Immune system diseases

To the Editor: Strongyloidosis in Australia has been reported in Indigenous Australians, war veterans who have served in South-East Asia and travellers and immigrants from regions in which strongyloidosis is endemic.1,2 The condition is caused by ...

Hannah M Soulsby · Saliya Hewagama · Stephen Brady

Restoration of immune responses against opportunistic pathogens after commencing antiretroviral therapy (ART) may cause immune restoration disease (IRD) in about 10%–40% of HIV patients with low CD4+ T-cell counts and usually presents clinically as a type of immune reconstitution inflammatory syndrome (IRIS). IRIS may be associated ...

Martyn A H French MD, FRACP, FRCPath

Mackay and Burnet’s Autoimmune diseases, published in 1962, marked the beginning of autoimmunity as a clinical science and led to the future acceptance of the existence of autoimmunity. While there is still controversy regarding the mechanisms of autoimmunity, the authors’ insightful hypothesis based on clonal selection theory and the emergence of “forbidden clones”, due to somatic mutations, is still current, with recent evidence giving further credence to this hypothesis. We salute Mackay and Burnet on the 50th anniversary of this seminal publication. It is particularly pleasing that it has an iconic Australian origin.

Peter J Roberts-Thomson MD, DPhil(Oxon) · Michael W Jackson BSc, PhD · Thomas P Gordon FRACP, FRCPA, PhD

To the Editor: The approach of spring, together with high winter rainfall in and around Melbourne,1 heralds another severe pollen season, raising the risk of allergic rhinitis and asthma in pollen-sensitive individuals. It is therefore timely to report an epidemic of “thunderstorm asthma” that occurred in Melbourne during spring 2010. Thunderstorm asthma is the phenomenon of a sudden increase in acute asthma exacerbations temporally related to a thunderstorm.2 Previous epidemics in 1987 and 1989 saw up to 10-fold increases in asthma presentations to emergency departments across Melbourne over 24-hour periods.3 Those commonly affected are young adults with a history of seasonal allergic rhinitis but not necessarily asthma, and people with a previous diagnosis of asthma, many of whom do not use preventer medication.4 Rye-grass pollen is believed to be the major causative allergen in Melbourne thunderstorm epidemics.2 In Melbourne, this common springtime aeroallergen is generally filtered out by the nose due to its relatively large 20-micron diameter, causing allergic rhinitis in sensitised individuals. When exposed to moisture, such as in a developing storm cloud, osmotic stress can lead rye-grass pollen to rupture into submicronic particles that are respirable to the lower airways.2 Thunderstorms have outflow winds which concentrate these particles at ground level,4 resulting in epidemics of asthma in exposed, pollen-sensitive individuals. We analysed pollen counts and numbers of asthma presentations at the emergency department of Austin Health (a tertiary hospital servicing north-eastern Melbourne) in the days before and after the thunderstorm of 25 November 2010 (Box). There was a clear spike in asthma presentations immediately after the storm, similar in magnitude to previous epidemics.3 Although we report the experience of one institution only, this was a city-wide event that caused considerable media interest and implementation of the ambulance disaster response plan due to the large number of emergency calls received.5 Pollen counts were in the extreme range (> 100 grains/m3) during some of the days before the thunderstorm, but they were only moderate on the day of the storm (Box). Therefore, while pollen counts can be used as a guide for atopic individuals, they are not the only indicator of an allergenic environment. We propose that additional warnings of elevated risk of asthma exacerbations in pollen-allergic individuals should be made when springtime and summertime thunderstorms follow several days of high or extreme pollen counts. Individuals with seasonal asthma should use preventer medication, at least during spring, and should have an asthma management plan. Patients with allergic rhinitis should be warned of the possibility of new-onset thunderstorm asthma and advised to seek assistance rapidly if asthma symptoms manifest. Allergen immunotherapy may be administered in carefully selected individuals to prevent springtime symptoms and assessment of such patients by an allergy physician is recommended. Daily pollen counts in Melbourne and Austin Health emergency department presentations for acute asthma before and after a thunderstorm in Spring 2010* * Pollen count data were provided by Ed Newbegin, School of Botany, University of Melbourne.

Megan L Howden · Christine F McDonald · Michael F Sutherland

Objective: To determine the Australian native ant species associated with ant sting anaphylaxis, geographical distribution of allergic reactions, and feasibility of diagnostic venom-specific IgE (sIgE) testing.Design, setting and participants: Descriptive clinical, entomological and immunological study of Australians with a history of ant sting anaphylaxis, recruited in 2006–2007 through media exposure and referrals from allergy practices and emergency physicians nationwide. We interviewed participants, collected entomological specimens, prepared reference venom extracts, and conducted serum sIgE testing against ant venom panels relevant to the species found in each geographical region.Main outcome measures: Reaction causation attributed using a combination of ant identification and sIgE testing.Results: 376 participants reported 735 systemic reactions. Of 299 participants for whom a cause was determined, 265 (89%; 95% CI, 84%–92%) had reacted clinically to Myrmecia species and 34 (11%; 95% CI, 8%–16%) to green-head ant (Rhytidoponera metallica). Of those with reactions to Myrmecia species, 176 reacted to jack jumper ant (Myrmecia pilosula species complex), 18 to other jumper ants (15 to Myrmecia nigrocincta, three to Myrmecia ludlowi) and 56 to a variety of bulldog ants, with some participants reacting to more than one type of bulldog ant. Variable serological cross-reactivity between bulldog ant species was observed, and sera from patients with bulldog ant allergy were all positive to one or more venoms extracted from Myrmecia forficata, Myrmecia pyriformis and Myrmecia nigriceps.Conclusion: Four main groups of Australian ants cause anaphylaxis. Serum sIgE testing enhances the accuracy of diagnosis and is a prerequisite for administering species-specific venom immunotherapy.

Simon G A Brown MB BS, PhD, FACEM · Pauline van Eeden BAppSci(MLS), PhD · Michael D Wiese BPharm, MClinPharm, PhD · Raymond J Mullins PhD, FRACP, FRCPA · Graham O Solley MB BS, FACP · Robert Puy MB BS, FRACP · Robert W Taylor PhD · Robert J Heddle PhD, FRACP, FRCPA

To the Editor: Animal and human studies confirm the view that colonisation by non-typeable Haemophilus influenzae (NTHi) of airways already damaged by inhaled toxins initiates a second major pathway of damage in chronic obstructive pulmonary disease (COPD). This provides a framework for novel and effective management strategies for this condition, which has previously been considered to be a self-induced disease of elderly people for which nothing can be done.1 Acute exacerbations of COPD are recognised as critical determinants of acute and long-term outcomes. They represent a shift within the bronchus of the balance between two pressures — colonising NTHi and protective recruitment of phagocytic cells — that favours the bacteria and results in an inappropriate and excessive inflammatory response. A novel oral vaccine that reduces acute exacerbations in COPD is currently undergoing an advanced clinical trial in 21 centres across Australia. Oral immunotherapy with enteric-coated inactivated NTHi enhances the efficiency of mucosal immune protection (Box). In a rodent model, specific T cells, derived from stimulation of Peyer’s patches by orally administered NTHi, enhanced clearance of bacteria from the bronchus by recruiting and activating phagocytes.2 In mice co-infected with NTHi and influenza virus, oral administration of NTHi abrogated the increase in levels of both bacteria and virus, suggesting NTHi is a final common pathway for both viral and bacterial infections.2 In humans who smoke, seasonal increase in circulating specific T cells was significantly augmented after oral immunotherapy with NTHi, blocking access of inhaled NTHi into peripheral airways.3 These data support a mechanism whereby NTHi increases physiological protection based on aspiration of bronchus content into the gut. Qualitative2-4 and quantitative2,3 sputum analysis showed that protection was correlated with a reduction of all pathogens and a significant 3-log fall in NTHi, as expected from specific activation of a non-specific clearance mechanism (phagocytosis). In COPD, T cell-recruited neutrophils within sputum undergo a phenotypic change characterised by longevity and enhanced phagocytosis, maintained by autocrine loops.2 Early clinical trials4 of oral immunotherapy showed reductions in the frequency and severity of exacerbations, with consistent decreases in antibiotic usage of more than 50%. A potent and well characterised NTHi isolate with broad cross-protection in screening assays has now been developed for use as the vaccine HI-164OV (unpublished data). Phase II clinical studies of the vaccine have shown it is safe and effective3 and resulted in significant reductions in exacerbations treated with systemic corticosteroids (63%) and hospital admissions (90%)5 among patients with severe COPD taking best-practice treatment. Phase IIb trials are now underway. Evidence of IgE antibody to NTHi in both COPD and treatment-resistant asthma predicts broader clinical value for oral therapy with HI-164OV, through its capacity to prevent inhaled bacteria (allergens) penetrating into small airways.3 Enhancement of mucosal immune protection by oral immunotherapy with enteric-coated inactivated non-typeable Haemophilus influenzae1 Aspiration of bronchus content (including bacteria) into the gut (1) stimulates Peyer’s patches (3) to release T lymphocytes that “home” to the bronchus (4). T lymphocytes — directly or indirectly — secrete cytokines and chemokines that augment recruitment and activation of phagocytes (5). Phagocytes reduce the colonising load of bacteria in the damaged bronchus mucosa. Ingestion of inactivated non-typeable Haemophilus influenzae (2), as a vaccine, augments this protective loop.

