered. Rather, a chronic pain syndrome was diagnosed as the cause of the myalgia, and was managed with narcotic analgesia. The patient’s medications also included thyroxine (50 μg daily). Her body mass index was 29.5 kg/m2; normal findings were obtained on physical examination, and she was clinically euthyroid on thyroxine replacement. Hashimoto’s hypothyroidism with under-replacement of thyroxine, secondary hyperparathyroidism with vitamin D deficiency, and impaired fasting glycaemia were biochemically confirmed (Table). A high vitamin B12 level was also noted, and this was attributed to recent intramuscular injection of vitamin B12. Bone density was measured using the Lunar Prodigy DXA system (GE Healthcare, Madison, Wis, USA), which revealed osteopenia with lumbar bone mineral density (BMD) of 1.02 g/cm2 (T-score, − 1.9 SD) and total femoral BMD of 1.02 g/cm2 (T-score, − 1.6 SD). Titration of thyroxine to a weekly dose of 1400 μg and vitamin D3 replacement dosage of 6000 IU daily, over a 6-month period with confirmed compliance, failed to ameliorate hypothyroidism and vitamin D deficiency. In view of her history, previous investigations and progress, serological testing for coeliac disease was carried out. Results were positive for endomysial IgA antibodies, with normal total IgA antibody titre. Also, histological analysis of a small bowel biopsy specimen was consistent with coeliac disease (Figure). A 6-month gluten-free diet resulted in complete resolution of lethargy, diarrhoea and myalgia. Hypothyroidism was corrected with a weekly dose of 750 μg thyroxine, and both secondary hyperparathyroidism and impaired fasting glycaemia resolved (Table). Histological examination of small bowel mucosa Histological examination showed focal, partial villous atrophy and crypt hyperplasia, with evidence of chronic inflammation in the lamina propria (original magnification, × 400) — consistent with coeliac disease. Results of laboratory investigations At presentation After 6 months of gluten-free diet Reference range Thyroid-stimulating hormone (mIU/L) 13.4 8.3 0.3–4.0 Thyroxine, free (pmol/L) 12 15 10–25 Thyroid antimicrosomal antibody titre 25 600 — < 100 Calculated ionised calcium (mmol/L) 1.08 — 1.00–1.25 25-hydroxyvitamin D (nmol/L) < 15 34 40–150 Parathyroid hormone (pmol/L) 6.0 4.5 1.0–5.2 Fasting glucose (mmol/L) 6.3 5.4 < 5.6 Glycated haemoglobin (%) 6.2 5.5 < 6.0 Vitamin B12 (pmol/L) > 1470 — 145–637 Ferritin (μg/L) 124 — 15–200 While the prevalence of coeliac disease in the European population has been estimated to range from 1 in 150 to 1.5 in 1000,1 the prevalence in the Indian population is unknown due to lack of population-based data,2 leading to the common misconception that coeliac disease is rare. However, recent studies using new serological screening methods have demonstrated gross underdiagnosis of coeliac disease in the past,1-3 and an unexpectedly frequent prevalence in countries populated by non-Europeans. The highest reported population prevalence is in the Saharawi people of Arab–Berber origin, who live in the Sahara desert, with a prevalence of 5.6% — almost tenfold higher than that reported from most European countries.4 Similarly, recent studies in India found a prevalence of 9%–26% in patients who presented with chronic diarrhoea or malabsorption.5,6 The pathogenesis of coeliac disease is related to intolerance of gluten that results in a T-lymphocyte-mediated, small intestinal enteropathy in genetically predisposed individuals, who commonly express the HLA-DQ2 or HLA-DQ8 haplotypes.7 Such genetic predisposition is common in Europeans, but also occurs in Indian patients, as evident from detection of the HLA-DQ2 heterodimer in 14 out of 15 North Indian patients with coeliac disease.8 The HLA-DQ2 haplotype is also found in almost 25% of the healthy North Indian population, similar to the Western population,9 which has led to speculation that some Indians share ancestral origin with “ancient Caucasians” from the Fertile Crescent.9,10 Environmental challenge from the increasingly popular Western diet, which is gluten-rich, may also contribute to observed changes in the epidemiology of coeliac disease. For example, “summer diarrhoea” has been described in communities of Punjabis and Gujaratis from India. Traditionally, wheat replaces maize during summer in India, and Punjabis and Gujaratis residing in England and Canada have been reported to develop coeliac disease when exposed to a gluten-rich diet.11,12 Another misconception about coeliac disease patients is that they are all underweight. In one study, the mean body mass index of 371 patients with coeliac disease was 24.6 kg/m2, with only 5% being underweight, while 39% and 13% were in the overweight and obese ranges, respectively.13 Our patient’s body mass index was in the overweight range, which may have contributed to the delay in diagnosis until she was referred to our clinic. Coeliac disease is also associated with a wide range of autoimmune conditions. The presence of Hashimoto’s hypothyroidism was a clue to an autoimmune cluster in our patient, and persistent hypothyroidism despite large replacement doses of thyroxine is highly suggestive of a malabsorption disorder, such as coeliac disease. The complex symptomatology of our patient illustrates the non-specific, extraintestinal manifestations of coeliac disease, including lethargy, neuropsychiatric complaints, and myalgia from vitamin D deficiency; the latter may also lead to impaired insulin secretion and result in impaired fasting glycaemia.14 A high index of suspicion is required to screen for the disease, which is associated with significant morbidity. In conclusion, screening for coeliac disease with serological testing is non-invasive and should be considered in Indian patients with suggestive symptoms or associated autoimmune conditions. It is important for clinicians to overcome historical bias and consider coeliac disease as a diagnosis in non-European patients. Early diagnosis may help to avoid unnecessary investigation and reduce the long-term risk of small bowel malignancies associated with coeliac disease. Compliance with a gluten-free diet not only reduces symptoms, but also rectifies malabsorption of micronutrients and medications, which impact on comorbidity such as, in this case, abnormalities of thyroid replacement and metabolism of bone and glucose. Lessons from practice Coeliac disease is not limited to Europeans; it has been increasingly reported in patients from non-European backgrounds. Not all patients with coeliac disease are underweight, and a significant minority are overweight or obese. Serological testing is non-invasive and should be considered in patients with suggestive symptoms or associated autoimmune conditions, regardless of racial background. Presentation of coeliac disease can be non-specific, and is not limited to gastrointestinal manifestations. A high index of suspicion is required to screen for the condition in patients with predominant extraintestinal presentation.

