Respiratory disease

To the Editor: I recently received written advice from the Australian Safety and Compensation Council (a division of the Department of Employment and Workplace Relations) that the records of the Australian Mesothelioma Surveillance Program (AMSP) have been lost. As some of your readers would be aware, the AMSP, which ran between 1980 and 1985, was one of the most comprehensive medical surveys of mesothelioma undertaken anywhere in the world.1 The records of the program contain full occupational and environmental histories of about 1000 mesothelioma cases reported in the early 1980s. The program has played a significant role in helping to understand the epidemiology of mesothelioma in Australia. The level of detail of data in the AMSP has not been repeated by the Australian Mesothelioma Register, which succeeded the AMSP in 1985. This less detailed reporting scheme is the current basis for mesothelioma reporting to cancer registries in the country. I am a geologist with an interest in medical geology currently studying to obtain a doctorate on naturally occurring asbestos and mesothelioma risk in Australia. I had hoped to use the detailed environmental and occupational data of the AMSP to help determine the possible influence of naturally occurring asbestos on mesothelioma in Australia, in particular in the eastern states and South Australia, but without the records this is no longer possible. Data from the Australian Mesothelioma Register are not sufficiently detailed for this purpose. My intention in writing this letter is not to embarrass staff from the Australian Safety and Compensation Council, who have done their best to find the records and have been supportive of the project, but to create awareness of the loss, in the hope that the publicity may jog someone’s memory and result in the records being located. The potential permanent loss of these records would be a great loss to mesothelioma research in Australia and raises questions about the federal government’s policies surrounding long-term storage and archiving of nationally significant scientific research datasets that may be of benefit to future researchers.

Marc Hendrickx

Comment: The Australian Mesothelioma Surveillance Program (AMSP) operated between 1980 and 1985 and was maintained by the Commonwealth School of Public Health and Tropical Medicine at the University of Sydney. These files were transferred to the National Occupational Health and Safety Commission (NOHSC) on its establishment in 1985. The NOHSC was relocated from Sydney to Canberra in 2001, and AMSP records went into storage at that time. In February 2005, the NOHSC was succeeded by the Australian Safety and Compensation Council. We attempted to locate the records over several months in 2007. This involved manually searching through all files and boxes held by our contracted storage company marked as relating to either the AMSP or the Australian Mesothelioma Register. In addition, we had a staff member of the storage facility manually search the warehouse for these records in case they were in unmarked boxes or filing cabinets. In November 2007, having been unable to locate the records, we informed Mr Hendrickx that we would be unable to assist him with access to the AMSP records for his doctoral studies. It is certainly not our policy to discard records such as these and we were disappointed when they could not be easily located. We regret the potential loss of these important records to the research community and are still attempting to locate them.

Julie Hill

A 25-year-old woman presented with progressively worsening shortness of breath, which was attributed to cardiac tamponade caused by pericardial effusion. Urgent pericardiocentesis revealed haemorrhagic fluid, which continued to accumulate after the procedure. A repeat echocardiogram after pericardiocentesis showed dilatation of the right ventricle and severe pulmonary hypertension. Subsequent computed tomography revealed a massive pulmonary embolism in the right lung (Figure) and multiple small emboli in the left lung, while cytological examination of pericardial and pleural fluid showed adenocarcinomatous cells from a primary lung cancer. Pericardial effusion and pulmonary embolism usually present in isolation. Their coexistence in this patient — presumably related to the underlying neoplasm — may paradoxically have saved her life, as the raised right ventricular pressure created by the pulmonary emboli delayed the onset of cardiac tamponade.1 Her condition improved initially with chemotherapy and anticoagulation, but she died a year later due to progression of the lung cancer. PE = pulmonary embolism. PCE = pericardial effusion. PLE = pleural effusion.

Namal Wijesinghe · Cherian Sebastian · Hugh McAlister

Objective: To review the literature for any promising strategies for the primary care management of mild-to-moderate asthma and chronic obstructive pulmonary disease (COPD) in adults.Methods: Using “MeSH” terms for COPD, asthma and primary health care, we conducted an extensive literature search for relevant meta-analyses, systematic reviews, narrative reviews, reports and individual studies. Grey literature was also included. We chose a narrative review approach because of substantial heterogeneity of study designs in the literature.Results: 1119 articles of potential relevance were retained, of which 246 were included in our review. There was insufficient evidence to determine whether general practitioners with a special interest (GPwSI) in respiratory care improved the diagnosis and management of mild-to-moderate COPD. An asthma service involving GPwSI increased respiratory drug costs but reduced the costs for less specific drugs. No clear benefit has been shown for practice nurse-run asthma clinics in primary care compared with usual care in altering asthma morbidity, quality of life, lung function or medication use. Evidence to determine the effectiveness of practice nurse-run COPD clinics could not be found. Self-management education, GP review and action plans may produce short-term benefits for asthma patients, particularly those with moderate-to-severe disease, but the evidence for a similar approach to patients with mild-to-moderate COPD is equivocal. There has been poor uptake of respiratory clinical guidelines relevant to primary care — partly because most guidelines are based on moderate-to-severe disease. Spirometry programs in primary care are useful for differential diagnosis of asthma and COPD. Spirometry may alter the management of mild asthma, but there is a lack of evidence that it alters the management of COPD in primary care.Conclusion: The role of primary health care in management of mild-to-moderate asthma and COPD requires further investigation using randomised controlled trials.

Josephine M Cranston BSc(Hons) · Alan J Crockett PSM, MPH, PhD · John R Moss MSocSci, MB BS, FCHSE · Robert W Pegram BSc, MB BS, MHSM · Nigel P Stocks MB BS, MD, FRACGP

Re: “Respiratory syncytial virus infections in children in Alice Springs Hospital”, the letter to the Editor by Apakasimaka Dede, David Isaacs, Paul J Torzillo, John Wakerman, Rob Roseby, Rose Fahy, George Clothier, Andrew White and Paula Kitto, in the 18 February issue of the Journal (Med J Aust 2008; 188: 261). A processing error caused the ninth and final author, Paula Kitto, BSc, BM BS, General Practice Registrar at the Centre for Remote Health, Alice Springs, NT, to be omitted from the authors’ byline. The web version of the article was corrected on 10 March 2008.