Robert L Clancy · Margaret Dunkley

Avoidance of allergenic foods in the first year of life is no longer recommended Since the 1980s, the world has experienced an epidemic of allergic disease. The prevalence of asthma rose rapidly during the 1990s, followed by increases in the prevalence of eczema and allergic rhinitis, both of which continue to rise. Of great concern is new evidence that yet another allergic condition — food allergy — is also on the rise, particularly in infants and young children. An estimated 10%–15% of the population report symptoms of food allergy,1 although the prevalence of IgE-mediated food allergies (ie, symptoms such as urticaria, angioedema, vomiting or anaphylaxis within minutes of food ingestion, in the context of a positive skin prick test result or food-specific serum IgE level) has not, until recently, been adequately studied at the population level. Results of population studies examining food allergy prevalence have been hampered by small sample sizes, selection bias related to sampling methodology and response rates, and use of parental or self-report of allergy or a skin prick test result as a proxy for food allergy diagnosis. Even studies that have used the diagnostic gold standard of oral food challenge, where the allergen of interest is fed to the child, have been limited by a lack of predetermined objective criteria to define the outcome. However, there have now been reports that hospitalisations for food allergy-related anaphylaxis — the most serious and life-threatening manifestation — have increased markedly since 1990 in the United Kingdom, the United States and Australia,2 most dramatically, with a fivefold increase, in 0–4-year-olds. The HealthNuts study was recently mounted to describe the prevalence of food allergy in 1-year-old infants in Melbourne, using a sampling frame designed to recruit a representative population sample and predetermined criteria to assess food allergy outcomes at oral food challenge.3 Recruitment occurred at childhood vaccination sessions. Participants’ parents completed a questionnaire, and the infants received skin prick testing for commonly allergenic foods. Among 2848 participants (73% participation rate), those with any sensitisation to one of three foods (egg, peanut and sesame) were invited to attend an allergy research clinic for formal oral food challenge. Using this method, the study found population-based prevalences of 2.9% (95% CI, 2.3%–3.6%) for peanut allergy, 8.9% (95% CI, 7.8%–10.0%) for egg allergy, and 0.8% (95% CI, 0.5%–1.1%) for sesame allergy in 1-year-old infants.4 Certainly, these rates are the highest yet reported in the Western world, with up to 10% of 1-year-old infants in this study population exhibiting signs of IgE-mediated food allergy in a challenge setting. Although it is anticipated that many of those with egg or cows milk allergy will develop tolerance to these foods in the first 3–4 years of life, the high prevalence of peanut allergy remains concerning, as only 20% of children are expected to achieve resolution of this allergy by 5 years of age.5 Furthermore, there is now evolving evidence that food allergy, including cows milk and egg allergy, may represent the first step on the allergic pathway referred to as the “atopic march”.6 As such, the question remains as to whether this reported high prevalence of food allergy may reflect a second and evolving epidemic of allergic disease, with an early onset in the form of food allergy that will translate into increased rates of asthma and other chronic allergic disease later in life. The reasons behind this apparent increase in serious food allergy are unknown and there is little evidence to guide effective prevention. One of the most topical theories for the rise in allergic disease in general — the hygiene hypothesis — states that very early exposure to microbial antigens promotes healthy immune development and reduces the risk of developing allergies. However, this hypothesis has not been examined specifically with regard to risk of food allergy. Another theory relates to vitamin D insufficiency, with recent reports in both the northern and southern hemispheres showing increasing rates of food allergy with increasing distance of children’s residence from the equator.7 A further factor that has been thought to be important in the development of food allergy is food allergen exposure. Until very recently, expert guidelines for infants with a family history of allergy typically recommended delaying introduction of allergenic foods (including avoiding eggs until 2 years and nuts until 3 years of age in the US), as well as delaying solid foods until after 6 months of age, and breastfeeding for at least 12 months, to reduce the risk of food allergy. Until the publication of the HealthNuts study,4 no population study had directly examined the relationship between infant feeding in the first year of life and risk of challenge-confirmed infant food allergy. Data from the HealthNuts study were used to assess the impact of timing of introduction of allergenic foods. Compared with introduction at 4–6 months, introducing egg into the diet later was associated with higher rates of egg allergy (adjusted odds ratio for introduction after 12 months, 3.4 [95% CI, 1.8–6.5]).8 Most interestingly, introducing cooked egg (such as scrambled, boiled or fried) was more protective than simply introducing egg in baked goods (such as cakes and biscuits). Those introduced to cooked egg at 4–6 months of age were five times less likely to develop egg allergy than those waiting until the normally recommended age of 10–12 months, even after adjusting for confounding factors. There was no protective effect among infants who first had egg in baked goods introduced into their diet between 4 and 6 months of age, presumably because exposure to a lower dose does not provide protection. A further possibility is that early introduction of egg might increase the dose of vitamin D in the diet, and therefore the effect might indeed be mediated through a unifying concept of vitamin D sufficiency. These results are the first evidence-based findings to inform recently revised feeding guidelines, in Australia9 as well as in Europe and the US, that avoidance of any allergenic food in the first year of an infant’s life is no longer recommended. The findings also represent the first report of a modifiable lifestyle factor found to be associated with food allergy and, if these results are replicated in randomised controlled trials, it will have important public health implications for infant feeding worldwide. The emergence of this new epidemic of allergic disease poses significant questions relevant to ensuring a healthy start to life for future generations of children, including whether some aspects of the modern lifestyle, which includes unquestionable improvements in public health, have had an unexpectedly adverse effect at the population level. We also need to understand whether this new wave of food allergy in early childhood is likely to persist into later childhood, and further assess whether early-onset food allergy plays a role in the development of other chronic allergic diseases such as asthma.

Katrina J Allen MB BS, FRACP, PhD

To the Editor: Australian influenza notification and hospitalisation rates are highest in children aged under 5 years,1 the group most commonly affected by egg allergy (estimated to affect 8.9% of infants aged 12 months in a recent Melbourne study).2 The ability to safely vaccinate egg-allergic individuals is thus an important public health issue, particularly in the context of potentially pandemic influenza. More than 98% of over 4000 egg-allergic individuals have tolerated vaccination under direct medical supervision in published studies.3-6 As a result, Australian and several international guidelines3,5,6 recommend that influenza vaccination of the egg-allergic individual may be undertaken using a two-step protocol (10%–90% vaccine dose, 30 minutes apart with a final 30-minute waiting period), as long as vaccines contain less than 1 μg egg ovalbumin/dose. Prior allergy testing with the vaccine is not recommended. All currently available influenza vaccines for the 2011 season in Australia have less than 1 μg ovalbumin/dose, specifically Influvac (Abbott Pharmaceuticals, < 1 μg/dose), Intanza (Sanofi Pasteur, < 0.05 μg), Vaxigrip and Vaxigrip Junior (Sanofi Pasteur, < 0.05 and < 0.025 μg, respectively), Fluvax (CSL, < 1 μg), Agrippal (Novartis, < 0.20 μg) and Fluarix (GlaxoSmithKline Australia, < 0.05 μg). Based on current evidence, we suggest that the 2011 seasonal influenza trivalent vaccines can be safely administered in a medically supervised primary care setting as a single dose with a 30-minute observation period (rather than the standard 15 minutes) in those with non-anaphylactic reactions to egg. In those with a history of egg anaphylaxis (or positive allergy tests without a history of ingestion), we recommend a split-dose protocol after discussion with an allergy specialist. We acknowledge that these guidelines are at variance with those in the Australian immunisation handbook,7 but they are consistent with more recent evidence and international recommendations. Whether it is also safe to administer vaccines containing more than 1 μg ovalbumin/dose8 awaits confirmation in a larger patient population and is not currently recommended.

Raymond J Mullins · Michael S Gold

To the Editor: We read with interest the case by Nadeem and Khateeb of an elderly man with migratory lung lesions and the concurrent finding of mixed cryoglobulins.1 We are concerned about attributing this man’s symptoms to mixed essential cryoglobulinaemia. The clinical syndrome described in this patient is not typical of cryoglobulinaemia. The establishment of a diagnosis of essential mixed cryoglobulinaemia in this man is problematic, given a lack of cutaneous findings and no definite evidence of peripheral neuropathy and renal disease. Nerve conduction studies to establish the presence of peripheral neuropathy and renal biopsy to confirm membranoproliferative glomerulonephritis were not carried out. Given his age, the confirmation of membranoproliferative glomerulonephritis would potentially necessitate long-term and possibly intensive immunosuppression to prevent subsequent development of renal failure. The cryoglobulins reported in this case fulfil the criteria for type II cryoglobulins. However, they were of relatively low concentration (0.4 g/L of monoclonal IgM/kappa and 0.1 g/L of polyclonal IgG). As well as hepatitis C, type II cryoglobulins can be detected in association with hepatitis B and Sjögren’s syndrome.2 The absence of anti-Sjögren’s syndrome A and anti-Sjögren’s syndrome B antibodies by no means excludes the diagnosis of concurrent, subclinical Sjögren’s syndrome. In addition, hepatitis B and C have not been excluded as the cryocrit was not analysed for hepatitis B virus DNA and hepatitis C virus RNA. Furthermore, the relatively low concentration of cryoglobulin detected and the findings of chest opacities with very high levels of C-reactive protein (that fell to normal levels with antibiotic treatment) could also be due to an infective aetiology.3 We also note that the thermal amplitude of the cryoglobulins should be investigated in such cases, as it has been well described that cryoglobulins of higher thermal amplitudes are more likely to be clinically significant. In conclusion, given the long duration of this man’s admission, repeat cryoglobulin measurements after he was discharged would have helped to more clearly define the role of cryoglobulins in his disease. We therefore recommend caution when interpreting low levels of cryoglobulinaemia in patients who have a clinical syndrome that may or may not be consistent with clinical cryoglobulinaemia.