Paul Lee MB BS(Hons) · Katherine Samaras MB BS(Hons), FRACP, PhD

Clinical record A 44-year-old Samoan man presented in 2004 with a blistering skin rash affecting his face, trunk and upper limbs (Figure, A). There was no mucosal involvement and a positive Nikolsky sign (the production of a blistering lesion on applying pressure to non-affected skin) was demonstrated. Skin biopsy revealed acantholysis and cleft formation within the superficial layers of the epidermis, confirming a diagnosis of pemphigus foliaceus. Direct immunofluorescence testing of a perilesional skin biopsy specimen revealed deposition of IgG and C3 in the intercellular cement substance of all layers of the epidermis. Indirect immunofluorescence testing, using a monkey oesophagus substrate, demonstrated a high titre of autoantibodies in the patient’s serum. The condition failed to respond to prednisone combined with other immunosuppressive agents, including azathioprine, cyclosporin and mycophenolate mofetil. In late 2006, the patient developed a significant flare of the disease, associated with Staphylococcus aureus superinfection, which resulted in a lengthy hospital admission. Plasmapheresis was instituted, with clinical benefit and a concomitant decrease in antipemphigus antibodies to undetectable levels. However, the plasmapheresis was complicated by Citrobacter koseri sepsis due to colonisation of the intravenous catheter. Despite treatment of the sepsis and reinstitution of immunosuppression with prednisone and mycophenolate mofetil, the pemphigus flared again, accompanied by a dramatic increase in the titre of antipemphigus antibodies. The hospital drug committee approved off-label use of two courses of rituximab (375 mg/m2). This resulted in rapid resolution of the lesions and a marked decrease in antipemphigus antibodies. Depletion of B cells was evident on immunophenotyping of peripheral blood mononuclear cells, and the corticosteroid dose was subsequently weaned to 0.1 mg/kg/day. Nine months after treatment with rituximab, the patient’s clinical condition remained stable (Figure, B). Autoimmune blistering diseases are rare but potentially life-threatening.1 Pemphigus foliaceus is characterised by superficial erosion of the skin without mucosal involvement. The disease is mediated by autoantibodies directed against desmoglein-3,2 a structural protein involved in epidermal cell adhesion. The levels of these pathogenic autoantibodies can be measured by indirect immunofluorescence and, as illustrated in our patient, are useful for monitoring disease activity.2 The combination of prednisone and azathioprine is often used as first-line therapy,3 but other immunosuppressive agents, as well as intravenous immunoglobulins and plasmapheresis, have also been used to control disease activity.4 However, these therapies do not induce remission in all cases and they can be associated with significant adverse events. Lessons from practice Blistering skin diseases are potentially life-threatening and can have an autoimmune basis. Direct immunofluorescence of a perilesional skin biopsy is essential for diagnosis. Titres of autoantibodies in the patient’s serum, measured by indirect immunofluorescence, are useful for monitoring disease activity. Rituximab can be used successfully for the treatment of severe, refractory pemphigus foliaceus. Rituximab is a chimeric (human/murine) monoclonal antibody directed against CD20, a cell surface molecule specific to B cells. Although it was initially approved for use in B-cell non-Hodgkin’s lymphoma, a growing number of reports have described the efficacy of rituximab for B-cell depletion in the treatment of autoimmune diseases.5 The mode of action of rituximab in autoimmune diseases may include removal of the precursors of autoantibody-producing plasma cells and impairment of autoantigen presentation to T cells.6 A recent case series showed that rituximab induced remission in 18 of 21 patients with pemphigus, whose condition had not responded or who had contraindications to corticosteroid therapy. The treatment was generally well tolerated; however, two cases were complicated by severe infection, one resulting in death.7 Ongoing surveillance of patients treated with rituximab for pemphigus and other autoimmune diseases is required to monitor long-term complications. A recent review of the increasing use of rituximab for off-label indications in a large teaching hospital highlighted the need for a database to help determine optimal dosing regimens and to record clinical outcomes.8 In our patient, two infusions of rituximab resulted in depletion of peripheral B cells, a reduction in the level of circulating antipemphigus autoantibodies and remission of disease over a 9-month follow-up period. Hence, rituximab may be a suitable alternative for patients with pemphigus who have refractory disease or contraindications to first-line immunosuppressive therapy.

Suran L Fernando PhD, FRACP, FRCPA · Kate S O’Connor MB BS

To the Editor: It has been well established that traditional inhalational anaesthetic agents can cause mild and sometimes fulminant liver failure.1 However, while newer inhalational agents are a theoretical cause of hepatotoxicity, such cases have rarely been reported.2,3 We describe desflurane-induced acute liver failure in a 53-year-old woman with achalasia, hypertension, type 2 diabetes mellitus and hyperlipidaemia. She underwent a Heller myotomy for treatment of the achalasia in late 2004. During anaesthesia, desflurane was administered (1.2 minimum alveolar concentration [MAC]) via a Datex–Ohmeda Aestiva/5 anaesthesia delivery system (GE Healthcare, Sydney, NSW). After the operation, her serum alanine aminotransferase (ALT) concentration peaked at 943 U/L (reference range, < 35 U/L). This was attributed to antibiotic toxicity. As the initial myotomy was inadequate, the surgery was repeated 10 days later with desflurane (0.9 MAC) anaesthesia. The patient developed acute liver failure 96 hours after surgery (serum ALT level, 11 600 U/L; pH, 7.06; international normalised ratio, 3.7) and died despite supportive management. A postmortem examination confirmed massive hepatic necrosis and significantly elevated trifluoroacetyl chloride-specific IgG4 antibodies (optical density, 0.585; reference range, < 0.233) — consistent with an inhalational agent being the cause of the necrosis. There are few similar cases of desflurane-induced acute liver failure in the literature to date2,3 and none, to our knowledge, in Australia. Fulminant hepatic necrosis induced by halothane, the original offending agent, occurs in about one in 35 000 adults. This is thought to be immune-mediated and appears to be directly correlated with the metabolism of the anaesthetic, catalysed by cytochrome P450 2E1, to trifluoroacetylated hepatic proteins. The altered protein is seen as “non-self”, generating an immune response that, on re-exposure, leads to inflammation and cellular death.4 Desflurane is metabolised to inorganic fluoride and trifluoroacetyl chloride. However, due to a lower blood : gas partition coefficient and its resistance to degradation (as a result of replacement of chlorine by fluorine at the α-carbon position), desflurane is metabolised by hepatic enzymes to a lesser extent than halothane, enflurane and isoflurane.4 Thus, the degree of hepatic metabolism appears to be related to the potential for hepatic injury, as seen clinically. Evidence for immune-mediated, allergic sensitisation continues to emerge. Identification of IgG4 antibodies, the rarest and most IgE-like immunoglobulins, strongly suggests an allergic component in the pathophysiology of this disease.5 Although hepatotoxicity is a rare complication of the newer inhaled volatile agents, it may have devastating consequences. Anaesthetic agents should be considered in the differential diagnosis of hepatotoxicity, especially in the context of extreme elevation of serum transaminases, suggesting the presence of massive hepatic necrosis. In this case, postoperative ALT elevation was attributed to antibiotic — rather than desflurane — toxicity, with disastrous results following re-exposure, a scenario that might have been prevented if recognised earlier. A full incident report was made at the tertiary hospital involved, and the death was reported to (and examined by) the coroner. The main recommendation made from the case was that inhalational agents should be avoided in the setting of hepatitis.

Marcus W Chin · Dolores B Njoku · Gerard MacQuillan · Wendy S Cheng · Nickolas Kontorinis

To the Editor: Australian consensus guidelines for selecting formulas for infants with cows milk protein allergy (CMPA) have recently been published.1 We reviewed formula choices and outcomes for 51 children with immediate allergic reactions to cows milk protein who were referred to one of us (S S M) in a tertiary specialist clinic over a 2-year period before the guidelines were published. The formula was selected by the referring specialist medical practitioner in 44 cases (and by S S M in the other seven). Of the 51 children (mean age at initial reaction to cows milk protein, 7.8 months), 42 had skin and/or gastrointestinal features, and nine had an anaphylactic reaction with respiratory and/or cardiac features. Forty-six children had a positive skin prick test to cows milk protein, and one had a positive radioallergosorbent test. Four children with immediate (< 30 min) reactions of generalised erythema and/or angioedema (3) or vomiting (1), but a negative skin prick test, were also included. Soy was the most common formula used, followed by extensively hydrolysed formula (EHF) (Box). Three of eight children commenced on EHF had allergic reactions, with urticaria and angioedema, and one child also had a transient (60 s) cough. Three children were given partially hydrolysed formula (PHF), with one experiencing an immediate cutaneous reaction. These observations suggest that, in clinical practice, soy is frequently a satisfactory first choice for children with CMPA, as suggested in the guidelines.1 Some children with CMPA will also react to EHF, providing a rationale for choosing amino acid-based formula as a first-line treatment prior to allergy evaluation in children with anaphylaxis to cows milk protein. As about 5% of infants with CMPA also react to EHF,2 some allergists advocate the introduction of EHF under medical supervision in either all children with immediate CMPA3 or only those who have had severe life-threatening reactions.4 Although PHF is tolerated by a significant proportion of children (70%) with immediate CMPA,3 it is not recommended for the treatment of CMPA1 due to its high content of potentially allergenic cows milk protein. The fact that three children with CMPA were given PHF suggests there is confusion in the prescribing community, and that the availability of the new guidelines may help in achieving a more appropriate choice of formula. Feeding choice for 51 children referred with cows milk protein allergy Type of feeding selected No. of children Mean age at initial reaction to cows milk (months) No. who reacted to selected feeding Soy 29 9.5* 0 Extensively hydrolysed formula (EHF) 8 5.3 3 Amino acid-based formula (AAF) 6 4.2 0 Partially hydrolysed formula (PHF) 3 6.0 1 Breastfeeding 5 6.0 0 * P < 0.05 for soy versus PHF, EHF, AAF or continuing to breastfeed (t test).