Apakasimaka Dede · David Isaacs · Paul J Torzillo · John Wakerman · Rob Roseby · Rose Fahy · George Clothier · Andrew White · Paula Kitto

Should we be devoting energy and resources to reversing obstructive sleep apnoea in patients without symptoms? Over the past four decades, obstructive sleep apnoea (OSA) has emerged as a prevalent, clinically important disorder. Snoring, which is often a hallmark of OSA, is seemingly ubiquitous in middle-aged men. Over 80% of Australian middle-aged men snore for more than 10% of the night.1 Snoring is also common in women. Although it is undoubtedly an important social nuisance, it remains unclear whether snoring alone (in the absence of sleep apnoea) carries with it any serious health risk. Twenty-five per cent of middle-aged men and 10% of women have OSA, defined as > 5 obstructed breathing events per hour of sleep.2 The prevalence in women rises sharply after menopause. Other risk factors are obesity, older age and a family history of OSA. Population-based studies in China and India indicate that its prevalence is at least as high as that reported in Western countries. A complex interplay between regulation of breathing during sleep, facial anatomy and obesity predicts the development of OSA.2 In contrast to the uncertainty of the effects of simple snoring, OSA clearly has significant health consequences. Many patients with OSA experience excessive daytime sleepiness and impaired cognitive function, increasing the potential for traffic crashes, work accidents and reduced productivity at work.3 Over 50% of Australian truck drivers have mild OSA or worse.4 Moreover, Access Economics has estimated that the cost of sleep disorders to the Australian community is over $7 billion, and much of this cost relates to OSA.5 Increasing awareness of OSA has been followed by an appropriate increase in clinical investigations of sleepy patients with suspected OSA. This is further driven by the availability of cost-effective treatments, notably continuous positive airway pressure (CPAP) and mandibular advancement splints. Recent studies have suggested that OSA is associated with an increased risk of cardiovascular disease.6 Publicity about this research has led to an increasing tendency for people who are not sleepy or who have minimal symptoms to be referred for assessment and treatment of OSA. However, in contrast to the sleepy patient, for whom CPAP usage is reinforced by reduction in sleepiness, asymptomatic patients have more variable compliance.7 Should we be devoting substantial clinical energy and resources to reversing OSA in such patients to prevent cardiovascular disease and death? Certainly, data from cross-sectional and prospective population studies and sleep clinic studies indicate that OSA is associated with a higher prevalence of cardiovascular and cerebrovascular disease and insulin resistance.6 Untreated male patients with severe OSA have significantly greater risks of fatal and non-fatal cardiovascular events than healthy controls (odds ratios, 2.87 and 3.17, respectively).8 However, cross-sectional and observational studies have unmeasured confounders, such as visceral obesity.6 In addition, observational studies can be affected by treatment bias. Patients who refuse to use CPAP and seemingly have higher cardiovascular risk than those who comply with CPAP treatment8 may be the same people who refuse to stop smoking or take lipid-lowering or blood pressure-lowering medication. In contrast, there is good evidence from randomised controlled trials that CPAP lowers blood pressure (mean decrease in systolic and diastolic blood pressure of 2.46 and 1.83 mmHg, respectively), but most studies are relatively short (less than 8 weeks), and treatment effects are hard to demonstrate in patients who are not sleepy.9 The remaining short-term CPAP trials that have focused on other intermediate markers of cardiovascular disease (lipids, glucose control, high-sensitivity C-reactive protein) have been inconclusive. For example, a recent short-term randomised trial failed to show any improvement in insulin sensitivity in patients with type 2 diabetes and OSA.10 No data are available from long-term, well powered, randomised controlled trials assessing the effect of CPAP on hard cardiovascular endpoints, such as myocardial infarction and stroke, in patients with OSA. Medical research is well populated by “positive” results from cross-sectional, observational or short-term intervention studies, but their results have not been reproduced in rigorous, long-term, large-scale clinical trials. To remedy this lack of information, several long-term trials of CPAP treatment in OSA are being planned or have commenced, including one initiated by Australian investigators (Sleep Apnea CardioVascular Endpoints Study [http://www.savetrial.org]). These trials will determine whether treatment of OSA decreases the incidence of new cardiovascular events. In the interim, how should we manage patients with a diagnosis of repetitive OSA who present with complaints of snoring but have minimal or no daytime sleepiness? First, it is important to establish whether such patients are genuinely asymptomatic or simply underreport symptoms that are obvious to their families or work colleagues.11 Second, the disorders of these patients typically are characterised by higher rates of central adiposity, glucose intolerance and other vascular risk factors.6 Given that middle-aged men often neglect to monitor such risk factors, referral for snoring may provide an excellent opportunity for a general health assessment and to institute an intervention, such as advice to exercise and lose weight. Moreover, it would be reasonable to prescribe a trial of CPAP for a patient with asymptomatic OSA and hypertension refractory to maximal medical therapy and to monitor the blood pressure response over 24 hours. Finally, it would be reasonable also to inform asymptomatic patients with severe OSA and coexisting cardiovascular disease of the possible association between OSA and a risk of future vascular events. However, it would be inappropriate to coerce these patients into accepting a treatment that might falsely make them feel secure about future risk and might result in neglect of proven risk factors. Future research, ideally, will enable clinicians to get to the “heart of the matter” when discussing cardiovascular risk management and sleep apnoea with these patients.

Ronald R Grunstein MD, PhD, FRACP · Craig L Phillips BSc

An article published in April last year has prompted debate about the interpretation of time series analyses. (MJA 2007; 186: 408-411) To the Editor: Our comments and question relate to the interesting article by Wilson et al on asthma and chronic obstructive pulmonary disease (COPD) in Australia.1 The statistics on mortality trends for these diseases were complex, but the gist of the matter seems to relate to averaged trends for COPD and asthma over a 10-year period. However, the rigorous statistics missed (or the article did not comment on) what seemed from the figures to be a single step in opposite directions for COPD and asthma mortality in about 1997 — most marked in a downward direction for asthma from 1997 to 1998 and an upward direction for COPD in females from 1996 to 1997. (Box 3 and Box 4 from the original article by Wilson et al are reproduced here for ease of referral.) To us, the data seem, for the most part, to suggest sets of two horizontal lines linked by a sudden, presumably artefactual, discrete change for both conditions at around the same time. Do the complex statistical trend analyses miss an essential feature? Was there, for example, a change to International classification of diseases coding for airway disease specifically around 1997? 3 Deaths from chronic obstructive pulmonary disease (COPD) in Australia, 1993 to 2003, by sex (reproduced from original article by Wilson et al1) 4 Deaths from asthma in Australia, 1993 to 2003, by sex (reproduced from original article by Wilson et al1) In reply: In response to Walters and Wood-Baker, we point out that changes to the International classification of diseases, 10th revision (ICD-10) coding for mortality occurred in January 1997 and changes to morbidity coding occurred later.2 The General Record of Incidence of Mortality books identify “comparability factors” (CFs) for comparing the closeness of agreement between ICD-9 and ICD-10 codes. The CFs for asthma and chronic obstructive pulmonary disease (COPD) are 0.75 and 0.93, respectively. CFs close to 1.0 indicate little difference between the manual ICD-9 and automated ICD-10 coding. In the article by us that Walters and Wood-Baker refer to,3 there would seem to be a dislocation for asthma between 1997 and 1998 — not between 1996 and 1997, when the ICD coding changed. For COPD there was little or no change in trends for men and women over time, and coding made little difference to comparability before and after 1997. It is, therefore, difficult for us to accept an “artefactual” discrete change for both conditions at essentially the same time. Our conclusion from the data is that, over the observed period, there was a downward trend in deaths from asthma in both men and women. Deaths from COPD in men showed a similar downward trend, but the trend for COPD deaths in women showed no change. Given that COPD imposes a much greater burden on women than asthma, we think the most important question to ask is why this is so and what needs to be done about it — which was the main thrust of our article. Comment: Attributing cause in the context of sparse data is fraught with difficulty. I invite readers to consider what the four graphs depicted here (Box) have in common with Wilson and colleagues’ description of deaths from asthma in Australia.1 Surprising as it may seem, the graphs all describe similar phenomena — temporal changes in outcome (eg, incidence, mortality), which may or may not be related to an identified change in circumstance at a particular point in time — albeit in different contexts: breast cancer incidence (A),2 paracetamol poisonings (B),3 police shootings (C),4 and health care expenditure (D).5 The data in all of these graphs arise from uncontrolled time series. The vertical lines in the graphs mark an “interruption” in the time series — a point at which a nominated change occurred. The common question in such studies is simple (and expressed eloquently by Walters and Wood-Baker6): did the interruption result in a change? The answer, I’m afraid, will be unpalatable to some: we don’t know for sure. No amount of statistical analysis will make up for lack of data or the presence of extraneous effects threatening internal validity (eg, events that co-occur with the intervention and that account for the observed changes). In such cases, statements attributing causality are, at best, speculative. While speculations may lead to testable hypotheses, those that can not be tested remain conjectural and must be viewed in this manner. “Interrupted” time series* * Vertical lines mark an interruption in the time series. A: Incidence rate of breast cancer in Australian women aged 50–69 years with nominal start of population-based screening mammography. B: Age-standardised mortality rate for poisoning involving paracetamol in England and Wales with nominal start of legislation restricting availability of drug. C: Rate of police shootings in Philadelphia, Pa, USA, with nominal change in statutory law. D: Per capita expenditure for inpatient care in Taiwan with nominal peak of severe acute respiratory syndrome period.