Carl A Kennedy · David Gillis · Richard C W Wong

Clinical record A 22-year-old woman of European ancestry who had a 4-year history of treatment-resistant bipolar disorder presented with symptoms of mania. On admission to hospital, a full blood examination and biochemistry results were normal. Her current doses of lithium (1500 mg daily) and risperidone (2 mg daily) were maintained while treatment with carbamazepine was commenced at 100 mg daily and then increased by 100 mg every 3 days. The patient was discharged from hospital on a regimen of 400 mg carbamazepine daily. Her plasma carbamazepine level at this time was 19 μmol/L (reference range [RR], 16–50 μmol/L). She was in good physical health, and a full blood examination and biochemistry results were normal. Three weeks after starting to take carbamazepine, the patient developed a mild, barely visible, erythematous maculopapular rash on her arms and chest that disappeared after a few days. She had no other symptoms, and full blood examination and biochemistry results remained normal. After a further 3 weeks, the patient developed marked lethargy, exercise intolerance, muscle aches, night sweats, rigors and a rash. There had been no changes to her medication and she had been complying with her treatment regimen. She lived with her family, and her parents contacted her family general practitioner as well as me (her psychiatrist). She was advised to stop taking carbamazepine, increase the dose of risperidone and seek urgent medical attention. The carbamazepine was stopped over 2 days — 45 days after it was first administered. The family consulted an emergency service on four occasions over 6 days, and the patient was variously diagnosed with contact dermatitis, non-specific allergic reaction, cytomegalovirus and rubella. She was finally admitted to hospital and was found to be febrile (temperature, 38–40º C) and tachycardic (heart rate, 108 beats per minute), with an intensely pruritic maculopapular rash that had spread over most of her body. Her face was swollen, showing periorbital oedema. There was no mucosal involvement or epidermolysis. She had occipital, supraclavicular and inguinal lymphadenopathy, and hepatosplenomegaly. Liver function test results were markedly abnormal (alanine aminotransferase [ALT], 1203 IU/L [RR, < 41 IU/L]; alkaline phosphatase, 156 IU/L [RR, 30–120 IU/L]) and her serum albumin level was low (29 g/L [RR, 35–50 g/L]. She had lymphocytosis (lymphocyte count, 5.9 × 109/L [RR, 1.0–4.0 × 109/L), but her C-reactive protein level was not raised. A diagnosis of anticonvulsant hypersensitivity syndrome was made. The patient was transferred to the intensive care unit, where she remained for 48 hours, and treatment with prednisolone 40 mg daily was commenced. Her physical state improved rapidly. After 7 days her ALT level had dropped to < 500 IU/L and she was deemed well enough to be discharged. The prednisolone was gradually tapered by 5 mg per week. Topical betamethasone helped to soothe her pruritus and inflammation, and some mild exfoliation occurred. The patient continued to improve over the next 6 weeks. Her rash disappeared, as did her hepatosplenomegaly, and liver function test results normalised. She recovered fully and has remained on lithium and risperidone. Anticonvulsants are being used increasingly for mood disorders and chronic pain. Anticonvulsant hypersensitivity syndrome (ACHS) has been reported to occur with use of phenytoin, carbamazepine, phenobarbitone and lamotrigine, but not valproate. It is a rare and potentially fatal complication. ACHS is indicated by the presence of a triad of characteristic clinical features — fever, rash and internal organ involvement. It is estimated to occur in about 1 in 1000 to 1 in 10 000 patients who are exposed to these anticonvulsants.1 A similar reaction has also been described with exposure to sulfonamides, sulfones, allopurinol and non-steroidal anti-inflammatory drugs (piroxicam in particular).2 This reaction has also been referred to as drug-related rash with eosinophilia and systemic symptoms (DRESS) syndrome, and drug-induced hypersensitivity syndrome (DIHS).3 This patient showed a pattern of symptoms quite typical of ACHS, which usually appears after a brief delay of 2–4 weeks after anticonvulsant exposure, but may appear up to 12 weeks later.1 Her symptoms began to emerge about 6 weeks after she commenced taking carbamazepine, although a mild rash appeared after 3 weeks. Transient rashes are quite common following initiation of carbamazepine therapy and are not an indication for stopping the drug. Clinicians often fail to consider a diagnosis of ACHS.4 Although the seriousness of the illness was initially not obvious, it was fortunate that administration of carbamazepine had been stopped as soon as significant symptoms began to emerge. It is noteworthy that the patient’s physical state continued to deteriorate following withdrawal of carbamazepine, and only improved 1 week later, after hospital admission and treatment with prednisolone. Her mental state did not worsen during her acute illness, and she showed great resilience. Prednisolone has potent mood-altering properties and presents a significant risk for inducing either depression or mood elevation. Close monitoring of mental state and psychiatric involvement is recommended. Carbamazepine has been linked with a variety of hypersensitivity reactions, ranging from mild and benign urticaria and erythematous maculopapular eruptions to Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). ACHS is usually not as serious as SJS or TEN but can be life-threatening, and deaths from it have been reported.5 The skin condition can be extensive in ACHS, but is not as severe as the detachment of body surface area seen with SJS or TEN, which often involves gastrointestinal or tracheobronchial epidermal surfaces. Lessons from practice Anticonvulsant hypersensitivity syndrome (ACHS) is a rare and potentially fatal complication of treatment with the anticonvulsants phenytoin, carbamazepine, phenobarbitone and lamotrigine. Diagnosis is clinical and based on a triad of features: fever, rash and internal organ involvement. Early suspicion of diagnosis is essential, as the critical component of treatment is cessation of the implicated drug. Pharmacogenetic testing for the human leukocyte antigen allele B*1502 should be considered before commencing carbamazepine in patients of Asian ancestry. Genetic factors predispose individuals towards the development of these reactions, and recent data have linked human leukocyte antigen allele B*1502 as a marker in Asian populations, except among people of Korean and Japanese ancestry. Genotyping is recommended for at-risk groups;6 the prevalence of the allele is negligible in other ethnic groups.6 ACHS is associated with complex immunological changes that include chemotoxic and T-cell-mediated inflammatory injuries to tissues containing cytochrome oxidases.2 Viral infection may increase an individual’s vulnerability.7 The most critical component of management of ACHS is discontinuation of the implicated drug.1 All clinicians who prescribe anticonvulsant drugs therefore need to be aware of ACHS and the requirement for early suspicion of the diagnosis. General supportive measures and systemic corticosteroids are usually given, which in most instances results in full recovery. There is cross-sensitivity among aromatic anticonvulsant drugs (phenytoin, carbamazepine, phenobarbitone and lamotrigine), which means that patients who have had ACHS should avoid all of these drugs.4 In addition, a familial association with ACHS exists, and family members of these patients need to be informed that they may be at increased risk of developing this syndrome. Anticonvulsant drugs that are generally considered safe are valproate and benzodiazepines.4

Isaac Schweitzer MD, DPM, FRANZCP

To the Editor: We view with concern the listed minimum investigations for chronic suppurative lung disease and bronchiectasis in children and adults recommended in the position statement from the Thoracic Society of Australia and New Zealand and the Australian Lung Foundation, published in the Journal.1 We do not agree with the inclusion of measurement of IgG subclasses in the list. Interpretation of IgG subclasses is fraught with difficulties.2 It is unclear whether the isolated finding of low levels of one or more IgG subclasses is a risk factor for developing severe recurrent bacterial infections. Individuals with complete absence of IgG subclasses due to gene deletions may remain entirely asymptomatic, and the finding of a low or absent response to specific bacterial protein and/or polysaccharide is more closely associated with propensity to infection. In addition, the lack of reproducibility of IgG subclass assays and lack of well standardised age-specific reference ranges hinder interpretation of results. Of major concern is the lack of evidence to provide clear guidance on the efficacy of immunoglobulin replacement therapy in IgG subclass deficiency. In general, the finding of isolated IgG subclass deficiency is not sufficient grounds for commencement of immunoglobulin therapy and is not recommended as an indication for intravenous immunoglobulin therapy in the current Australian guidelines.2 We urge the authors to reconsider the inclusion of IgG subclasses in the list of minimum investigations for chronic suppurative lung disease and bronchiectasis.