Sam S Mehr · Andrew S Kemp

Objective: To examine trends in invasive pneumococcal disease (IPD) in Indigenous people in north Queensland following the introduction of the 7-valent pneumococcal conjugate vaccine (7vPCV).Design: Trends in IPD were compared over three 3-year periods: before the introduction of 7vPCV for Indigenous children (1999–2001), and two consecutive periods after its introduction (2002–2004 and 2005–2007).Main outcome measures: Incidences of IPD in Indigenous children and adults in 1999–2001 and 2005–2007; trends in IPD caused by 7vPCV and non-7vPCV serotypes; and trends in indirect protective effects and emergence of non-7vPCV serotype IPD.Results: From 1999–2001 to 2005–2007, there was a 60% decline in IPD, with the virtual elimination of 7vPCV serotype IPD in young (< 5 years) Indigenous children. There is no evidence yet of an increase in non-7vPCV serotype IPD in these children. Although the annual incidence of IPD in Indigenous adults remained virtually unchanged, there was a 75% decline in 7vPCV serotype IPD in these adults (χ2trend = 11.65, P < 0.001). However, the incidence of IPD caused by non-7vPCV serotypes more than tripled in adults (χ2trend = 7.58, P = 0.006). Serotype 1 IPD has been prominent over the 9 years, but there is no evidence of a recent increase in serotype 19A IPD.Conclusions: Vaccinating Indigenous children with 7vPCV has protected Indigenous adults in north Queensland through an indirect “herd immunity” effect. However, this benefit has been offset by a recent increase in non-7vPCV IPD in Indigenous adults. Newer pneumococcal conjugate vaccines could prevent, both directly and indirectly, a considerable amount of the persisting IPD in Indigenous people in the region.

Jeffrey N Hanna MPH, FAFPHM · Jan L Humphreys · Denise M Murphy DipMedTech

Reducing the growing burden of food allergy requires a chronic disease management model, clarification of responsibilities, and better communication of both risks and uncertainties Food allergy and anaphylaxis are increasing in the Australian community, particularly in preschool-aged children,1,2 although, paradoxically, mortality occurs almost exclusively in school-aged children and adults.3 Food allergy and anaphylaxis are high-stakes and highly uncertain issues, where the outcome may be the sudden and unpredictable death of a child.4 The concept that a patient is “at risk” inevitably invokes uncertainty. It is possible to prospectively identify those at risk by virtue of having food allergy, but diagnostic tests are not highly predictive of anaphylaxis. The population with food allergy is substantially larger (about 10–20-fold) than the population who will experience anaphylaxis. Patients and their carers therefore live with being at risk, while not knowing exactly what the nature or extent of the risk is. In clarifying what we mean by “anaphylaxis risk”, the conventional wisdom in risk communication literature is to avoid essentially meaningless terms such as “potential risk” or “high risk” and to instead employ techniques that more accurately convey quantitative estimates of risk. This is risk as numbers, or “the probability that an event will occur, eg, that an individual will become ill or die within a stated period of time”.5 Mortality figures for food anaphylaxis in New South Wales show that the numerical risk that a teenager allergic to peanut or tree-nut will die from anaphylaxis in the next year lies between 1 in 10 000 and 1 in 100 000 — in the same order as the chance of an Australian resident being murdered in the next year.6 The risk that a child aged under 5 years will die from food anaphylaxis in the next year lies between 1 in 1 million and 1 in 10 million — the same order as the risk of death from being struck by lightning.6 However, there are problems with this numerical approach to risk assessment: the data to calculate probabilistic risk for anaphylaxis are either unavailable or not generalisable; numerically small risks are difficult to communicate; and death by lightning or violence is not necessarily viewed in the same way as a child dying from eating food. Due to its emotive characteristics, the risk of food anaphylaxis is likely to be appreciated by experiential rather than analytical cognitive processes,7 which are intuitive, automatic, and greatly influenced by associations and affect. Fear of the unpredictable death of a child may outweigh any rational consideration of its numerical likelihood. Care must therefore be taken when discussing anaphylaxis risk with patients and parents, with a key consideration being the need to sensitively communicate uncertainty as much as communicate risk. As food is essential, some exposure to risk is unavoidable. Although food labelling is becoming clearer, there are persistent uncertainties about mislabelling and cross-contamination with allergens, coinciding with broader concerns about food quality and production, and societal expectations that parents and others will provide safe food for children. Accordingly, food allergy is as much a sociocultural as a medical issue, and, for some, the constant obligation to make careful decisions about what to eat or feed their child, together with ongoing uncertainty about the risks, can create an enormous burden. Reducing this burden requires a coordinated and intersectoral response, from consumers, the health care, teaching and childcare professions, the food and pharmaceutical industries, and statutory bodies at both state and federal level. Clarification of responsibilities is required for food labelling and production, care in schools and preschools, anaphylaxis education (involving anaphylaxis recognition and risk minimisation, as well as correct use of EpiPen autoinjectors [CSL Limited, Melbourne, Vic]), and monitoring EpiPen use. It is encouraging that, in recent months, the Victorian Government has announced legislation mandating a school anaphylaxis management standard8 and the Western Australian Government has committed $6.6 million to a program of interventions.9 Nevertheless, as with other “messy” and uncertain problems, pure science and rationality alone are not sufficient.10 In formulating policy, the process of representation, clarification of common aims and interests, and debate over what we mean by “anaphylaxis risk” may be more important for developing a coherent and coordinated framework for action than would identifying an elusive “right” response. At the service provision level, there has been a tendency for medical treatment of an acute emergency to be the focus of food allergy management. Emergency treatment itself brings additional uncertainties — guidelines for EpiPen prescription leave much to individual judgement, and one study found that only 2% of doctors in a major Australian paediatric teaching hospital could correctly demonstrate all steps in EpiPen administration.11 Fortunately, despite the many uncertainties, most food-allergic patients are generally well and the EpiPen is appropriately unused. Nevertheless, it is more appropriate for food allergy, with its unpredictable “exacerbations” or reactions, and its requirement for community management of risks, to adopt a chronic disease management model, centring on self-management, patient and carer education, continuity of care and multidisciplinary services. Such an approach, including ongoing support from dietitians and nurse educators, is likely to reduce the uncertainties of daily management. The need for parent and carer education is evidenced by an Australian survey of EpiPen use, which found that only 29% of parents administered the EpiPen when indicated.12 Parental satisfaction with information provision is also associated with less seeking of second opinions.13 Thus, adequate parent and carer education and follow-up may ease pressure on referral services, which currently have 10–14-month waiting times for hospital paediatric allergy consultations. The uncertainties surrounding food allergy arise from a lack of scientific, epidemiological and personal knowledge, the need to negotiate between different sectors and interests, and ambiguous language and concepts that are difficult to communicate. Different responses are required at interpersonal, service delivery and policy levels. While some uncertainties are irreducible, patients and carers are also experiencing unnecessary uncertainties. What is certain is that food allergy has become a significant concern for public health, paediatric and general medical practice.