E Haydn Walters · Richard Wood-Baker · David H Wilson · Graeme Tucker · Robert J Adams · Elmer V Villanueva

To the Editor: Little is known about the epidemiology of respiratory syncytial virus (RSV) in arid, desert regions generally, and in central Australia in particular. We performed a 5-year retrospective study from 2000 to 2004, inclusive, of children aged less than 2 years who were admitted to Alice Springs Hospital and identified as having RSV infection. RSV was detected using direct immunofluorescence (Light Diagnostics SimulFluor; Millipore, Billerica, Mass, USA) on nasopharyngeal secretions. The test has a reported sensitivity of 92%.1 We extracted demographic data from case notes and obtained population data from the Northern Territory Department of Health2 and the Australian Bureau of Statistics.3 From case notes over the 5 years, we identified 173 eligible children with RSV infection. The annual incidence rate was 21.4 per 1000 children under 2 years old. The rate in Aboriginal children was 30.9 per 1000, and the rate in non-Aboriginal children 11.6 per 1000 (P < 0.0001). The monthly distribution of cases is shown in the Box. Cases occurred throughout the year, and in every month, but there was a peak in admissions from March to August, which covers the Australian winter. Because Alice Springs Hospital is the only large hospital in the region, and almost all children needing hospital admission for RSV infection will be admitted there, our incidence rates of hospitalisation for RSV infection closely approximate population rates. However, we may have under-estimated the incidence because we only included children in hospital with proven infection, so we may have missed children who were not tested, or whose immunofluorescence test results were falsely negative. There may have been selection bias regarding admissions. Nevertheless, we found that Aboriginal children were more likely than non-Aboriginal children to be hospitalised with RSV infection, a finding in keeping with the known high incidence of pneumonia and bronchiectasis in Aboriginal children.4,5 While the incidence of RSV infection peaked in winter in central Australia, infections occurred throughout the year, and the winter predominance was less marked than is the case in temperate Australia.6 These data provide valuable information about RSV infection in an arid, desert region and can inform decisions about active or passive immunisation against RSV infection in central Australia. Monthly distribution of admissions to Alice Springs Hospital of children aged less than 2 years with respiratory syncytial virus, 2000–2004* * Inclusive.

Apakasimaka Dede · David Isaacs · Paul J Torzillo · John Wakerman · Rob Roseby · Rose Fahy · George Clothier · Andrew White · Paula Kitto