David S Gillis · D Sean Riminton

In reply: We thank Gillis and Riminton for their comments highlighting the inclusion of IgG subclasses in the list of suggested investigations when reviewing a patient with chronic suppurative lung disease or bronchiectasis. We agree that a finding of one or more low IgG subclasses in isolation is not an indication for immunoglobulin therapy and that interpretation of serum IgG subclass concentrations is difficult. Indeed, this was debated at length by the position statement authors. However, after considerable discussion, we decided that measurement of IgG subclasses should be included. Although the data are weak, it is an important area of possible aetiology, and there are varying opinions regarding associations with impaired adaptive immunity.1-3 As with some other investigations, an abnormal test result in the context of a child or adult with suppurative lung disease would lead to discussion with an appropriate subspecialist for advice on interpretation and/or further evaluation. Space limitations in the Journal version of our position statement did not permit us to elaborate further.4 In the full document available online,5 we stated that: The benefits of performing IgG subclasses in isolation are particularly controversial as the role of a reduction of a subclass is likely over-diagnosed.[88-91] If IgG subclass is low, assessment of response to vaccinations is advocated.

Anne B Chang

In the absence of evidence of infection with the hepatitis C virus (HCV), detecting the immunological disorder of mixed cryoglobulinaemia is a challenge. Only after extensive investigation did we suspect that our patient’s recurrent acute dyspnoea, lower limb paraesthesia and renal impairment with active urinary sediment were attributable to the rare phenomenon of non-HCV-related mixed essential cryoglobulinaemia — our suspicion was confirmed by significant serum levels of cryoglobulins. (MJA 2010; 194: 142-144) Clinical recordIn October 2008, an 84-year-old man with increasing dyspnoea on exertion for 1 week was referred for hospital admission by his general practitioner. His medical history included rheumatic heart disease leading to aortic valve replacement (AVR) in 1973. In 2001, he underwent a redo AVR, a mitral valve replacement (non-mechanical) and coronary artery bypass grafting. He then required implantation of a permanent cardiac pacemaker for complete heart block. He had chronic kidney disease (Stage 3) of unknown cause and mild, well controlled asthma. He was a lifelong non-smoker and occasionally drank alcohol. At presentation, he was afebrile and haemodynamically stable, with a respiratory rate of 20 breaths per minute and oximetry of 95 per cent on room air. There were no signs of fluid overload or peripheral stigmata of infective endocarditis. Chest auscultation revealed bibasal crackles, and loud first and second heart sounds in keeping with previous valve surgery. Mild stasis eczema was the only notable skin lesion. He reported experiencing, for the past few months, lower limb paraesthesia and sicca-like symptoms. His daily medications included perindopril 2.5 mg, digoxin 125 μg, frusemide 40 mg and warfarin at varying doses. For asthma, he was prescribed a daily inhalation of fluticasone 250 μg, with salmeterol 25 μg, and inhalations of salbutamol 100 μg as needed. Results of blood, urine and sputum tests done at presentation are shown in Box 1; results showed an inflammatory response and renal impairment with active urinary sediment (repeat urinary analysis a week after presentation also revealed active urinary sediment). An electrocardiogram showed no arrhythmias. Chest x-ray at presentation showed air bronchograms at the right lower zone (Box 2). Our patient was admitted and treated for right lower lobe pneumonia with intravenous antibiotics. He was also prescribed high-dose oral steroids, with gradual tapering of doses. A computed tomography scan showed probable right lower chest infection. During the early weeks of his hospitalisation, the patient had further episodes of acute dyspnoea, and repeat chest x-rays showed bilateral migratory opacities (Box 3). Acute episodes of dyspnoea were treated with high-dose oral steroids and intravenous antibiotics; a regular regimen of low-dose steroids was maintained between episodes. During each acute episode, his biochemistry results showed an inflammatory response, with varying elevated serum levels of C-reactive protein (CRP): 243 mg/L; 332 mg/L; 73 mg/L; 16 mg/L; 148 mg/L; and 90 mg/L (reference range [RR], < 5.0 mg/L). With treatment, the CRP level fell to 5.3 mg/L. Repeated blood and urine cultures produced no growth. A transthoracic echocardiogram revealed a normal left ventricular ejection fraction and no regurgitation from the prosthetic valves, and a transoesophageal echocardiogram showed no valvular vegetations. The serum level of B-type natriuretic peptide was 246 ng/L (RR, < 100 ng/L), making acute left ventricle failure unlikely in view of the patient’s renal impairment. No respiratory viruses were detected in nasopharyngeal aspirate. The patient’s serological tests were negative for hepatitis B virus, hepatitis C virus (HCV), HIV, cytomegalovirus, mycoplasma, Chlamydia, Legionella pneumophila, Legionella longbeachae, Brucella, Histoplasma, and Toxoplasma. The result of the QuantiFERON-TB Gold assay (Celeste) was indeterminate. Serum electrophoresis was negative and no Bence–Jones protein was detected in urine. Liver ultrasound showed no evidence of chronic liver disease. Screening for autoimmune discrepancies was significant but inconclusive — test results for serum levels of rheumatoid factor (RF) and antinuclear antibody were positive but other antibody test results were negative or within reference ranges (Box 4). On further investigation (5 weeks after admission), the patient’s serum levels of complement components C3 and C4 were 0.77 g/L (RR, 0.70–1.60 g/L) and < 0.02 g/L (RR, 0.10–0.30 g/L), respectively; repeated test results were C3, 0.74 g/L and C4, < 0.02 g/L. Such a result — low C4 with normal C3 levels — may be due to cryoglobulinaema, C4 null alleles, hereditary angioedema or activation of the classical complement pathway. Types and levels of cryoglobulins found in the patient’s serum were: monoclonal IgM/kappa, 0.4 g/L and polyclonal IgG, 0.1 g/L. HCV RNA was not detected. On the basis of the presence of cryoglobulins in serum and supported by evidence of lung and inflammatory involvement, a diagnosis of mixed essential cryoglobulinaemia (Type II cryoglobulinaemia) was made. The patient was reviewed by an immunologist, who agreed with the diagnosis. To exclude lymphoma, particularly B-cell lymphoma which is the most frequent malignant complication of mixed cryoglobulinaemia, a bone marrow biopsy was done; no significant population of B-cell biomarkers (CD19+/CD20+ cells) was found, nor any other suggestion of lymphoma. Despite the investigative effort, we did not identify a cause for our patient’s cryoglobulinaemia. He gave informed consent for all investigations. DiscussionCryoglobulins are single or mixed immunoglobulins that, in serum and other body fluids, undergo reversible precipitation at low temperatures (below 37°C in serum). According to the Brouet classification, cryoglobulinaemia is grouped into three types based on the composition of the detected cryoglobulins. Type I cryoglobulinaemia, or simple cryoglobulinaemia, is the result of a monoclonal immunoglobulin, which rarely has RF activity and is not known to activate complement in vitro. The cryoglobulins of Types II and III cryoglobulinaemia (mixed cryoglobulinaemia) contain RF, which forms complexes with the “fragment crystallisable” (Fc) portion of polyclonal IgG. The actual RF may be monoclonal immunoglobulin (in Type II cryoglobulinaemia) or polyclonal immunoglobulin (in Type III cryoglobulinaemia). Types II and III cryoglobulinaemia represent 80% of all occurrences of the disease. HCV is associated with most cases of mixed cryoglobulinaemia, with the prevalence of anti-HCV antibodies or HCV RNA ranging from 70% to almost 100%.1 The clinical manifestations of cryoglobulinaemia are generally caused by the inflammatory effects of circulating immune complexes on multiple organs. The criteria for diagnosing mixed cryoglobulinaemia are: detection in serum of mixed cryoglobulins, along with purpura and leukocytoclastic vasculitis; or detection in serum of mixed cryoglobulins, along with peripheral neuropathy, membranoproliferative glomerulonephritis, chronic hepatitis or skin rashes.1 Signs and symptoms that our patient showed fulfilled the latter set of criteria. Although our patient had no skin lesion typical of the disease (and suitable for biopsy), nor evidence of liver disease, he had lower limb paraesthesia and tested positive for renal impairment and active urinary sediment. The success of steroid treatment indicated an inflammatory component to the problem. Furthermore, lung involvement is reported to be quite frequent in mixed essential cryoglobulinaemia,2 and migratory lung lesions have been associated with the disease.3 What is notable about this case is the lack of evidence of HCV infection. To the extent that we are able to establish (two PubMed searches of English-language articles were undertaken), it is the first reported case of mixed essential cryoglobulinaemia with migratory lung lesions and unrelated to HCV infection. 1 Results of patient’s blood, urine and sputum investigations at presentation Test Result Blood Haemoglobin 110 g/dL (RR, 135–180 g/dL) White cell count 9.2 x 109 cells/L (RR, 4.0–11.0 x 109 cells/L) Neutrophils 6.5 x 109 cells/L (RR, 2.0–8.0 x 109 cells/L) Platelets 174 x 109 cells/L (RR, 140–400 x 109 cells/L) C-reactive protein 243 mg/L (RR, < 5.0 mg/L) Sodium 138 mmol/L (RR, 135–145 mmol/L) Potassium 4.8 mmol/L (RR, 3.5–5.1 mmol/L) Urea 13.3 mmol/L (RR, 2.9–8.2 mmol/L) Creatinine 160 μmol/L (RR, 64–108 μmol/L) Cultures (three sets) No growth after 1 week incubation Urine Microscopic analysis Active sediment* Dipstick Moderate blood, 2 + leukocytes, trace protein Culture No growth after 1 week incubation Sputum Culture Normal respiratory flora RR = reference range. * Active urinary sediment is sediment found in a centrifuged urine sample and showing red cells, red cell casts and at times white cells and white cell casts; it indicates active kidney inflammatory disease such as glomerulonephritis, interstitial nephritis or vasculitis. 2 Patient’s chest x-ray at presentation showing air bronchograms at right lower zone (2 October 2008) 3 Patient’s chest x-rays several weeks after presentation showing bilateral migratory opacities (A, 16 November 2008; B, 24 November 2008) 4 Results of patient’s autoimmunity screening tests at presentation and 4 weeks after presentation Test Initial result Result at 4 weeks Rheumatoid factor (RR, < 20 IU/mL) 51 IU/mL < 20 IU/mL Anticyclic citrullinated peptide antibody (anti-CCP) < 6 U/mL — Antinuclear antibody (ANA) (RR, < 40 titre) > 2560 titre 640 (homogenous) titre Anti-double-stranded DNA antibodies negative — Anti-Sjögren’s syndrome A / anti-Sjögren’s syndrome B antibodies (anti SSA/SSB antibodies) negative — Direct Coombs test negative — Antithyroid peroxidise antibodies (RR, < 50 IU/mL) 1 IU/mL — Antithyroglobulin antibodies (RR, < 100 IU/mL) 7 IU/mL — Antitissue transglutaminase antibody (anti-TTG [IgA]) (RR, < 5 U/mL) 0 U/mL — RR = reference range