Andrew S Kemp MB BS, PhD, FRACP · Wendy Hu MB BS, PhD, FRACGP

To the Editor: In their report of a child with peanut allergy who developed sunflower seed allergy, Hsu and Katelaris caution against marketing claims of “safe alternatives” in allergic children.1 Their report also raises practical issues for those advising the parents of a child with food allergy: what is the risk of a new allergy developing; should a child with peanut or tree nut allergy avoid similar foods as well; and will food avoidance prevent new allergy from developing? The natural history of peanut and tree nut allergy is for polysensitisation to develop over time. One study demonstrated that, in children younger than 2 years with peanut or tree nut allergy, 19% were sensitised and 2% were clinically reactive to more than one nut.2 By the age of 14 years, the percentages had risen to 72% and 47%, respectively. This has led to people with peanut or tree nut allergy being advised to avoid all nuts and seeds.2 Strategies commonly advised to reduce the risk of allergy developing are to avoid food allergens and to delay the introduction of allergenic foods until the age of 2 years, but evidence to support their effectiveness is limited,3 particularly for preventing food allergy.4 While studies in infants at high risk of allergic disease have reported an increased risk of eczema with early introduction of solids (before the age of 3–4 months),3 and a protective effect against asthma and eczema with the avoidance of environmental and food allergens in the first 6 months of life,4 a recent systematic review found “no strong evidence to support the association between early solid feeding and the development of persistent asthma, persistent food allergy, allergic rhinitis, or animal dander”.5 Furthermore, there is currently no evidence that avoidance strategies applied beyond 6 months of age are effective for allergy prevention, and provisional evidence that such strategies might actually promote sensitisation and food allergy rather than tolerance.6 So how should we advise patients? The peanut and tree nut avoidance strategies advised will be largely dictated by: choking hazards in infants; the risks of cross-contamination in commercially prepared foods; and the potential for confusion in young children (and caregivers) trying to differentiate one “nut” product from another. Regarding the risk of developing new food allergy, we should advise patients that: new allergies may develop with time; this risk is unpredictable; we have little evidence to recommend avoidance beyond the age of 6 months as an effective preventive strategy; and parents should not be optimistic (given the current state of knowledge) that such strategies will prevent new sensitisation once food allergy has developed.

Mimi Tang · Raymond J Mullins

Cryoglobulins are plasma immunoglobulins or immunoglobulin-containing complexes that precipitate on exposure to cold and redissolve on warming. They should be distinguished from red cell agglutinins and from the blood-component cryoprecipitates manufactured from donor plasma. The typical clinical triad of cryoglobulinaemia comprises purpura, arthralgia and weakness, with possible multisystemic organ involvement, notably glomerulonephritis and neuropathy. In blood smears prepared at room temperature, cryoglobulins can be detected by their peculiar morphology, which can assume globular, rhomboid or cylindrical amorphous precipitates (Figure, A–C, arrows; Wright–Giemsa stain, original magnification, × 200). Occasionally, these may be mistaken for blood cells, leading to spuriously high blood cell counts. Cryoglobulins are associated with infections (eg, hepatitis C), lymphoproliferative diseases and autoimmune diseases. Plasmapheresis is a useful adjunctive treatment for severe active disease, but the replacement fluid must be warmed to prevent precipitation of circulating cryoglobulins.

Herman H Lee · Chi-hung Hui

Three types of infant formula (soy, extensively hydrolysed and amino acid) may be appropriate for treating cows milk protein allergy. Selection of a formula depends on the allergy syndrome to be treated. Extensively hydrolysed formula is recommended as first choice for infants under 6 months of age for treating immediate cows milk allergy (non-anaphylactic), food protein-induced enterocolitis syndrome, atopic eczema, gastrointestinal symptoms and food protein-induced proctocolitis. Soy formula is recommended as first choice for infants over 6 months of age with immediate food reactions, and for those with gastrointestinal symptoms or atopic dermatitis in the absence of failure to thrive. Amino acid formula is recommended as first choice in anaphylaxis and eosinophilic oesophagitis. If treatment with the initial formula is not successful, use of an alternative formula is recommended.

Andrew S Kemp PhD, FRACP · David J Hill FRACP · Katrina J Allen FRACP, PhD · Kym Anderson FRACP · Geoffrey P Davidson FRACP · Andrew S Day MD, FRACP · Ralph G Heine MB ChB · Jane E Peake FRACP, DTM · Susan L Prescott BMedSc, PhD, FRACP · Albert W Shugg DCH, FRACGP, FRACP · John K Sinn MMed(ClinEpi), FRACP