A 61-year-old woman diagnosed with multifocal, poorly differentiated epithelial mesothelioma in September 2002 went into sustained spontaneous remission within months. She was completely disease-free within 6 months, and remained so 5 years later. This case demonstrates that this tumour may, very rarely, regress spontaneously, with no recurrence for many years. A greater knowledge of the underlying immune mechanisms would aid future management of this and other tumours. Clinical recordIn early September 2002, a 61-year-old woman was referred to our centre from the emergency room of a local private hospital. She had presented with a 2-day history of intermittent, sudden onset, severe right-sided lateral pleuritic chest pain lasting a few minutes. In the private hospital emergency room, chest radiography and computed tomography (CT) had shown pleural masses, which were subsequently found to be poorly differentiated epithelial mesothelioma. The patient reported that, over the previous week, she had felt weak and lethargic, but was otherwise well. She had no previous serious illnesses, but had recently started taking iron supplements for anaemia and occasionally took non-steroidal anti-inflammatory agents for osteoarthritis. She was a non-drinker, and had ceased smoking 5 months previously. (She started smoking at the age of 16 years and had been smoking 40 cigarettes a day.) She was a widow with three adult children, and had emigrated from the United Kingdom in 1969. Her husband died at the age of 39 years of a myocardial infarction. Her father died of carcinoma of the oesophagus, and her mother of “old age”. Her four siblings and three adult children were all well. Although she had no history of asbestos exposure from any of her husband’s occupations, she could have been exposed to asbestos during two periods of her life. From the age of 15–22 years in the UK, she worked as a machinist in a factory where asbestos lagging was used for the steam pipes of steam presses and central heating. Then, in 1984, her son worked for a year for a company making asbestos gaskets, and throughout this period she washed his work overalls. On examination, she looked well and was not in pain. She weighed 74 kg and was of normal build, but had slight conjunctival pallor. An electrocardiogram showed sinus rhythm; her blood pressure was 140/60 mmHg, and her jugular venous pressure was not elevated. There was no cyanosis or clubbing. Examination of the chest, cardiovascular system, breast, abdomen and peripheries showed no abnormalities. InvestigationsA chest radiograph taken before referral showed a pleural density measuring 10 cm × 2 cm overlying the posterior aspect of the right lower lobe, with no pleural plaques or other stigmata of asbestos exposure. A CT pulmonary angiogram performed the same day to exclude pulmonary embolism showed three pleural masses in the right side of the chest — the first corresponding to the opacity visible on the chest radiograph in the right costovertebral gutter at the level of the tracheal bifurcation, the second having a diameter of 6 cm and located in the right cardiophrenic angle (not of fatty attenuation), and the third in the right posteromedial costophrenic recess, just above the diaphragm (Box 1A and Box 1B). The lungs, mediastinum and upper abdomen (including the pancreas and para-aortic nodes) were normal. Laboratory tests showed her haemoglobin level was 104 g/L (reference range [RR], 115–160 g/L), with a normochromic normocytic anaemia; she had thrombocytosis (555 × 109/L [RR, 150–450 × 109/L]) and leukocytosis (11.2 × 109/L [RR, 4.0–11.0 × 109/L]), with mild neutrophilia (8.2 × 109/L [RR, 2.0–7.5 × 109/L]). Her erythrocyte sedimentation rate was markedly elevated at 110 mm/h (RR, 1–30 mm/h), as was her serum C-reactive protein level (294 mg/L [RR, 0–6 mg/L]). She had mildly elevated concentrations of liver enzymes (alanine aminotransferase, 98 U/L [RR, 0–45 U/L]; aspartate aminotransferase, 70 U/L [RR, 0–41 U/L]; and lactate dehydrogenase, 268 U/L [RR, 80–250 U/L]), with normal serum bilirubin and alkaline phosphatase levels. Her serum iron level was low (2 μmol/L [RR, 10–33 μmol/L]). A core biopsy (20 mm × 1 mm) of one of the right pleural masses showed morphological and immunohistochemical features of a poorly differentiated epithelial mesothelioma. A pathology report by an experienced pathologist with a special interest in pulmonary and pleural pathology read: There is a proliferation of poorly cohesive large cells many of which had vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm. Occasional binucleate and multinucleate forms are present and there is a small amount of associated collagenous stroma with a mild chronic inflammatory cell infiltrate [Box 2A]. There is no evidence of mucin production, and immunoperoxidase stains for a variety of keratins are strongly positive, along with positive staining for calretinin [Box 2B] and cytokeratin 5/6, both markers of mesothelial differentiation [Box 2C]. Stains for LCA and S100 protein are negative. The pathology results were later reviewed by another pathologist with considerable experience of mesothelioma, who drew the same conclusion. ManagementThe patient was told the diagnosis and referred to an oncologist with a special interest in mesothelioma in another tertiary hospital where clinical trials of drugs for the treatment of mesothelioma were in progress. She was offered chemotherapy and entry in a thalidomide trial, but, by the time she was entered, the tumour was already showing signs of spontaneous regression. The patient opted for no treatment, as she felt well. By 30 December 2002, a repeat CT scan of the chest showed a decrease in the size of the large, right-sided pleural mass in the costovertebral gutter from 17 mm × 9 mm (CT chest scan, 29 November 2002) to 12 mm × 6 mm. The second pleural mass was now so small it was difficult to see. The third mass was not visible, and there were two small intrapulmonary nodules — one in the right middle lobe and the other in the left lower lobe. By March 2003, the first and second pleural masses were even smaller (Box 1C) and, by June 2003, they had disappeared (Box 1D). A CT chest scan in June 2004 was normal except for the two tiny intrapulmonary nodules that had not changed in size and were probably granulomas. The patient was last reviewed in June 2007 and was in good health, with no evidence of tumour, and was scheduled for next review in 6 months. DiscussionThere have been a few reports of spontaneous regression of malignant mesothelioma, but prolonged, disease-free periods are rare. Our report appears to be the first to describe a patient in Australia with a poorly differentiated, multifocal epithelial mesothelioma that regressed spontaneously, with the disease remaining in remission for 5 years. There has been one case report of a patient with malignant mesothelioma of the pleura that regressed spontaneously, but after 6 years there was a single recurrence, which was resected surgically, and the patient was followed up for a total of 12 years.1 This raises the question in such cases of the duration of follow-up. In the latter case, a prominent host response to tumour was seen in both the primary tumour and the recurrence. In another case, a patient had a spontaneous remission of a malignant peritoneal mesothelioma, and had high spiking fevers when the tumour recurred.2 A report from Western Australia described a woman whose tumour regressed spontaneously but who eventually died 20 months later.3 It was noted that the tumour tissue was infiltrated with mononuclear cells, and as the tumour recurred some malignant mesothelioma antigens disappeared. Several aspects of our case should be noted. Histopathology The histopathological findings for our patient’s tumour were re-examined by another pathologist. Not all three lesions were biopsied, as it was felt highly probable that the pathological findings for all three would be identical. Author’s experience I have considerable experience in the management of mesothelioma and benign asbestos-related conditions and currently see about 600 patients with this condition a year. I also act as an expert witness for the courts. Mesothelioma is a relatively common condition in Australia at present and, as a result, our thoracic physicians, oncologists and pathologists have considerable experience in this area. Course of the disease The patient had markedly elevated inflammatory markers and is likely to have had the tumour for several months before diagnosis. It is suspected that her natural killer cells and cell-mediated immunity accounted for the regression of the tumour. Evidence of the beginning of spontaneous regression was unusually rapid, occurring within months of diagnosis. Exposure Our patient’s exposure to asbestos seems to have been relatively mild and incidental, as often occurs with women who develop mesothelioma. Self-treatment The patient did not use any unusual therapies, such as alternative medicines, diets and faith healing, after the diagnosis. This case highlights the possibility that spontaneous regression of mesothelioma may occur occasionally. Spontaneous tumour regression therefore should be seen as part of the spectrum of the natural history of mesothelioma and other tumours. A detailed study of the immunity of such individuals “after the event” is unlikely to reveal any particular abnormality but, in hindsight, it would have been interesting to have performed detailed immunological studies during the initial regression period. The role of mesothelin-related serum proteins needs further evaluation. The understanding of this process is likely to be pivotal in the improved treatment of this usually lethal condition. 1 Computed tomography (CT) scans of the chest at referral (September 2002) and 6 and 9 months later A, B: CT pulmonary angiogram at referral (September 2002) showing (A) the pleural-based mass in the right costovertebral gutter at the level of the tracheal bifurcation (arrow) and (B) the two lower pleural-based masses — one in the right cardiophrenic angle and the other in the right posteromedial costophrenic recess (arrows). C: CT scan (March 2003) showing that the pleural-based mass in the right costovertebral gutter had all but disappeared (arrow). D: CT scan (June 2003) which appeared normal apart from a small stable nodule in the left lower lobe which was probably a granuloma (arrow). 2 Histological examination of a core biopsy specimen from one of the pleural masses (Box 1) A: Histological section of the core biopsy of the pleural mass in Box 1A showing sheet-like proliferation of pleomorphic epithelioid cells with abundant eosinophilic cytoplasm, representing a poorly differentiated epithelioid malignant mesothelioma. B: Core biopsy showing a positive result on immunoperoxidase staining for calretinin. C: Core biopsy showing a positive result on immunoperoxidase staining for cytokeratin 5/6.