Muhammad Kashif Nadeem MB BS, MRCP · Mohammed A Khateeb MB BS, FRACP

Objective: To determine antibody levels and estimate incidence of infection with pandemic (H1N1) 2009 influenza in children and pregnant women during the 2009 winter in Western Australia.Design, setting and participants: Two cross-sectional serosurveys using stored specimens collected for unrelated pathology testing, from before and after (3 August to 30 November 2009) circulation of the pandemic virus, and before commencement of the pandemic vaccination program. Specimens were from three groups: children aged 1–4 years, older children and teenagers aged 5–19 years, and pregnant women aged 21–45 years. The groups were geographically representative of the WA population.Main outcome measures: Reactivity against pandemic (H1N1) 2009 and seasonal A(H1N1) influenza viruses measured using haemagglutination inhibition (HI) assays.Results: Antibody titres were determined for 648 individuals in the prepandemic period and 736 in the postpandemic period. In the prepandemic period, HI titres ≥ 40 against the pandemic virus were found in 0 (95% CI, 0.0%–1.6%) children aged 1–4 years, 8.3% (95% CI, 5.3%–12.7%) of older children and teenagers, and 4.5% (95% CI, 2.4%–8.3%) of pregnant women. In postpandemic specimens collected from 1 September 2009 (when influenza activity had declined to near-baseline levels), estimated infection rates (subtracting prepandemic levels) were 25.4% (95% CI for difference, 18.6%–33.4%) in 1–4-year-old children, 39.4% (95% CI, 29.8%–48.5%) in older children and teenagers, and 10.2% (95% CI, 4.1%–17.1%) in pregnant women.Conclusions: A quarter of preschool children and about 40% of school-aged children and older teenagers had serological evidence of pandemic influenza infection during winter 2009, indicating high levels of mild or asymptomatic infection. The infection rate in pregnant women was much lower. The high infection rates in children help explain the reduced impact of the pandemic virus during the 2010 winter. Augmented by vaccination, there should be sufficiently high levels of immunity in the Australian population to significantly reduce the impact of the virus in future influenza seasons.

Gary K Dowse MB BS, MSc, FAFPHM · David W Smith BMedSc, MB BS, FRCPA · Heath Kelly MB BS, MPH · Ian Barr PhD · Karen L Laurie BSc(Hons), PhD · Anthony R Jones BSc, MASM · Anthony D Keil MB BS, FRCPA · Paul Effler MD, FAFPHM

Objective: To describe the clinical features and laboratory findings in patients with definite red-bellied black snake (RBBS; Pseudechis porphyriacus) bites, including correlation with results of venom assays. Design, patients and setting: Prospective cohort study of patients with definite RBBS bites, recruited to the Australian Snakebite Project from January 2002 to June 2010. Main outcome measures: Clinical and laboratory features of envenoming; peak venom concentrations and antivenom treatment. Results: There were 81 definite RBBS bites; systemic envenoming occurred in 57 patients (70%) and local envenoming alone occurred in one patient. Systemic envenoming was characterised by local envenoming in 55 patients (96%), systemic symptoms in 54 patients (95%), anticoagulant coagulopathy with a raised activated partial thromboplastin time (aPTT) in 35 patients (61%) and myotoxicity in seven patients (12%). One patient required non-invasive ventilation for severe myotoxicity that resulted in muscle weakness. Three patients developed local ulceration. There were no deaths. Twenty-two envenomed patients (39%) received tiger snake or black snake antivenom, and administration within 6 hours of the bite was associated with normalisation of the aPTT. Eight patients (36%) had immediate hypersensitivity reactions to antivenom, including one case of anaphylaxis. The median peak venom concentration in 37 systemically envenomed patients with serum available was 19 ng/mL (interquartile range, 12–50 ng/mL; range, 3–360 ng/mL), which did not correlate with clinical severity. In 17 patients who received antivenom and had venom concentration measured, no venom was detected in serum after the first antivenom dose, including nine who were given one vial of tiger snake antivenom. Conclusion: RBBS envenoming caused local effects, systemic symptoms, anticoagulant coagulopathy and, uncommonly, myotoxicity. One vial of tiger snake or black snake antivenom appears to be sufficient to remove venom and neutralise reversible effects, but hypersensitivity reactions occurred in over a third of patients.

Andrew Churchman BM BS(Hons) · Margaret A O’Leary PhD · Nicholas A Buckley BMed, FRACP, MD · Colin B Page MB ChB, FACEM, MMedSci(Clin Epi) · Alan Tankel BSc, MB ChB, FACEM · Chris Gavaghan MB BS, FACEM · Anna Holdgate MB BS, FACEM, MMed · Simon G A Brown MB BS, FACEM, PhD · Geoffrey K Isbister BSc, FACEM, MD