Autoimmune hepatitis is a rare but increasingly recognised serious complication of treatment with the tumour necrosis factor-α (TNF-α) blocking agent, infliximab. This report adds to the small but growing number of articles describing this significant adverse effect. Baseline liver function should be routinely tested in all patients receiving anti-TNF-α agents, and periodic monitoring for the development of hepatitis is important. Clinical recordA 56-year-old woman was referred with a 15-year history of ankylosing spondylitis, with clinical features of inflammatory back pain, fused sacroiliac joints, spondylosis and a positive test result for human leukocyte antigen (HLA)-B27. She was an ex-smoker and non-drinker, and was taking no regular medication. She had taken non-steroidal anti-inflammatory agents initially, but tolerated them poorly. Leflunomide therapy was trialled for 9 months in 2004, then ceased because of a poor clinical response; this therapy had no adverse effects (including hepatic complications) in this patient. Infliximab (infusion dose, 5 mg/kg) was introduced in 2005. Baseline findings included normal liver function test (LFT) results, and a negative anti-nuclear antibody (ANA) test result. During infliximab therapy, routine blood tests (including LFTs) were performed every 3 months. A minor elevation in transaminase level was noted within 3 months of commencing infliximab therapy. After a total of six infusions, infliximab therapy was ceased because the patient developed epigastric discomfort, jaundice and pale stools, and her LFT results showed gradual deterioration, with a mixed hepatitic/cholestatic picture. Results of her blood tests at cessation of infliximab therapy are shown in Box 1. Computed tomography of the abdomen showed diffusely non-homogeneous liver texture consistent with chronic liver disease, with no intra- or extrahepatic duct dilatation. A past cholecystectomy was also evident. A liver biopsy showed marked inflammatory infiltrate, particularly around the portal tract, with neutrophils, lymphoid, and plasma cells, bridging necrosis and piecemeal necrosis consistent with autoimmune chronic active hepatitis (Box 2). Prednisone therapy was commenced and, after 3 months, the patient’s clinical condition had improved with the only persisting liver function abnormality being an elevated γ-glutamyl transferase level (162 U/L; normal, 5–30 U/L). At this time the patient tested positive for ANA (titre, 1/160, homogeneous pattern); mildly positive for double-stranded DNA antibody (anti-dsDNA; titre, 5.7 IU/mL); and positive for smooth muscle antibody (titre, 1/2560). An attempt to introduce azathioprine therapy was unsuccessful because the patient developed a drug fever. DiscussionTumour necrosis factor-α blocking agents (anti-TNF-α agents) are used for treating conditions such as Crohn’s disease, ankylosing spondylitis, rheumatoid arthritis, and psoriatic arthritis. Commercially available anti-TNF-α agents include etanercept, infliximab, and adalimumab. Both infliximab and etanercept have been evaluated in double-blind placebo-controlled studies for the treatment of Crohn’s disease, rheumatoid arthritis, and ankylosing spondylitis. Minor side effects of treatment with anti-TNF-α agents are common, and include upper respiratory tract infections, rash, myalgias, asthenia, sinusitis, flushing, fever and headache.1 More serious side effects include the reactivation of latent Mycobacterium tuberculosis; reactivation of hepatitis B in chronic carriers; infusion reactions (related to induction of anti-chimeric antibodies against infliximab); severe neutropenia and thrombocytopenia; demyelinating disorders; autoimmune antibody formation; and hepatotoxicity. Minor abnormalities in LFT results are relatively common with the use of anti-TNF-α agents.1 Severe hepatic reactions are much less common. These may include jaundice, hepatitis and cholestasis, autoimmune hepatitis, and acute liver failure. It is noteworthy that a number of cases of liver failure resulting in liver transplantation or death have now been reported.2,3 According to the manufacturer of infliximab, at least 35 patients were reported to have had severe hepatic adverse events in the postmarketing period up to 2004.4 Autoimmune hepatitis (AIH) is a rare but nonetheless increasingly recognised complication of treatment with infliximab. Ten cases of AIH had been reported to the manufacturer of infliximab up to 2003, eight of which were considered either possibly or probably related to infliximab (H B, personal correspondence). However, events had been submitted voluntarily and thus may be under-reported. This report is important in highlighting a case of the de-novo development of autoantibodies and onset of AIH related to the use of infliximab in a patient not receiving concurrent confounding immunosuppressive therapy such as methotrexate. It adds to the small but increasing number of published cases of these adverse effects. Most cases published to date describe reversibility of the hepatitis and resolution of LFT abnormalities with immunosuppressive therapy. Box 3 shows a comparison of our case and several other published cases of postulated infliximab-related AIH, including a case of acute liver failure which led to liver transplantation.2 Neither that patient2 nor our patient received concurrent immunosuppressive therapy during treatment with infliximab. Autoimmune manifestations may possibly be more significant when infliximab is used alone, or in higher doses. This is often the situation with spondyloarthropathy or psoriasis, where additional immunosuppression may not necessarily be part of the protocol. This differs from the treatment of, for example, rheumatoid arthritis, for which patients often also take methotrexate. One published report describes the development of autoantibodies and liver inflammation following infliximab therapy in two women treated with infliximab for rheumatoid arthritis.2 Liver disease occurred 8 and 17 months, respectively, after infliximab therapy was initiated, and there was de-novo development of ANA in both patients. In the first and most striking case, a 39-year-old woman eventually required liver transplantation after a 45-day admission with hepatic failure and cirrhosis. She had previously been taking leflunomide (20 mg/day for 3 months) with no significant response. Before infliximab therapy, her LFT results were normal, and she tested negative for ANA. At last report, post-transplant, she was well on immunosuppressive therapy including cyclosporin and corticosteroids. In the second case, a 54-year-old woman with rheumatoid arthritis developed acute hepatitis after infliximab treatment. A complete recovery (based on symptoms and LFT results) was noted 1 month later, after treatment with prednisolone (0.5 mg/kg/day) and azathioprine (50 mg/day). Two major types of AIH have been described: type 1 classic AIH, as seen in our patient (related to ANA and/or smooth muscle antibody seropositivity; and type 2 (related to liver/kidney microsomal antibody seropositivity). The histological hallmark of AIH is interface hepatitis, characterised by mononuclear cells, lymphocytes, plasma cells and macrophages infiltrating the portal tract.7 The primary pathogenetic mechanism of AIH is thought to be a loss of tolerance against the patient’s own liver.8 This predominantly periportal hepatitis is thought to be initiated by CD4+ T cells, which recognise self-antigen. Hepatocytes in patients with AIH are postulated to aberrantly express HLA class II molecules on their surface, a process normally involved in the presentation of antigen to CD4+ T cells and other inflammatory cells. Autoimmune disease results from the resultant inflammatory cell activation, with subsequent hepatocyte destruction (cell-mediated autoimmunity).7,8 AIH may also involve the unmodulated production of autoantibodies directed against the hepatocyte membrane (antibody-dependent autoimmunity). This includes elevated immunoglobulin G levels, seen in up to 80% of patients with AIH.7 A genetic predisposition is also thought to be important, with the HLA DR3 and DR4 alleles being associated with the development of type 1 AIH.8 Infliximab is thought to contribute to development of AIH in predisposed patients by triggering development of autoantibodies. These include ANA and anti-dsDNA.9 One possible explanation for this is that TNF-α blockade interferes with the normal cytotoxic T lymphocyte suppression of auto (self)-reactive B cell production. Another is that anti-TNF-α agents interfere with the induced cell death of CD8 T cells, leading to an accentuated lymphocyte presence.9 Studies in patients with rheumatoid arthritis support infliximab-related autoantibody development,9,10 showing elevations in both ANA and anti-dsDNA titres after infliximab therapy. The occurrence of AIH, and other serious, though uncommon adverse drug reactions, may become more evident with increased use of anti-TNF-α agents. Monitoring of liver function is not routine for patients being treated with anti-TNF-α agents (or those receiving other disease modifying agents, such as methotrexate and leflunomide). Routine blood tests, including LFTs, should be considered for all patients receiving anti-TNF-α agents. 1 Results of blood tests at cessation of infliximab therapy Parameter Patient Reference range Electrolytes, renal function Normal Normal Bilirubin 97 pmol/L 2–21 pmol/L Albumin 25 g/L 35–53 g/L Alkaline phosphatase 521 U/L 30–115 U/L γ-Glutamyl transferase 614 U/L 5–30 U/L Alanine aminotransferase 621 U/L 7–33 U/L Aspartate aminotransferase 821 U/L 10–45 U/L Prothrombin time 13 s 11–17 s Anti-nuclear antibody titre 1/640 < 1/40 Anti-nuclear antibody pattern Homogeneous No pattern or speckled Anti-dsDNA titre 5.7 IU/mL 0–5 IU/mL Anti-smooth muscle antibody titre 1/2560 Negative Anti-mitochondrial antibodies Negative Negative Anti-liver/kidney antibodies Negative Negative Viral hepatitis serum tests Negative Negative Iron studies Normal Normal Caeruloplasmin Normal Normal Anti-dsDNA = double-stranded DNA antibody. 2 Thin sections of the core liver biopsy sample A: × 50 view, showing inflammation around portal tracts with architectural distortion. B: × 200 view, showing lymphocytes, plasma cells, neutrophils and occasional eosinophils, piecemeal necrosi and focal apoptotic cells. 3 Comparison of our case with other published cases of postulated infliximab-related autoimmune hepatitis Patient Sex Age (years) Disease Infliximab infusions Methotrexate use ANA titre Anti-dsDNA development Steroid response Reversible condition Dose (mg/kg) No. Concurrent Past Pre- infliximab Post- infliximab A2 F 39 RA 3 6 No No 0 1/640 Yes No No† B2 F 54 RA 3 12 Yes Yes 0 1/160 nd Yes Yes C5 F 36 RA 3 3 No Yes 1/20 1/640 Yes Yes Yes D6 F 53 PsA 3 8 Yes Yes 1/80 1/160 Yes Yes Yes E* F 56 AS 5 6 No No 0 1/640 Yes Yes Yes * Our patient. † Requiring liver transplantation. ANA = anti-nuclear antibodies. Anti-dsDNA = double-stranded DNA antibody. AS = ankylosing spondylitis. nd = not done. PsA = psoriatic arthritis. RA = rheumatoid arthritis.