Roger K A Allen FRACP, FCCP, PhD

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

A 52-year-old woman presented with bilateral soft, reducible anterior neck swellings on coughing, following a recent respiratory tract infection. Plain x-rays of the neck and upper chest showed a normal appearance. Computed tomography of the neck and chest while the patient performed the Valsalva manoeuvre showed bilateral large apical lung hernias, which extended through the thoracic inlet into the root of the neck (Figure). This lung herniation was probably caused by a congenital deficiency in the suprapleural membrane (Sibson’s fascia), combined with increased thoracic pressure created by the respiratory tract infection. Surgical repair was not necessary as the hernias were asymptomatic and not associated with chronic cough.

Jyotsna M Joshi MD

Significant similarities between the challenges of lung transplantation in patients of all ages should lead to better access to this life-saving surgery for children and adolescents Lung transplantation (LTx) is firmly established as a therapy for end-stage lung and pulmonary vascular diseases in patients aged over 18 years and into the seventh decade of life.1,2 However, for those under the age of 18, be they child or adolescent, the role of LTx is less clear.3,4 In Australia, this has contributed to a perception that the risk of undertaking LTx in children and adolescents does not warrant the reward. Indeed, presently in this country, there is no major paediatric hospital offering a lung transplant program, likely recognising the complexity of treating such patients coupled with the potential risk of achieving poor results with a low case load — the reality is that the projected case numbers will only be of the order of four to eight per year across Australia and New Zealand. Thus, by focusing on successful LTx outcomes for an adolescent population, the article by Morton and colleagues in this issue of the Journal5 highlights a number of the key issues regarding the efficacy and utility of LTx for younger Australians (→ Successful lung transplantation for adolescents at a hospital for adults). Although adolescence refers to a transitional state from childhood to adulthood, patients 15 years and younger are generally excluded from adult hospitals and those 18 years and above excluded from paediatric hospitals. Two-thirds of the patients in the study by Morton et al could have been “routinely” treated in adult hospitals. Notwithstanding this limitation, the report gives important insight into the issues, experience and successful outcomes that can be achieved in younger lung transplant recipients. From this article, it is apparent that in Australia, a well developed, large adult LTx unit is able to use its highly specialised services to overcome some of the problems and deficiencies that can limit a stand-alone service for such a small population as children and adolescents requiring LTx. However, the age of any potential Australian lung transplant recipient is critically important — at this time, this technology is not being routinely offered to younger children. Indeed, at present, Australia’s youngest ever lung transplant recipient was aged 9 years at the time of LTx.6 The improved outcomes for LTx now described in adolescents5 should provide an impetus to provide access for younger potential LTx recipients. In looking to achieve this advance, we need to keep in mind that the transplant recipient’s age can matter in several different ways. Fortunately, severe lung disease warranting consideration of LTx in children and adolescents is relatively rare, although interestingly, it does have a bimodal distribution. The International Society for Heart and Lung Transplant (ISHLT) Registry 2005 paediatric report notes about 65 procedures performed worldwide each year.7 In older paediatric patients, typically over 12 years of age, about 70% will have cystic fibrosis as the primary indication for LTx, whereas in infants aged less than 3 years, the indication in about 60% is congenital heart disease or pulmonary hypertension. Despite the perception that transplant recipients fare worse if they are younger, the recent ISHLT Registry reports a half-life of around 5 years after LTx, and no significant survival difference between adults, adolescents and the very young.7 Rates of early graft dysfunction and late graft dysfunction (ie, bronchiolitis obliterans syndrome [BOS]) are also similar. However, causes of death are quite different, with adults and adolescents dying from respiratory failure related to BOS, and younger children dying from infection. The functional status of survivors is excellent, with over 80% reporting no activity limitations at 5 years,7 although morbidity related to the obligatory immunosuppressant drugs is very common across all age groups. Further, there are some specific issues (medical, psychosocial and legal) associated with LTx in adolescents and children compared with adults. Post-transplant lymphoproliferative disorders, growth retardation, respiratory tract infections and medical non-adherence appear much more commonly in children.8 As discussed by Morton and colleagues, facilitating compliance with therapies and medication are particularly challenging areas when working with adolescents.5 As an example, immunosuppressive protocols need to reflect potential concerns about physical appearance. Also, a particular “at risk” period arises when paediatric LTx recipients transition from paediatric to adult care.9 Performing major surgery with substantial short-term and long-term mortality risks in a patient unable to give consent presents ethical and legal dilemmas. For paediatric patients with severe lung disease, recent technological advances provide the potential to build on the excellent results of LTx in adolescents presented by Morton et al.5 Minimal waiting list mortality is a critical component of any assessment of the efficacy and utility of organ transplantation. Thus, the management of severe lung disease by experienced teams, with appropriate use of newer therapies such as bi-level positive airway pressure (BiPAP), dornase alfa and azithromycin in patients with cystic fibrosis, may lead to a successful “bridge to transplant”. Similarly, intravenous epoprostenol, oral bosentan and sildenafil may provide a bridge to transplant for patients of all ages with severe pulmonary hypertension. The study by Morton et al included several terminally ill individuals transplanted after support with mechanical ventilation or extra-corporeal membrane oxygenation.5 Morton and colleagues are to be commended for their successful endeavour, but we contend that further detailed discussion about excessive early mortality10 and resource use is needed before bridging in this fashion is routine in any age group. Such bridging has become increasingly used in the United States (11% of all LTx in 200611) and we believe that many, including ourselves, would argue that Australia does not have the intensive care facilities and staff to routinely bridge in this manner. There are also other developments that should increase transplant opportunities and access to LTx for children and adolescents, hopefully shortening waiting times, thereby further decreasing waiting list mortality, and potentially allowing at least the possibility of retransplantation in the event of late graft dysfunction. One possibility is that large-volume LTx transplant centres (typically not small-volume paediatric-only centres, as yet) might increase organ availability by using extended donor lungs (eg, where there are secretions or an abnormal chest x-ray, etc),12 or cadaveric or living-related lobar transplants (eg, so-called “cut-down lungs”).13 The use of cut-down lungs typically involves transplanting one lobe from each of two adults to make a bilobar transplant for a child or smaller adolescent. Although this resource-intensive and challenging operation is possible, some question the philosophy of undertaking the only known procedure to have a “potential 300% mortality”.13 Donation-after-cardiac-death (DCD) retrieval of lungs for transplantation (as distinct from the usual donation-after-brain-death retrieval) is also now a viable prospect being used to acquire adult lungs for LTx,14 and will soon be extended to paediatric DCD lung donation.15 Thus, evidently, expanding the complexity and extent of LTx offered to children and adolescents might consume significant resources, so LTx results must be carefully considered and evaluated to ensure continued successful outcomes. In this regard, we note with great interest the recent institution of a complex mathematical lung allocation score model by the American United Network for Organ Sharing (UNOS).16 This model uses disease-relevant clinical and physiological variables to predict who will get the most significant improvement in survival with LTx and, therefore, who should be preferentially transplanted. Although historically based, the model will evolve with ongoing clinical experience and should be able to provide new evidence to guide future practice. Interestingly, because of differences in diagnostic categories and post-LTx outcomes in younger lung transplant recipients, the UNOS lung allocation score is only to be applied to those aged over 12 years.16 So, although there are important differences to consider when evaluating the efficacy and utility of LTx across the wide age-spectrum of disease and physiology in the very young, adolescents and adults with terminal lung disease, there is also significant overlap. Medical and allied health experts in paediatric and adolescent medicine have much to offer adult LTx programs venturing into adolescent transplantation; their involvement should be routine. Similarly, units experienced in adult LTx bring knowledge and technology to paediatric and adolescent LTx that can only benefit the small number of critically ill young Australians previously without local access to LTx expertise.