Clinical record A 78-year-old woman who was previously very active and in good health presented to hospital feeling unwell and with an extensive rash, involving both upper limbs (C3–T1 dermatomes), consistent with herpes zoster. Three weeks later, extensive diffuse left upper limb neuropathic pain developed over her C5–C7 dermatomes. The following week, her condition worsened to include progressive severe paresis of the left upper limb; weakness in the right hand; bilateral lower limb weakness; patchy areas of paraesthesia affecting many areas of the upper limbs, trunk and proximal lower limbs; severe constipation; and urinary retention, which required insertion of an indwelling catheter. She was bedbound and needed assistance with all self-care activities. About 10 days after the onset of weakness, a neurologist diagnosed a cervical myelopathy and recommended magnetic resonance imaging of the spine. This revealed an area of inflammation at C2–C4 involving the full thickness of the spinal cord at that level, consistent with transverse myelitis (Figure). She was diagnosed with herpes zoster myelitis. Sagittal T2-weighted magnetic resonance image with gadolinium enhancement showing an ovoid hyperintense lesion in the upper cervical spinal cord (arrow). About 6 weeks after her initial presentation, the patient was transferred to another acute hospital for further assessment. Detailed examination revealed asymmetric tetraparesis; upper limbs (left greater than right) were affected more than the lower limbs. On manual muscle testing she had muscle strength in her limbs as follows: 0/5 in the proximal and 1/5 in the distal left upper extremity, 4/5 in the right upper extremity and 2/5 in both lower limbs, with partial loss of sensation from her C4 to L3 dermatomes. Laboratory findings for full blood cell count, urea and electrolytes were unremarkable except for mild hyponatraemia and mild derangement of liver enzymes. Because of the severity of the herpes zoster infection, the patient was tested for underlying immunocompromise. She was found to have a κ monoclonal gammopathy of undetermined significance (12.0 g/L IgG; reference range [RR], 7.0–16.0 g/L) and borderline low values of immunoglobulins IgA (0.40 g/L; RR, 0.7–4.0 g/L) and IgM (0.31 g/L; RR, 0.4–3.0 g/L). It was thought that all of these immune abnormalities were of questionable significance. Treatment was initiated with intravenous methylprednisolone (1 g/day for 6 days) and intravenous (300 mg three times a day for 6 days) then oral (800 mg five times a day for 2 weeks) aciclovir. During the course of this treatment, gradual improvement in power of all four limbs became evident. She was subsequently admitted to a spinal rehabilitation unit and discharged 8 weeks later with evidence of ongoing neurological and functional improvement. Her hospital stay was complicated by severe postherpetic neuralgia, which was eventually controlled with gabapentin (400 mg three times a day). She recovered bladder function but needed aperients to achieve controlled faecal continence. At discharge, neurological examination revealed persisting asymmetric tetraparesis. She had 4/5 upper extremity muscle strength in C7–T1 myotomes on the left, 4/5 in L2 and L3 myotomes in both lower limbs and her remaining myotomes were of normal power. She was able to walk with a four-wheel frame or a single-point stick for 10–20 m and was independent for many activities of daily living. At follow-up 9 months after her initial presentation, her condition was still improving gradually. She had weaned off the gabapentin with no residual postherpetic neuralgia. She was able to walk short distances unaided and had regained full independence with most of her self-care using aids. Herpes zoster is associated with several neurological complications, including postherpetic neuralgia, aseptic meningitis, meningoencephalitis, transverse myelitis, peripheral nerve palsies, cranial nerve palsies and granulomatous cerebral angiitis.1 These complications are particularly prevalent among older people and patients with immunodeficiency. A causative relationship with herpes zoster in many of these syndromes is probably more common than suspected owing to difficulties in diagnosis and lack of awareness among clinicians. However, to our knowledge, there are no published reports of any known association between the neurological complications of herpes zoster, including myelitis, and postherpetic neuralgia. Transverse myelitis is a focal inflammatory disorder of the spinal cord. It results in sensory, motor and autonomic dysfunction 2 Onset may be acute, developing over a few hours or several days, or subacute, developing over 1 to 2 weeks. The critical factor is an abnormal immune response to infection, rather than the direct effect of an infectious agent.3 Transverse myelitis may be an isolated entity or may occur with a background of viral diseases, vaccinations, systemic lupus erythematosus, vasculitis, multiple sclerosis, heroin misuse or trauma.3 About 25%–40% of cases of transverse myelitis are caused by viral infections with herpes viruses or poliovirus.2 A recent publication provides useful additional information about transverse myelitis.4 Lessons from practice Herpes zoster myelitis is rare in the context of normal immunity; it is more common among patients with immunocompromise. Clinicians should be aware of the close temporal relationship between skin rash and the onset of myelitis so that appropriate investigations and treatment can be instigated. Magnetic resonance imaging of the spine should be performed to aid diagnosis. Although early treatment of herpes zoster myelitis is preferable, delayed treatment may also be worthwhile. Transverse myelitis following herpes zoster or herpes zoster myelitis (HZM) is rare, and typically occurs in hosts who are immunocompromised. Its onset is usually acute, occurring shortly after the appearance of the rash, with the development of sensory, motor and autonomic dysfunction.5 No diagnostic test is completely accurate, as the virus cannot usually be isolated from blood or cerebrospinal fluid in HZM.5 In most cases, diagnosis of HZM is clinical and based on detection of typical vesicular lesions in dermatomal distribution in association with clinical features of transverse myelitis. Suggested treatment involves high doses of corticosteroids and aciclovir.5 The prognosis ranges from spontaneous recovery to ascending neurological progression and death.6 The frequency of transverse myelitis during or after varicella infection is reported to be 0.3%.7 Devinsky and colleagues analysed their findings in 13 immunocompromised patients with HZM.8 The pathogenesis of HZM is unclear, but it may be due to direct viral invasion, which was demonstrated in one autopsy case.9 Diagnosing HZM can be challenging. The importance of a careful clinical assessment to establish the likelihood of this diagnosis and the level of the spinal cord damage, in combination with confirmatory magnetic resonance imaging (MRI)7cannot be overstated. MRI not only provides information about the site but also the extent of spinal cord involvement, and excludes other possible diagnoses. In our patient, HZM was diagnosed based on the temporal relationship of myelopathy to the rash and MRI findings. Although the area of the spinal cord that was involved on the MRI scan was less extensive than that affected by the herpetic rash, we do not see this as clinically inconsistent. There are no proven treatment regimens for HZM, but there is anecdotal evidence for treatment of HZM with high doses of aciclovir and corticosteroids.5,10 It appears that antiviral treatment was not provided early to our patient because it was not initially recognised that the rash was due to herpes zoster. Once HZM was diagnosed, this treatment was provided. Despite the delay of 3 weeks following the onset of rash, improvement appeared consistent with a clinical response to this therapy. Although early treatment of herpes zoster with antivirals is crucial to prevent the development of postherpetic neuralgia, there is little evidence that such treatment reduces the risk of HZM. To date, no evidence has emerged regarding the protective efficacy of the new live, attenuated herpes zoster vaccine (Zostavax) against HZM. Trials assessing the impact of antivirals or the herpes zoster vaccine on risk of HZM would require very large numbers of participants, given the rarity of this complication. Nevertheless, the vaccine has proven to be efficacious in reducing the incidence of and morbidity associated with herpes zoster and postherpetic neuralgia in older adults.11 It has been noted in a previous case report that, following the diagnosis of HZM, even delayed treatment with oral antivirals may prevent neurological progression.12 Our case provides support for this assertion.

Olivia L W Ong MB BS, BMedSci · Andrew C Churchyard PhD, MB BS, FRACP · Peter W New MB BS, MClinEpi, FAFRM(RACP)

To the Editor: Allergen avoidance is the mainstay of food allergy management. Consumers with food allergies rely on accurate labelling of foods to avoid ingestion of allergens and subsequent allergic reactions. Current Australian legislation states that ingredients derived from common allergens (peanuts, tree nuts, eggs, wheat, cows milk, soy, fish, shellfish and sesame) must be clearly labelled.1 However, use of shared processing facilities can result in cross-contamination of other ingredients with these allergens. This has led to the use of advisory statements such as “may contain traces of” by manufacturers. A recent Food Standards Australia New Zealand survey found that consumers with food allergies are frustrated by such labelling.2 There is also confusion among the medical profession about whether to advise patients with food allergies to avoid all foods with allergen avoidance advisory statements. The perception by some in the general population and in the medical community is that these statements are so widely used that avoidance would be overly prohibitive. However, there are currently no published data on the extent of advisory labelling use in Australia. We aimed to assess the prevalence of advisory labelling for three common food allergens — peanuts, tree nuts and eggs — on the packages of products for which these allergens were not listed as ingredients. Products containing one type of tree nut (eg, macadamia nut) could still have advisory labelling for other tree nuts (eg, almond). All products were therefore examined for advisory labelling for any tree nut which was not listed as an ingredient. Packages of non-refrigerated processed foods were examined between August and September 2008 at a large supermarket in Melbourne. All product types were examined within each category (eg, for the savoury biscuits category, we examined rice crackers, flavoured wheat crackers and water crackers) and, for each product type, one flavour per brand was selected for examination. Single-ingredient foods, such as flour, sugar, fruit and vegetables, were excluded. Advisory statements included, but were not limited to, “may contain traces of”, “processed on the same line as” and “made on equipment that also processes”. Overall, 761 products were examined. Of these, 384 (50%) carried an advisory statement for one or more tree nuts. Of 737 products that did not list peanut as an ingredient, 348 (47%) carried an advisory statement regarding peanut. Of 641 products that did not list egg as an ingredient, 146 (23%) carried an advisory label for egg. The presence of advisory statements varied between categories of food, with sweet biscuits most likely to carry labelling for peanut and tree nuts and bakery items most likely to carry labelling for egg (Box). Advisory statements have been widely adopted by manufacturers across a range of products, and are likely to limit food choices for consumers with food allergies who avoid all foods labelled with advisory statements. Unfortunately, there is no evidence on the frequency of trace allergen contamination in Australian products, although studies in the United States found that only 10% of 179 products with advisory labelling for peanut contained detectable levels3 and that, as for Australia, this labelling was widely used for some product categories.4 There is also no evidence regarding the proportion of consumers with food allergies who will develop an allergic reaction (including anaphylaxis) to trace contamination of food. Scientific assessment of the risks posed to consumers with food allergies by trace contamination is urgently required. This evidence would allow the development of informative labelling guidelines, including changes to legislation where required, to allow consumers with food allergies to safely manage their allergies, hopefully without the need to avoid entire categories of common foods. Allergen avoidance advisory statements on packaged processed foods at a large supermarket in Melbourne, August–September 2008 Number (%) of products with an advisory statement* Category of food Peanut Tree nuts Egg Sweet biscuits (n = 130) 117 (93%) 120 (92%) 48 (70%) Chocolates (n = 60) 43 (80%) 49 (82%) 2 (4%) Bakery items (eg, cakes) (n = 35) 24 (71%) 30 (86%) 10 (71%) Muesli bars and snack bars (n = 27) 13 (67%) 20 (74%) 4 (15%) Dinner bases and stocks (n = 32) 19 (59%) 9 (28%) 5 (17%) Savoury biscuits (n = 41) 23 (56%) 23 (56%) 20 (51%) Lollies (n = 55) 29 (56%) 25 (45%) 1 (2%) Breakfast cereals (n = 63) 25 (41%) 37 (59%) 3 (5%) Instant noodles (n = 18) 7 (39%) 6 (33%) 8 (50%) Pasta sauces (n = 15) 5 (33%) 4 (27%) 0 Bread (n = 16) 5 (31%) 5 (31%) 5 (31%) Soups (n = 20) 3 (15%) 3 (15%) 4 (21%) Cake mixes (n = 30) 4 (13%) 20 (67%) 11 (58%) Tinned meals (n = 17) 2 (12%) 2 (12%) 1 (7%) Baby foods (n = 30) 3 (10%) 3 (10%) 1 (4%) Pasta (n = 13) 0 0 4 (39%) Chips (n = 20) 0 0 0 Other (eg, tinned fish, breadcrumbs, sauces, custard powder) (n = 139) 26 (19%) 28 (20%) 19 (14%) * Number of products that had an advisory statement but did not have the allergen of interest listed as an ingredient. The denominators used to calculate percentages were the numbers of products within each category of food that did not have the allergen of interest listed as an ingredient.