Gerard Ozorio MB BS · Bruce McGarity MB BS, FRACP · Haesung Bak MB BS, FRACP · Andrew S Jordan MB BS, BSci(Med) · Henry Lau MB BS, FRCPA, FACTM · Cathy Marshall MB BS

To the Editor: The Australian Pharmaceutical Benefits Scheme records 35 657 prescriptions (for either one or two devices) for EpiPen autoinjectors (CSL Limited, Melbourne, VIC), the self-injectable form of adrenaline, in 2006. This is a 650% increase on the 4758 prescriptions for EpiPens in 1998. The increase is much greater than the increase in the rate of food allergy. It is not enough to merely prescribe an EpiPen. It is vital that carers (of children), patients and prescribers understand its use. A previous South Australian study of children who had been prescribed an EpiPen at an allergy clinic found that, in 71% of severe reactions, the parents failed to use the device appropriately. Another study found that only two of 100 doctors in a major Australian paediatric teaching hospital could correctly demonstrate EpiPen use. In 2006, we surveyed EpiPen use by 120 parents of children attending the allergy clinic at the Children’s Hospital at Westmead. Children with egg allergy who were aged under 5 years when seen in 2003 were selected. Seventy per cent (84/120) of the children were prescribed an EpiPen. Half of the children had additional food allergies. Of those prescribed an EpiPen, 69% always carried it, 13% often carried it, 13% sometimes carried it and 5% never carried it. Ten per cent of parents had ever used the device, and 86% stated they were confident that they knew how and when to use it. Despite this, almost 40% stated they had concerns about using the EpiPen in an emergency. These included doubting their ability to correctly administer the EpiPen, whether they would have enough time and would inject correctly, concerns they may hurt their child, concern for the child in the event they needed it, doubt about the effectiveness of the EpiPen, and concern about appropriate timing. In the United Kingdom, 69% of parents were found to have problems using the EpiPen.4 Where, when and how to use the EpiPen was recently identified as one of 12 core parental information needs in our clinic.5 The findings that, even for parents of children attending a specialist allergy clinic where education strategies for EpiPen use are in place, 30% did not always carry the EpiPen, and 40% had concerns about its use in an emergency situation highlight the facts that just providing the device is an inadequate measure and that education and reinforcement, both in EpiPen use and in avoiding relevant allergens, are critical.

Clare W Allen · Dianne E Campbell · Andrew S Kemp

Clinical records Patient 1 A 27-year-old man presented to an infectious diseases outpatient clinic in May 2006 with a 3-month history of nocturnal dry cough, paroxysmal dyspnoea, malaise and unintentional weight loss of 5 kg. He had previously presented to a general practitioner and was treated with two courses of antibacterial drugs without a decrease in symptoms. He had no significant past history of chronic respiratory illness or tuberculosis, was a non-smoker and had been working in Australia for 5 years. He was born in India and had recently returned there on a holiday to visit family and friends. Physical examination, including respiratory system examination, was unremarkable. Full blood examination revealed marked eosinophilia (28.8 × 109/L; reference range [RR], 0.0–0.5 × 109/L). A chest x-ray and computed tomography (CT) showed a diffuse, bilateral fine micronodular pattern throughout both lung fields (Figures A and B). The patient had a raised serum IgE concentration of 24 020 kU/L (RR, 0–120 kU/L), and was positive for filarial IgG by enzyme immunoassay, but negative for filaria on a midnight blood smear. Strongyloides serological tests were also positive, but treatment with two doses of ivermectin did not resolve the nocturnal cough. Three stool specimens were examined for helminths, all of which were negative. The patient was given antifilarial treatment with diethylcarbamazine (150 mg three times daily) for 14 days. Symptoms decreased rapidly, and the eosinophil count was nearly normal (2.7 × 109/L) by 4 weeks. Tropical pulmonary eosinophilia was diagnosed on the basis of the clinical syndrome, positive serological results for filaria, exclusion of other parasitic infections and successful clinical response to a trial of antifilarial treatment. Patient 2 A 25-year-old woman from Sri Lanka presented to the Royal Melbourne Hospital emergency department in September 1994 with a 3-day history of productive cough, pleuritic chest pain and increasing exertional dyspnoea. She had arrived in Australia 6 months previously. Empirical treatment with salbutamol and doxycycline prescribed by her GP had not decreased the symptoms. Examination revealed scattered bilateral expiratory wheezes. A full blood examination revealed an eosinophil count of 21.5 × 109/L, and the initial chest x-ray showed diffuse pulmonary infiltrates, which were confirmed on CT. A bronchoscopy was performed to investigate these pulmonary lesions, which showed pus cells but no visible parasites. An open lung biopsy was then performed, before knowledge of relevant serological results, which revealed an eosinophilic infiltration of the alveolar spaces, suggestive of an eosinophilic pneumonia (Figures C and D). Results of other investigations included three negative stool specimens, a strongly positive serological result for filaria, negative blood film for microfilariae, and a raised serum IgE concentration (28 400 kU/L). Serological tests for schistosomiasis and strongyloides were also both positive at low titres. Given the marked eosinophilia, widespread chest infiltrates and strongly positive filarial serological result, the most likely diagnosis was thought to be tropical pulmonary eosinophilia. The patient was treated with diethylcarbamazine (100 mg three times daily) for 21 days. After some initial nausea, her symptoms decreased, and the eosinophil count was resolving (0.7 × 109/L) by 8 weeks after treatment. Patient 3 A 30-year-old man from India presented to an infectious diseases outpatient clinic via migrant screening in October 2006 with an abnormal appearance on chest x-ray, which showed fine reticulonodular opacities throughout both lung fields. The patient was born near Calcutta and had arrived in Australia 3 months previously. He was a non-smoker and reported a history of non-productive cough over several days. Physical examination was unremarkable including the respiratory system examination. A full blood examination revealed eosinophilia (13.0 × 109/L) and a positive serological result for filarial IgG. Results of other investigations included a raised serum IgE concentration (> 5000 kU/L), a positive serology result for strongyloides and negative serology results for schistosomiasis and toxocara, a negative immunochromatography result for Wuchereria bancrofti, and three negative stool specimens to particularly exclude strongyloides. A blood film did not show microfilariae. Pulmonary function tests showed moderate restriction (forced vital capacity, 3.0 L, or 67% of reference range) without obstruction and normal gas transfer. The patient was initially treated for strongyloides infection with ivermectin, but the eosinophilia persisted. Diethylcarbamazine (150 mg three times daily) was given for 14 days. Within 2 weeks, the eosinophil count had dropped to 1.0 × 109/L. The patient was clinically well at follow-up 3 months later. A: Patient 1 — chest x-ray showed diffuse fine nodules. B: Patient 1 — computed tomography showed a widespread, bilateral fine micronodular pattern. C, D: Patient 2 — low and high magnification (× 200 and × 400) views of a lung biopsy specimen showed eosinophilic infiltration of alveolar spaces (haematoxylin and eosin stain). Tropical pulmonary eosinophilia is a rare but well recognised syndrome characterised by pulmonary interstitial infiltrates and marked peripheral eosinophilia. We report three cases of this syndrome presenting with cough in immigrants to Australia, to highlight awareness of this treatable infectious disease. This condition is more widely recognised and promptly diagnosed in filariasis-endemic regions, such as the Indian subcontinent, Africa, Asia and South America. In non-endemic countries, patients are commonly thought to have bronchial asthma.1,2 Chronic symptoms may delay the diagnosis by up to 5 years.1 Early recognition and treatment with the antifilarial drug, diethylcarbamazine, is important, as delay before treatment may lead to progressive interstitial fibrosis and irreversible impairment.3 Lessons from practice Tropical pulmonary eosinophilia should be considered in patients who have lived in filaria-endemic countries, such as the Indian subcontinent, and present with respiratory symptoms and hypereosinophilia. The most common misdiagnosis is asthma, with overlapping symptoms of chronic cough, paroxysmal dyspnoea and wheeze. Early diagnosis and treatment with diethylcarbamazine (DEC) may prevent progressive pulmonary disease. The condition of marked eosinophilia with pulmonary involvement was first termed tropical pulmonary eosinophilia in 1950.4 The syndrome is caused by a distinct hypersensitivity immunological reaction to microfilariae of W. bancrofti and Brugia malayi.3,5 However, only a small percentage (< 0.5%)6 of the 130 million people globally who are infected with filariasis apparently develop this reaction. The clearance of rapidly opsonised microfilariae from the bloodstream results in a hypersensitive immunological process and abnormal recruitment of eosinophils, as reflected by extremely high IgE levels of over 1000 kU/L.3,7 The typical patient is a young adult man from the Indian subcontinent.5 The diagnostic criteria for tropical pulmonary eosinophilia7 include: history supportive of exposure to lymphatic filariasis; peripheral eosinophilia count (> 3 × 109/L); elevated serum IgE levels (> 1000 kU/L); increased titres of antifilarial antibodies; peripheral blood negative for microfilariae; and clinical response to diethylcarbamazine. High antifilarial IgG titres to microfilariae often result in cross reactivity with other non-filarial helminth antigens,8,9 such as strongyloides and schistosoma antigens, as demonstrated in our reported cases. It is important to exclude other parasitic infections before tropical pulmonary eosinophilia is diagnosed, by serological tests, examination of stool specimens in a laboratory experienced in parasitic infections, or a trial of antihelminth medication. Other parasitic infections, such as the zoonotic filariae, dirofilariasis, ascariasis, strongyloides, visceral larva migrans and hookworm disease, may also be confused with tropical pulmonary eosinophilia because of overlapping clinical features, serological profile and response to diethylcarbamazine3,7,9,10 (Box 1). Radiological findings are non-specific, with normal appearance on chest x-ray in up to 20%.5 Although lung biopsy was performed in Patient 2, it is not part of the routine diagnostic work-up of tropical pulmonary eosinophilia. No universal treatment guidelines have been established for tropical pulmonary eosinophilia.1,7 The antifilarial diethylcarbamazine (6 mg/kg/day for 21 days6) remains the main therapeutic agent and is generally well tolerated. Reported side effects include headache, fever, pruritis and gastrointestinal upset.11 The eosinophil count often falls dramatically within 7–10 days of starting treatment.3 Diethylcarbamazine is available only through the Special Access Scheme of the Therapeutic Goods Administration. Symptoms persist after treatment in up to 25% of patients.5 The role of adjunctive therapy with corticosteroids in preventing long-term fibrosis has not been studied. Our three cases demonstrate the variable clinical presentations and symptom duration of tropical pulmonary eosinophilia. With increased travel and migration of patients from filaria-endemic areas, physicians need to remain aware of tropical pulmonary infections presenting with cough, dyspnoea and variable systemic symptoms, as delayed recognition of this uncommon clinical entity may increase morbidity. 1 Characteristic features of parasitic infections with pulmonary symptoms and eosinophilia Condition Parasite Respiratory symptoms Geographical distribution Laboratory diagnosis Treatment Tropical pulmonary eosinophilia Wuchereria bancrofti, Brugia malayi Nocturnal cough, wheeze, dyspnoea Tropical and subtropical areas, especially India and Sri Lanka Serology, blood film, IgE levels Diethyl- carbamazine Strongyloides Strongyloides stercoralis Loeffler’s-like syndrome,* hyperinfection syndrome Tropical and subtropical, including northern Australia Serology, stool Ivermectin Schistosomiasis Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum Katayama fever, pulmonary hypertension, cor pulmonale Asia, Africa, South America Serology, stool and urine Praziquantel Ascariasis Ascaris lumbricoides Loeffler’s-like syndrome* Asia, Africa, South America Stool Albendazole Visceral larva migrans Toxocara canis, Toxocara cati Eosinophilic pneumonia, wheeze, dyspnoea Worldwide Serology Albendazole Dirofilariasis Dirofilaria immitis Pulmonary lesion Tropical and subtropical, including Australia Serology None Hookworm disease Ancylostoma duodenale Loeffler’s-like syndrome Tropical and subtropical areas Stool Albendazole * Loeffler’s-like syndrome: transient pulmonary infiltrates and eosinophilia from transpulmonary passage of helminth larvae.