Gregory I Snell MB BS, FRACP, MD · Glen P Westall MB BS, FRACP · Trevor J Williams MB BS, FRACP, MD

Objective: To describe the results of lung transplantation (LTx) in adolescents at a hospital for adults.Design and setting: Prospective cohort study set in an LTx unit at an adult tertiary referral hospital from 1991 to 2006.Patients: 37 consecutive adolescent lung transplant recipients including 13 males and 24 females (mean age, 16.7 ± 2.0 [SD] years; range 12–19 years) who received heart–lung (six patients) or bilateral LTx (31 patients) for cystic fibrosis (29), congenital heart disease (four), acute respiratory failure (two), or another disorder (two). Two patients were transplanted after invasive ventilation, five after non-invasive ventilation and two after extracorporeal membrane oxygenation.Main outcome measures: Overall survival compared with an adult cohort; survival free of bronchiolitis obliterans syndrome (BOS); overall and BOS-free survival in those transplanted before and after January 2000.Results: Mean waiting time was 273 days (range, 5–964 days; median, 163 days), mean donor age was 28 years (range, 9–53 years). Median inpatient stay was 11 days (range, 7–94 days). Mean follow-up was 1540 ± 1357 days (range, 35–5163 days). The 5-year survival rate for the 16 patients transplanted before January 2000 was 38%, versus 74% for the 21 transplanted since January 2000 (P = 0.05; Mantel–Cox). Overall, 18 of 35 evaluable patients developed BOS. Only BOS was associated with an increased mortality risk (P < 0.01).Conclusion: LTx may be performed successfully in adolescents at a hospital for adults.

Judith M Morton MB BS, FRACP · Monique A Malouf MB BS, FRACP · Marshall L Plit MB, FRACP, PhD · Phillip M Spratt MB BS, FRACS · Allan R Glanville MB BS, FRACP, MD

Objectives: To determine (i) the relationship between asthma management and socioeconomic status; (ii) whether recent estimates from the International Study of Asthma and Allergies in Childhood (ISAAC) conducted in Melbourne apply to a broader cross-section of Victorian children; and (iii) age-related trends in asthma prevalence.Design: A questionnaire survey, based on the ISAAC protocol.Participants and setting: Subjects were children aged 4–13 years from a random sample of primary schools in the Barwon region of Victoria. The survey was conducted between March and September 2005.Main outcome measures: Parent-reported wheeze and wheeze-related use of health resources during the preceding 12 months.Results: Questionnaires were returned by 7813/9258 students (84%). Lower socioeconomic status was associated with increased frequency of regular asthma reviews (P < 0.01 for trend), but not of emergency department visits (P = 0.19). The prevalence of wheeze among 6- and 7-year-old children in the Barwon region was similar to that in Melbourne children (20.2% v 20.0%, respectively).There was an age-related increase in the proportion of children with ≥ 12 episodes of wheeze (P = 0.01); but an age-related decrease in emergency department visits (P = 0.02).Conclusions: Disadvantaged children have good access to regular asthma reviews and are no more likely to attend an emergency department with an episode of acute wheeze. Asthma prevalence in 6- and 7-year-old children in the Barwon region is similar to that in Melbourne. The prevalence of children with very frequent wheeze increases with age, but their use of health resources decreases.

Peter J Vuillermin FRACP · Mike South MD · John B Carlin PhD · Maree I Biscan Mstrs · Sharon L Brennan Mstrs · Colin F Robertson MD

Re: “Use of thoracic computed tomography by general practitioners”, by Graham Simpson and Garry S Hartrick, in the 2 July issue of the Journal (Med J Aust 2007; 187: 43-46). A university affiliation of one of the authors was omitted. Graham Simpson’s affiliations are Director, Thoracic Medicine and Regional TB Control Unit, Cairns Base Hospital, Cairns, QLD, and Clinical Associate Professor, Department of Medicine, James Cook University, Cairns, QLD. The html and pdf versions of this article have been corrected.

Graham Simpson · Garry S Hartrick

To the Editor: While Joosten et al highlight the uncommon but serious problem of potential carbon dioxide (CO2) narcosis after emergency management of respiratory illness,1 it is important that their findings are kept in perspective and do not lead to inadequate administration of oxygen to patients with acute dyspnoea. Their findings are based on a retrospective chart review. The main claim that the administration of oxygen causes increased length of hospital stay and possibly death for those presenting to emergency departments with exacerbation of chronic obstructive pulmonary disease (COPD) can be challenged by selection bias, sample size, assessment of severity of illness, and the definition of clinically significant hypercapnia. Ninety per cent of their study patients arrived by ambulance, presumably indicating the relatively sudden onset of acute distressing symptoms — a call for urgent help, not the “killing me slowly” drowsiness and confusion of CO2 retention. Of those who received more than 4 litres of oxygen (O2) per minute, 57% (16 of 28) were in triage category 1 and 2, but only 31% (4 of 13) of those who received O2 at a lower flow rate were in triage category 1 and 2. Sixty per cent (12 of 20) of those with a high partial pressure of arterial oxygen (Pao2), when measured after arrival and treatment were in triage category 1 or 2, but only 14% (3 of 21) of those with a lower Pao2 were in triage category 1 or 2 (P = 0.002; Fisher’s exact test). Clearly the first group was a sicker group on arrival, and the increased length of stay of these patients was more likely to be the result of this, rather than of O2 therapy supervised by emergency specialists in an emergency room of a teaching hospital. The contention that oxygen therapy in emergency departments is “often uncontrolled” is not supported by any data supplied. Critical care staff, including ambulance and emergency personnel, are acutely aware of the challenges posed by patients with chronic respiratory disease. However, they are also aware of the need to achieve adequate oxygenation in patients with acute dyspnoea. Patients are observed closely for signs of clinically significant hypercapnia and respiratory support is adjusted accordingly. Some patients may require a higher fraction of inspired oxygen (Fio2), particularly in the initial phases of care, to achieve this. As the patient’s condition improves, the Fio2 is often reduced. The methods in the study by Joosten et al fail to account for this. Respiratory rate, for example, was not reported. Treating the patient, not the chart, is of most importance. It would be a pity if the article by Joosten et al resulted in the withholding of oxygen from acutely dyspnoeic patients with a rapid respiratory rate and adequate respiratory drive because of some fear that they could be retaining CO2. We agree that a better and seamless patient-centred information system with cooperation between sectors of the health system, the patient, the patient’s general practitioner, and ambulance, emergency and in-hospital services, would assist in identifying those at risk of CO2 narcosis and improve patient care.