Jennifer J Koplin · Nicholas J Osborne · Katrina J Allen

Recent reviews suggest a low risk of allergic reactions to egg-cultured influenza virus vaccines Australian influenza notification and hospitalisation rates are highest in children aged under 5 years,1 the group most commonly affected by egg allergy. While vaccines derived from influenza virus grown in mammalian cell cultures exist, those currently distributed in Australia and New Zealand are grown in hen eggs. The ability to safely vaccinate egg-allergic individuals (particularly in the context of epidemic influenza) will remain an important public health issue, well after concerns surrounding recent non-allergic adverse reactions in young children subside (Australian governments recently suspended seasonal flu vaccination for healthy children aged under 5 years; see http://www.immunise.health.gov.au). Product information and current Australian vaccination guidelines list egg anaphylaxis as an absolute contraindication to influenza vaccination,2 yet recent studies suggest that most egg-allergic individuals can be safely vaccinated. Most reported cases of anaphylaxis in egg-allergic patients after influenza vaccination occurred over 20 years ago, when the amount of egg protein in vaccines was substantially higher. The amount of egg protein (measured as ovalbumin) in vaccines distributed in Australia and New Zealand in recent years has been about 1 μg or less per dose (manufacturer data), which is substantially less than the estimated 130 μg likely to trigger reactions in patients with egg allergy if taken orally.3 Are concerns about vaccinating egg-allergic individuals evidence-based? Recent reviews suggest a very low risk of allergic reactions to influenza vaccination.4 A United States population study reported 11 cases of non-fatal anaphylaxis (none involving egg allergy) after 48 million doses of influenza vaccine had been given.5 Although this suggests there is a low risk of harm from the vaccine, patients with egg allergy were probably excluded from the vaccination program. More useful information is obtained from recent prospective studies. In a US study of 83 egg-allergic patients (27 with anaphylaxis) and 124 controls, positive vaccine skin tests were detected in four allergic patients and one control subject, yet all tolerated split-dose vaccination (a 10% dose followed by the remaining 90% 30 minutes later).6 An Italian study demonstrated a similar safety profile in 44 children with asthma and egg allergy (10 with anaphylaxis).7 In a Canadian study of split-dose H1N1 vaccination of 830 egg-allergic children, nine developed rash (treated with antihistamines) and three developed bronchospasm, but none progressed to anaphylaxis.8 In an expanded vaccination program, the same study reported rash, cough, or throat irritation or constriction in 71 of 3640 patients, but none developed anaphylaxis.8 In Western Australia, after the death from influenza of three otherwise healthy preschoolers in 2007, 165 egg-allergic children aged 6 months to 16 years (48 with anaphylaxis) were vaccinated. One patient developed mild facial urticaria after the first dose, but tolerated the second dose.9 In a recent US study, 164 of 171 patients (aged 6 months to 18 years) with non-anaphylactic egg allergy tolerated split-dose vaccination. Six experienced urticaria or wheeze after the 10% vaccine dose and one experienced flushing and hives after the 90% dose, but none had anaphylaxis.10 British, Canadian, European and US consensus guidelines4,8,11,12 suggest that most patients with egg allergy can safely receive seasonal and H1N1 vaccines if they contain no more than 1 μg/dose of egg ovalbumin. The Australasian Society of Clinical Immunology and Allergy concurs with these views and has released guidelines for vaccination of the potentially egg-allergic patient (http://www.allergy.org.au/content/view/27/8). We acknowledge that these proposals are at variance with Australian immunisation guidelines.2 People presenting for vaccination may be classified into three risk groups: Those considered to be at no additional risk. This includes people with non-egg food allergy, past egg allergy (who can now eat whole egg), and family (not personal) history of egg allergy, as well as those who react to raw egg but can tolerate at least a teaspoon of lightly cooked egg (eg, scrambled or boiled). This group can receive the vaccine as a single dose, followed by the 15-minute observation period recommended in Australian guidelines2 (20 minutes in NZ). Importantly, egg allergy is not a contraindication for the measles–mumps–rubella vaccine, which contains no egg protein. Those with non-anaphylactic allergic reactions to eggs or egg-containing food. Some authorities recommend a 10%–90% split-dose regimen, 30 minutes apart, if no adverse reaction occurs after the first dose; others recommend a single dose. Data from split-dose protocols6-10 have not indicated any significant adverse reactions in this risk group, despite administration of the full dose over 30 minutes. Based on current evidence, we suggest that the vaccine can be safely administered as a single dose with a 30-minute observation period, rather than the standard 15 minutes. Those who have had egg anaphylaxis in the past, and those who have never ingested egg in any form, but have had positive skin or blood test results for egg allergy. As reactivity and severity cannot be assessed in advance, these patients merit consideration as a potentially higher-risk group. The decision to vaccinate should include a risk–benefit evaluation of the vaccination, consultation with an allergy specialist (including initial telephone contact), direct medical supervision of vaccination, and use of a split-dose protocol (10%–90%, 30 minutes apart), with another 30-minute observation period after the final dose. Skin-prick or intradermal allergy testing with the vaccine before administration is not recommended, as results correlate poorly with vaccine tolerance. If the first vaccination is tolerated, the second vaccine dose can be given as a single dose in the same year. Since tolerance one year does not guarantee safety the next (due to yearly fluctuations in egg vaccine content), we recommend that the same process be followed each year. Rare allergic reactions (including reactions to non-egg vaccine ingredients) cannot be totally excluded. Vaccines should always be administered in facilities with health professionals able to recognise and treat anaphylaxis. Adverse events following vaccination should be reported to the Advisory Committee on the Safety of Medicines (Australia) or Medsafe (NZ), documenting the timing of onset, nature and severity of symptoms, likelihood of a relationship with vaccination, and any other relevant health details.

Raymond J Mullins MB BS,PhD, FRACP · Andrew Kemp MB BS, PhD, FRACP · Michael Gold MB ChB, MD, FRACP

To the Editor: We report the case of a 19-year-old female veterinary student who presented with a 2-week history of a rapidly growing mass on the lateral side of the deltoid area of her left arm. On examination, the mass was soft, freely movable, slightly warm and non-tender. There was no regional lymphadenopathy. The patient was afebrile, with no signs of systemic illness. Ultrasound showed a 3.2 × 2.3 × 1 cm, low-echogenic, lobulated lesion in the subcutaneous fat, with surrounding increased echogenicity suggestive of inflammation. Magnetic resonance imaging showed a poorly defined lesion throughout the deep and superficial fascia, with infiltration into the underlying deltoid muscle (Box 1). A provisional diagnosis of sarcoma was made, but an ultrasound-guided core biopsy sample showed non-necrotising epithelioid granulomas (Box 2). Two weeks after presentation, the patient noticed a smaller raised lump, about 1 cm in diameter, on the volar aspect of her left forearm. Four months before presentation, following negative results of both Q fever serological testing and a Q fever skin test administered on the volar aspect of her left forearm (at the site of the smaller lump), the patient had received a Q-VAX (CSL, Melbourne, Vic) vaccination in the left deltoid (at the site corresponding to the larger mass). Three months after this, and about 3 weeks before the deltoid mass first appeared, the patient received a Fluvax (CSL, Melbourne, Vic) influenza vaccination at the same left-deltoid site as the Q fever vaccination. This raises the possibility that the influenza vaccination may have been associated with the subsequent Q fever granuloma reaction. Q fever, a disease caused by the zoonotic rickettsial organism Coxiella burnetii, is an occupational hazard for many Australians in animal-related professions. The disease is characterised by an acute, self-limiting febrile illness, with pneumonia and hepatitis being infrequent complications. In 2001, an Australian national Q fever vaccination program was initiated, which led to a 50% decline in the incidence of Q fever.1 Side effects are normally rare and minor; during 2001–2004, only 86 adverse reactions were reported from about 49 000 vaccinations.2 Development of non-necrotising granulomas following Q fever vaccination is uncommon, with only six cases previously described.3-5 To explore the possibility of a causal association between influenza vaccination, Q fever vaccination, and development of a granuloma, we traced four of these six patients with Q fever granuloma by contacting the authors of the previous reports. One patient had been vaccinated against influenza 2 months before the time of Q fever vaccination, and another had influenza vaccination afterwards (as in our case). Of the five cases (including our case) for which clinical history was available, three had a temporal association between influenza vaccination and Q fever vaccination, followed by the development of the non-necrotising granuloma. The indurated lesion at the separate Q fever skin-test site on the volar forearm, found in two other patients5 as well as ours, supports the notion of a systemic immune reaction rather than simply a local reaction at the vaccination site. The Naranjo score in this case was 7, indicating a “probable” adverse drug reaction. Although the granuloma was self-limited in all known cases, this case shows that there is significant risk of misdiagnosis on clinical grounds. It seems prudent to be aware of the possible association between these two vaccinations. Magnetic resonance images of lesion Axial (top) and coronal T1-weighted fat-saturated post-contrast (bottom) images demonstrate a poorly defined enhancing lesion (red arrows) in the subcutaneous fat, which superficially infiltrates and extends in a plaque-like manner in relation to the underlying deltoid muscle (white arrows). 2 Ultrasound-guided core biopsy sample of lesion The core biopsy of fibroadipose tissue shows numerous well formed non-necrotising epithelioid granulomas (arrows). The granulomas are composed of epithelioid histiocytes and a few multinucleated giant cells, surrounded by numerous lymphocytes (a mixture of B and T cells, with a greater proportion of T cells). (Original magnification × 100; haematoxylin–eosin stain.)