Michelle K Yong MB BS · Caroline L Marshall FRACP · Damon P Eisen FRACP, MD

Objective: To investigate the effectiveness and safety of acupuncture in persistent allergic rhinitis (PAR)Design: Randomised, single-blind, sham-controlled trial conducted from May 2004 to February 2005.Participants and intervention: 80 patients with PAR (age, 16–70 years) were randomly assigned to receive real or sham acupuncture. After a 1-week baseline period, participants were treated twice weekly for 8 weeks and followed up for another 12 weeks.Main outcome measures: Nasal obstruction, sneezing, rhinorrhoea and nasal itch were each self-assessed daily on a 5-point scale, and scores were aggregated weekly. The sum of the symptom scores (total nasal symptom score, TNSS) was also determined. A secondary outcome was use of PAR relief medication.Results: After 8 weeks’ treatment, the weekly mean difference in TNSS from baseline was greater with real (−17.2; 95% CI, −24.6 to −9.8) than with sham acupuncture (−4.2; 95% CI, −11.0 to 2.7) (P = 0.01). The decrease in individual symptom score was also greater with real acupuncture for rhinorrhoea (P < 0.01) but not the other symptoms. At the end of follow-up, the greater difference in TNSS from baseline in the real acupuncture group was still apparent: real, −21.0 (95% CI, −29.1 to −12.9) versus sham, − 2.3 (95% CI, −10.2 to 5.6) (P = 0.001). Moreover, the differences from baseline in all four individual symptom scores were greater for the real than for the sham group (P < 0.05). Real and sham acupuncture were both well tolerated.Conclusion: Our findings suggest that acupuncture is effective in the symptomatic treatment of PAR.Trial registration: Australian Government Therapeutic Goods Administration CTN 034/2004.

Charlie C L Xue BMed, PhD · Xuedong An BMed, MApplSc · Thomas P Cheung MSc · Cliff Da Costa PhD · George B Lenon PhD · Frank C Thien MD · David F Story PhD

Objective: To examine changing demand for specialist food allergy services for children aged 0–5 years over the 12 years from 1995 to 2006 as an index of changing prevalence.Design, setting and participants: Retrospective analysis of the records of 1489 children aged 0–5 years referred to a community-based specialist allergy practice in the Australian Capital Territory (population, about 0.33 million).Main outcome measures: Trends in demand for assessment for food allergy, dietary triggers and severity over 12 years, compared with Australian hospital morbidity data.Results: 47% (697/1489) of 0–5 year-old children seen in private practice had food allergy (175 with food-associated anaphylaxis), most commonly to peanut, egg, cows milk and cashew. Over 12 years, the number of children in this age group evaluated each year increased more than fourfold, from 55 cases in 1995 to 240 in 2006. There was no change in the proportion diagnosed with allergic rhinitis in 1995 and 2006 (14.5% and 13.3%, respectively), urticaria (14.5% and 12.9%) or atopic eczema (54.5% and 57.0%). By contrast, the proportion with asthma dropped from 33.7% in 1995 to 12.5% in 2006 and the number with food allergy increased 12-fold, from 11 to 138 patients (and from 20.0% to 57.5% of children seen) The number with food anaphylaxis increased from five to 37 children (9.0% to 15.4%) over the same period. There were similar trends in age-adjusted Australian hospital admission rates for anaphylaxis in children aged 0–4 years, which increased from 39.3 to 193.8 per million population between the financial years 1993–94 and 2004–05, a substantially greater increase than for older age groups, or for the population as a whole (36.2 to 80.3 per million population).Conclusions: There is an urgent need for coordinated systematic studies of the epidemiology of food allergy in Australia, to ascertain risk factors and guide public health policy. An increased prevalence of food allergy has implications for public health and medical workforce planning and availability of allergy services in Australia.