Andrew W Dent · George A Jelinek · Sandra L Neate · Tracey J Weiland · Ann-Maree Kelly

In reply: We performed a retrospective audit as part of a quality improvement program following a number of serious adverse events in various areas of our hospital. Our article showed that carbon dioxide retention in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is common (41 of 65 patients admitted with chronic obstructive pulmonary disease [COPD] over 4 months), and that guidelines on blood gas measurement and oxygen use were not being followed. Dent and colleagues state that more patients in our study who received more than 4 litres of oxygen per minute were in a triage category that indicated a more serious condition. However, the multivariate analysis showed that triage category did not predict length of stay. In contrast, partial pressure of arterial oxygen (Pao2) did, and patients with a Pao2 of less than 74.5 mmHg (range, 36.7–74.0 mmHg) had a shorter length of stay than those with a Pao2 of 74.5 mmHg or higher (range, 74.5–452.0 mmHg). Many patients had a Pao2 much higher than neccessary to achieve a haemoglobin saturation of about 90%. Dent and colleagues state that our data did not support the claim that oxygen therapy is often uncontrolled in the emergency setting. In fact, only 68% of the patients receiving more than 4 litres of oxygen per minute had arterial blood gas measurements performed. We agree with Dent et al that the management of AECOPD may not be as simple as following guidelines. However, we hope to raise awareness of the fact that hypercapnia in COPD is common, requires careful assessment, and that oxygen therapy should be titrated to physiological endpoints.

Simon A Joosten · David Smallwood · Mariko S Koh · Louis B Irving · Xiaoning Bu

There’s a lot of it about: acute respiratory infections in primary care Graham Worrall. Oxford: Radcliffe Publishing, 2006 (136 pp). ISBN 1 84619 084 3. Although there appears to have been a decline in attendance to general practitioners in Australia for acute respiratory infections (ARIs), they still account for close to 10% of the GP’s workload. The evidence base for their management has never been better defined and yet, given recent research and prescribing patterns, many GPs either find it difficult to, or do not, apply this evidence in practice. Worrall does not waste any time on trying to distinguish between upper and lower respiratory tract infections but discusses each condition in a separate chapter, starting with “The common cold” and ending with “Bronchiolitis”. Each chapter is a concise summary of the available literature and, despite now being an academic in Canada after many years as a GP in the United Kingdom, he limits the number of references he uses. However, as succinct as he may be in conveying the evidence in the text, it will be the summary boxes “Epidemiology and aetiology”, “Clinical course and diagnosis” and “Treatment” that many readers will be drawn to. This is a pity because a real understanding of the topic can only be drawn from the studies themselves and a discussion of their strengths and weaknesses; something the author does very well. The chapter on croup demonstrates this; summary boxes provide simple treatment details, but the text highlights the need for primary care-based randomised controlled trials to determine the best form of management for mild and moderate croup in the community. The final three chapters highlight the importance of clinical assessment and the lack of decision rules for the majority of ARIs, the relentless battle between bacteria and antibiotics and the potential role inappropriate prescribing of antibiotics in the community has had on emerging bacterial resistance, and finally, evidence-based strategies that GPs can use to change their own and their patients’ behaviour for the better (eg, delayed prescribing to reduce antibiotic use being one of the simplest and best). This textbook offers established GPs an opportunity to revisit and improve their current management of ARIs, and general practice registrars a chance to get it right from the start.

Nigel P Stocks

Objective: To analyse trends in asthma medications used by school-entry children whose parents report they have asthma.Design and setting: Annual cross-sectional study of all school-entry children (about 4400 each year) in the Australian Capital Territory in 2000–2005, by means of a questionnaire for parents on child health status and medication use; and a cross-sectional study of asthma prescriptions for children aged 5 years obtained from the Medicare Australia database for 2002–2005.Participants: All school-entry children in the ACT with parent-reported asthma (numbers in the years 2000–2005 ranged between 435 and 589).Main outcome measures: Changes in the use of different medications; changes in delivery devices for asthma; changes in the potency of inhaled fluticasone.Results: Response rates to kindergarten health screening were in the range 85%–89% for 2000–2005. Parent-reported asthma prevalence ranged from 11% to 15%. Each year, around 35% of children with asthma (age range, 4–6 years) used inhaled corticosteroids. An increase in the use of fluticasone (from 11% to 33% of children with asthma) was offset by decreases in beclomethasone use (from 14% to 3%) and budesonide (from 14% to 4%). Use of cromoglycate and nedocromil fell from 46% to 16%. Nebuliser use decreased (from 45% to 20%), while the use of spacer devices increased (from 70% to 83%). Use of combined salmeterol/fluticasone increased from 8% (in 2002) to 20% (in 2005) of children with parent-reported asthma. These trends were mirrored in Medicare Australia data for 5-year-old children in the ACT.Conclusions: There was marked volatility in the types of asthma medication used over the 6 years. Reciprocal trends leading to increased use of spacers and decreased use of nebulisers are in accord with national guidelines for better asthma management. The increasing use of products containing a combination of salmeterol and fluticasone requires ongoing monitoring.

Christine B Phillips MB BS, MPH, FRACGP · Helen Toyne BM BS, FRACGP · Karen Ciszek RN, RM · Robyn G Attewell BSc, MSc, AStat · Marjan Kljakovic MB ChB, FRACGP, PhD

Many lower respiratory tract infections (LRTIs) are caused by organisms that do not require antibiotics or could be safely treated with narrow-spectrum antibiotics. Reducing the unnecessary use of antibiotics, particularly broad-spectrum agents, could reduce costs and side effects and delay the emergence of antibiotic-resistant organisms. Various point-of-care tests are becoming available to help clinicians identify the cause of LRTIs at the time of consultation. Point-of-care tests can be used to diagnose influenza, pneumococcal infections, Legionella and respiratory syncytial virus infections, thus allowing early decisions to be made on appropriate management.