Deborah Burnett · Leslie Burnett

To the Editor: We read the article by Gibson and colleagues on the assessment and management of cough1 with some concern, specifically regarding the authors’ classification of levels of evidence for current therapies for allergic rhinitis. We would agree that a trial of antihistamines, intranasal corticosteroids and allergen immunotherapy is unlikely to help non-specific cough in the absence of allergic rhinitis. This consensus should be distinguished from the beneficial impact of these modalities on symptoms of allergic rhinitis, for which the authors misquote their main source of information2 and suggest that evidence of benefit from these is “weak”. Although evidence of benefit from allergen avoidance to help manage allergic respiratory disease is controversial,3 a large number of double-blind placebo-controlled trials of all other modalities show Level I evidence of benefit and category A strength of recommendation specifically for treatment of allergic rhinitis, as recently reviewed2,4-6 — evidence consistent with “strong” recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria.7 We do our patients and colleagues a disservice to suggest otherwise.

Raymond J Mullins · Constance H Katelaris · Janet Rimmer

To the Editor: We read with interest the Australian Cough Guidelines summary statement by the CICADA multidisciplinary group.1 However, we feel that the role of direct examination of the upper aerodigestive tract in assessing cough was underemphasised. Flexible nasal endoscopy (FNE) is a quick, relatively straightforward examination performed under topical anaesthesia as part of an ear, nose and throat (ENT) consultation. It allows direct visualisation of the nasal cavities, postnasal space, oropharynx and larynx, and can be performed on adults and older children and also some younger children.2 Nasal causes of cough, and hence the potential role of FNE, appear to have received more emphasis in previous chronic cough management strategies, including those proposed by the American College of Chest Physicians in 20063 and the European Respiratory Society task force in 2004.4 The diagnosis of chronic rhinosinusitis or upper airway cough syndrome (postnasal drip syndrome) is enhanced by direct examination. The presence of mucopus in the middle meatus of the nasal cavity is associated with a positive diagnosis of chronic rhinosinusitis.1 FNE can also provide direct evidence of the presence of gastro-oesophageal reflux affecting the larynx (laryngopharyngeal reflux), and plays a significant role in the clinical diagnosis of laryngopharyngeal reflux.5 FNE should be used in patients with alarm symptoms for serious underlying disease (as suggested by the CICADA group1), particularly those potentially related to laryngeal causes (hoarseness, haemoptysis, feeding difficulties, stridor or smoking). As part of a complete examination, FNE can help in targeting therapy for two of the three most common causes of cough in adults (gastro-oesophageal reflux and rhinosinusitis), and in excluding some of the significant causes of cough in both adults and children. It is particularly recommended in patients with a suspected nasal or laryngeal cause, in those with alarm symptoms, and in those for whom initial therapy fails.

Nicholas J Potter · Eduard I Pudel

In reply: The recently published CICADA cough guidelines1 draw attention to the important role of systematic assessment of chronic cough in children and adults, and provide an appraisal of the evidence that treating specific conditions will improve cough. Mullins and colleagues raise a key point that requires emphasis, and is relevant beyond the instance of allergic rhinitis that they cite. Chronic cough is associated with several common conditions, such as allergic rhinitis, asthma, gastro-oesophageal reflux disease and sleep apnoea. For each of these conditions, there are well established treatment guidelines that describe the effectiveness of treating that primary condition. However, in developing the CICADA guidelines we were considering the effect of the treatments on the symptom of cough, not on the primary condition. It was stated at the bottom of Box 1 (page 2661) that “The final GRADE recommendations were based on [the] votes [of committee members] and considered cough in the context of the respective conditions”. We agree that the evidence for treating symptoms of allergic rhinitis per se is strong, as published.2 But in the case of a patient presenting with cough and associated rhinitis, the CICADA group determined that the evidence that treating allergic rhinitis would resolve the cough was weak. It is often not possible to determine from successful trials of immunotherapy for rhinitis the outcome for cough. For example, trials of injectable or sublingual immunotherapy both mention cough only once, and it is not possible to determine the effect of the treatment on this symptom.3,4 We welcome the comments by Potter and Pudel giving more specific details of the role of FNE in assessing the upper airway in people with chronic cough. We agree that this is a quick and useful examination. We believe we have placed greater emphasis on upper airway disorders compared with other cough guidelines. Specifically, we have identified vocal cord dysfunction and sleep apnoea as relevant upper airway disorders that are associated with chronic cough. These conditions are not featured in previous guidelines, yet they respond well to specific therapy. We also devote comparatively more space to upper airway disorders that to lower airway disorders.

Peter G Gibson · Anne B Chang · Andrew S Kemp

To the Editor: The recent article by Davis and colleagues reported that the SMART-COP score underestimates the severity of pneumonia in tropical northern Australia, but can be improved by using locally relevant additions.1 The authors’ revised scoring system, SMARTACOP, increased the score for an albumin level < 35 g/L and added Aboriginal or Torres Strait Islander status as a variable. While these additions are useful, the reason for adding ethnicity was not fully clarified. A factor overlooked was low serum 25-hydroxyvitamin D [25(OH)D] levels among dark-skinned Australians.2 Smoking, identified as a marginally insignificant risk factor,1 is also associated with lower serum 25(OH)D levels.3 Vitamin D enhances the innate immune system through induction by 1,25-dihydroxyvitamin D of cathelicidin and defensins, which combat several types of bacterial and viral infections including upper respiratory tract infections.4 In the 1918–1919 influenza pandemic in the United States, many deaths were due to pneumonia that occurred as a complication of influenza infection. An ecological study found that indices for levels of vitamin D production from solar ultraviolet-B irradiance explained 50% of the variance in pandemic case-fatality rates among 12 communities.5 The mechanisms proposed for the beneficial effect of vitamin D were reduced proinflammatory cytokine production, which would reduce damage to the epithelial lining of the lungs, and induction of cathelicidin and defensins to fight the secondary bacterial pneumonia infection. If sera are available for those included in the Australian SMART-COP study,1 they could be analysed for 25(OH)D levels to test this hypothesis.

William B Grant

In reply: We thank Grant for his interest in our study on pneumonia severity assessment in tropical Australia. Our revised scoring system included increased weighting for hypoalbuminaemia, as well as adding a point for Indigenous status, because these two factors had the strongest association with the need for intensive respiratory or vasopressor support on univariate analysis.1 Unlike vitamin D status, these and the other factors included in the scoring system are readily available measures that can be used in the clinical setting to rapidly predict the need for intensive support. The scoring system was not intended to identify underlying aetiology or risk factors for severe pneumonia. For example, Indigenous status is likely to be a surrogate measure for undiagnosed comorbidities, lack of access to health care, and socioeconomic disadvantage. We agree that vitamin D is important in immune function and that the levels of insufficiency that result in impaired resistance to infection are not well defined.2 Most data on vitamin D deficiency in dark-skinned populations in Australia come from temperate areas,3,4 and the reference offered by Grant to support the concern about vitamin D deficiency does not cite any data from Australian populations north of southern Queensland.5 Further studies are needed on the prevalence of vitamin D deficiency in Indigenous Australians in tropical areas, and the additional contribution of vitamin D deficiency independent of known risk factors of severity and outcome.

Joshua S Davis · Allen C Cheng · Bart J Currie · Nicholas M Anstey

Cough is a common and distressing symptom that results in significant health care costs from medical consultations and medication use. Cough is a reflex activity with elements of voluntary control that forms part of the somatosensory system involving visceral sensation, a reflex motor response and associated behavioural responses. At the initial assessment for chronic cough, the clinician should elicit any alarm symptoms that might indicate a serious underlying disease and identify whether there is a specific disease present that is associated with chronic cough. If the examination, chest x-ray and spirometry are normal, the most common diagnoses in ADULTS are asthma, rhinitis or gastro-oesophageal reflux disease (GORD). The most common diagnoses in CHILDREN are asthma and protracted bronchitis. Management of chronic cough involves addressing the common issues of environmental exposures and patient or parental concerns, then instituting specific therapy. In ADULTS, conditions that are associated with removable causes or respond well to specific treatment include protracted bacterial bronchitis, angiotensin-converting enzyme inhibitor use, asthma, GORD, obstructive sleep apnoea and eosinophilic bronchitis. In CHILDREN, diagnoses that are associated with removable causes or respond well to treatment are exposure to environmental tobacco smoke, protracted bronchitis, asthma, motor tic, habit and psychogenic cough. In ADULTS, refractory cough that persists after therapy is managed by empirical inhaled corticosteroid therapy and speech pathology techniques.

Peter G Gibson MB BS, FRACP · Anne B Chang FRACP, MPHTM, PhD · Nicholas J Glasgow FRACGP, MD, FAChPM · Peter W Holmes MB BS, FCCP, FRACP · Peter Katelaris MB BS, MD, FRACP · Andrew S Kemp MB BS, FRACP, PhD · Louis I Landau AO, MD, FRACP · Stuart Mazzone PhD · Peter Newcombe DipT, BEd, PhD · Peter Van Asperen MB BS, MD, FRACP · Anne E Vertigan BAppSc(SpPath), MBA, PhD