Raymond J Mullins PhD, FRACP, FRCPA

The sudden and untimely death of John Ruhno has deprived many patients of his well regarded expertise in the fields of clinical immunology and allergy. For both patients and colleagues, John’s most significant contribution has been to the management of anaphylaxis in Australia. John was born on 23 July 1952 in Toowoomba, Queensland, and educated at The Southport School. He graduated in medicine from the University of Queensland in 1976. After specialising in paediatrics at Royal Brisbane Hospital, he trained in clinical immunology and allergy at Royal Newcastle Hospital. In 1985, as the Royal Australian College of Physicians’ Bencard Travelling Fellow, he took up the position of Fellow in Immunology and Molecular Virology at McMaster University, Ontario, Canada, documenting basic and clinical research findings on nasal polyposis. Returning to Australia in 1989, John worked in Sydney as a Visiting Medical Officer at The Children’s Hospital, Westmead, and in the Department of Allergy at Royal North Shore Hospital. He also went into private practice in Chatswood and provided a much needed outreach service to the town of Nowra in southern New South Wales. John played a large role in the Australasian Society of Clinical Immunology and Allergy (ASCIA) at a local, national and international level. He was NSW representative from 1995 to 1996 and ASCIA representative to the World Allergy Organization House of Delegates from 1998 to 2005. In addition, John brought valuable expertise to a number of committees including ASCIA’s Computer Committee, Education Committee, and Anaphylaxis Working Party. John was an early and enduring advocate for the ever burgeoning number of patients and their families suffering from anaphylaxis. He was co-founder of the Families of Anaphylactic Children Training and Support Group (FACTS) and Medical Advisor from its inception, then Chair of the Medical Advisory Board of Anaphylaxis Australia, which replaced FACTS. John’s interest in research continued, and in the last 10 years of his life he was involved in collaborative work on several projects investigating the mechanism of egg allergy as a model in allergic disease development. John had a wide range of interests. His knowledge of wine and fine food was prodigious, and his temperature-controlled wine cellar, complete with computerised records of its contents, was the envy of many. He was also a keen sailor and fisherman. Although suffering from cardiomyopathy in the 6 months before his death, John had returned to full-time work. He died on 15 December 2006, at the age of 55. He is survived by his wife Alexandra and daughter Christina.

Janet Rimmer

United airway disease is characterised by inflammation of the respiratory tract, in which asthma and rhinitis are the upper and lower respiratory tract manifestations, respectively, of the same disease process. Irrespective of cause, the upper and lower respiratory tract manifestations are characterised by a systemic inflammatory response. Patients with rhinitis or asthma should always be assessed for coexistent disease in the reciprocal area. Treatment of upper airway disease can modify the severity of lower airway disease and vice versa. The potential for early treatment of allergic rhinitis to prevent progression to asthma merits further study.

Janet Rimmer MD, MB BS, FRACP · John W Ruhno MB BS, FRACP

Eczema is common, occurring in 15%–20% of infants and young children. For some infants it can be a severe chronic illness with a major impact on the child’s general health and on the family. A minority of children will continue to have eczema as adults. The exact cause of eczema is not clear, but precipitating or aggravating factors may include food allergens (most commonly, egg) or environmental allergens/irritants, climatic conditions, stress and genetic predisposition. Management of eczema consists of education; avoidance of triggers and allergens; liberal use of emollients or topical steroids to control inflammation; use of antihistamines to reduce itch; and treatment of infection if present. Treatment with systemic agents may be required in severe cases, but must be supervised by an immunologist. Urticaria (“hives”) may affect up to a quarter of people at some time in their lives. Acute urticaria is more common in children, while chronic urticaria is more common in adults. Chronic urticaria is not life-threatening, but the associated pruritus and unsightly weals can cause patients much distress and significantly affect their daily lives. Angioedema coexists with urticaria in about 50% of patients. It typically affects the lips, eyelids, palms, soles and genitalia. Management of urticaria is through education; avoidance of triggers and allergens (where relevant); use of antihistamines to reduce itch; and short-term use of corticosteroids when antihistamine therapy is ineffective. Referral is indicated for patients with resistant disease.

Constance H Katelaris MB BS, PhD, FRACP · Jane E Peake MB BS, FRACP

Photo courtesy of Kathy McClellan, Safe Sight Institute, University of Sydney. Vernal keratoconjunctivitis (VKC) (also known as “spring catarrh”) is an uncommon disorder seen in children and young adults. Patients typically present with redness, intense itch, photophobia and watering in both eyes. VKC is characterised by a “cobblestone” appearance of the conjunctiva, seen on everting the upper eyelid. It is sometimes associated with allergic disorders, including allergic rhinitis, atopic dermatitis and asthma.1,2 It is a chronic disorder with a clinical course of 2–10 years. What treatments are available? Allergen avoidance may be of limited benefit, given the ubiquitous nature of allergens to which patients are sensitive. Symptomatic relief can be obtained by bathing the eyes with cold water or by using icepacks or cold compresses. Topical antihistamines or combined topical antihistamine/mast cell stabilisers (such as olopatadine or lodoxamide trometamol) are the cornerstones of treatment.2 Topical lubricants (preferably preservative-free) are also useful to improve the tear film and to help reduce the allergen load. A short course of topical (or even systemic) steroids may be needed to settle severe symptoms. Other useful therapies include topical non-steroidal anti-inflammatories, oral montelukast, topical cyclosporin (0.05%), subtarsal steroid injection and/or allergen-specific immunotherapy.3-5 Will it get worse? VKC is potentially severe, and may be complicated by corneal ulceration, scarring and neovascularisation, with occasional associated visual impairment. Careful slit-lamp examination, measurement of intraocular pressure and assessment for the presence of keratoconus is required. Patients requiring topical or systemic steroids should be assessed by an ophthalmologist, and an allergy specialist should advise on whether allergen-specific interventions are indicated. What else could it be? VKC should be distinguished from other types of allergic eye disease, including allergic rhinoconjunctivitis (seasonal [hayfever] or perennial) and atopic keratoconjunctivitis, which is more commonly seen in adults than children. Seasonal allergic conjunctivitis is characterised by the acute onset of conjunctival injection and conjunctival oedema, with or without lid oedema, after exposure to allergens. Perennial allergic conjunctivitis is a persistent form of allergic conjunctivitis that occurs throughout the year and is triggered by exposure to allergens such as animal dander, dust mite or mould spores. Atopic keratoconjunctivitis is characterised by eyelid inflammation (with or without complicating staphylococcal blepharitis), together with redness of the eyeball, discharge and photophobia, and sometimes the development of cataracts or keratoconus. Ocular examination is normal between episodes of VKC.1 Fact or fiction — true or false? A negative skin prick test to common aeroallergens excludes vernal keratoconjunctivitis (VKC) (T/F) False. Not all patients with VKC have positive skin prick tests. Non-IgE-mediated inflammatory mechanisms are probably involved in pathogenesis in some cases. Drug hypersensitivity reactions or chemical exposure can produce acute conjunctivitis similar to VKC, but these conditions can be distinguished from VKC by the patient’s history. Giant papillary conjunctivitis is a severe chronic conjunctivitis triggered by exposure to a foreign body such as a suture or a contact lens. Acute uveitis and angle closure glaucoma should be considered in the differential diagnosis for patients presenting with a red eye, but these conditions are usually unilateral, associated with changes in vision, and not itchy. Case scenario* A 15-year-old male presented to his general practitioner with severe ocular itching, irritation, photophobia and excessive watering of the eyes. He had previously been seen for management of his asthma, atopic dermatitis and intermittent allergic rhinitis. His ocular symptoms, present for the previous 9 months, had worsened significantly during the recent spring season. His vision was unchanged, but he had been wearing sunglasses (even sometimes indoors) because of photophobia. Treatment with topical and systemic antihistamines had given only limited relief. Examination revealed bilateral conjunctival injection, without evidence of blepharitis or eczema of the face or eyelids. Eversion of the upper eyelids revealed a rough, cobblestone appearance with a thick, tenacious discharge. The patient was referred to an allergy specialist for further evaluation. Investigation revealed an elevated IgE level of 780 kU/L, with positive skin prick tests to house dust mite and grass pollens. The patient was managed initially with a combination of corticosteroid eye drops, then maintained with topical olopatadine treatment, and dust mite minimisation measures were advised. Regular ophthalmological review failed to show evidence of corneal scarring or visual impairment. Immunotherapy with pollen extract the following year was associated with a dramatic improvement in symptoms, with minimal requirement for additional pharmacological intervention the following spring. * This is a fictional case scenario based on similar real-life cases.

Denis Wakefield MD, FRACP, FRCPA · Peter J McCluskey MD, FRACO, FRACS