Patrick G P Charles MB BS, FRACP · M Lindsay Grayson FRACP, MD, FAFPHM

Objective: To audit requests for computed tomography (CT) examination of the chest emanating from general practitioners and assess the appropriateness and usefulness of these requests.Methods: We reviewed 50 consecutive requests for CT examination received by two private radiology practices in Cairns between August 2004 and March 2005. Clinical details were abstracted from request forms and clarified by telephone if necessary. A subjective assessment of the appropriateness of the investigation was made by the authors. The study was performed in a large regional centre.Main outcome measures: Indications for requesting a CT scan; appropriateness of CT scan for indication specified.Results: Fifteen patients had had recent normal chest x-rays, all of whom proved to have normal CTs; eight had not had a recent chest x-ray performed. The CT scan was considered appropriate in 16 cases (32%), but 10 of these patients required referral to specialists anyway. Thirty-four CT scans (68%) were felt to be inappropriate and, of these, 10 were subsequently referred to specialists. In only six cases did the CT scan resolve the GP’s clinical problem. In six cases the wrong type of CT scan was performed (five were conventional CT scans instead of high-resolution scans; one was a high-resolution instead of low-resolution scan).Conclusions: Many CT examinations of the chest requested by GPs could be avoided or replaced by simpler, cheaper tests with lower radiation exposure. Assuming a fatal cancer risk of 1 in 3000, the radiation exposure involved in unnecessary chest CT scans could be responsible for about 40 fatal cancers a year in Australia.

Graham Simpson MD, FRACP, FRCP · Garry S Hartrick MB BS

Objective: To assess the use of domiciliary oxygen therapy (DOT) in Tasmania and the impact of a specialist oxygen clinic on service provision.Design: Retrospective observational study.Participants and setting: Patients prescribed government-funded DOT in Tasmania between December 2002 and April 2004.Main outcome measures: Indications for DOT; usage, prescription, reassessment and costs of DOT; influence of a specialist-run oxygen clinic.Results: 490 patients were using DOT, an overall rate of 102 patients per 100 000 population (varying between regions from 95 to 116 per 100 000 population). Of 267 patients (54%) prescribed DOT during hospitalisation, only 72% met national guidelines for DOT at commencement. Chronic obstructive pulmonary disease (COPD) was the most common indication (48% of prescriptions). The median time to reassessment after prescription was 5.5 months. Median usage in patients with COPD was 18.3 hours per day. The average cost per patient was $1498 per year, but differed regionally in relation to costs of ambulatory supplies. The oxygen clinic in the north-west region substantially reduced oxygen prescriptions, improved compliance with guidelines, decreased time to first reassessment from 21 to 6.6 months, and produced major cost savings.Conclusions: Prescription of DOT was often not in keeping with national guidelines. Reassessment was poor, despite more than half the patients being prescribed DOT as an inpatient. A dedicated oxygen clinic resulted in more appropriate prescription, decreased time to reassessment and a reduction in costs.

Andrew Jones MB BS · Richard Wood-Baker DM, FRACP · E Haydn Walters MA, DM, FRACP

Cyril Evans was born on 27 April 1921 in Sydney and attended Fort Street Boys’ High School. He graduated in medicine with credit from the University of Sydney in 1943, despite having had to work during the course to support his mother and sister and pay his university fees. He obtained a Diploma in Tropical Medicine in 1946. After doing his residency at Royal Prince Alfred Hospital, Sydney, Cyril joined the Australian Army in 1945. When the War ended, he worked for several years as a missionary doctor in the Solomon Islands. Between 1950 and 1954, he completed specialty training in internal medicine in the United Kingdom, working first at Hammersmith Hospital, London, and later in Cornwall and Wales. He became a Member of the Royal College of Physicians (London) in 1953. Cyril spent the next 21 years specialising in chest diseases, particularly tuberculosis, first in North Carolina, USA (1954–1955), then as Deputy Director of Tuberculosis Services in Queensland (1956–1968). During this time, he was seconded to the World Health Organization for 2 years (1964–1965) to work at the Tuberculosis Chemotherapy Centre in Madras, India. From 1969 to 1973, he served as Director of Tuberculosis Services for South Australia and then as Commonwealth Director of Tuberculosis Services in Canberra (1974–1975). In 1975, Cyril was appointed Deputy Director-General of the Commonwealth Department of Health. Over the next few years, he became a Fellow of the Royal Australasian College of Physicians (1975), the Royal College of Physicians (London) (1978) and the Royal Australian College of Medical Administrators (1979). He was highly regarded by his colleagues — respected not only for his expertise in public health, but also for his patience and consideration towards others. He was made an Officer of the Order of the British Empire in 1978. After retiring from government service in 1982, Cyril spent a year as Adviser in Chronic Diseases at the Western Pacific Regional Office of the WHO in Manila, The Philippines, and then over 10 years as Medical Director of the Australian Kidney Foundation (1986–1997). Cyril was passionate about the welfare of his fellow human beings. He decided against continuing to work in the USA in 1956 because of the racism he saw in the hospital and the community. From the 1960s, he volunteered his time to various programs to help people stop smoking and, more recently, was a keen supporter of Canberra ASH (Action on Smoking and Health) Inc. He was also a supporter of the Medical Association for Prevention of War and a long-time member of the Board of the Richmond Fellowship, a charity providing mental health care and accommodation to adolescents with behavioural problems. Cyril and his wife, Beryl, also provided a home-away-from-home for scores of people, particularly international students in Canberra, for more than 30 years. Cyril died on 1 February 2007 after a period of failing health associated with Parkinson’s disease and Alzheimer’s disease. He is survived by Beryl and children Bronwyn, David, Susan and Annette.

David B Evans · David de Souza

Two people employed for several years in the spawning shed of a mushroom farm developed mushroom worker’s lung. The first patient presented in respiratory failure, with radiological features characteristic of hypersensitivity pneumonitis. The condition of the second patient was subacute on presentation, with a computed tomography (CT) scan showing ground-glass opacities. With absence from the workplace and no steroid therapy, the symptoms of both patients subsided and the results of lung function tests and CT scans improved markedly. Clinical recordTwo employees of the same mushroom farm presented to our hospital within a 5-month period. The farm is a large commercial producer of Agaricus bisporus mushrooms. Both workers were employed in the spawning shed, where mushroom compost is tipped onto a conveyor belt for mushroom spawn (sterilised grain inoculated with mushroom mycelia) distribution. The process is associated with increased levels of ambient organic dust.1 The principal means of minimising organic dust in the shed was local exhaust ventilation. Neither worker recalled receiving instructions about respiratory protection or the specific hazard of organic dust exposure during their employee-induction process. Case 1A 36-year-old man, who was a non-smoker, had been employed at the mushroom farm for 8 years, and had worked in the spawning shed for 3 years. He described a 4-month history of non-productive cough that was noticeably worse in the afternoons at work and improved on weekends. Two weeks before presenting, he developed daily chills, sweats, myalgia, chest tightness and exertional dyspnoea. His symptoms consistently commenced 5 hours after arriving at work and persisted into the evening at home. They abated sufficiently by morning and over the weekend to allow him to return to work. He had lost 7 kg in weight over 4 weeks. He presented to the emergency department with worsening dyspnoea after a day at work. He was pyretic (38.1°C) and had bilateral basal inspiratory crackles. Measurement of arterial blood gases confirmed hypoxaemia (Pao2, 57 mmHg; reference range [RR], 80–100 mmHg). Inflammatory markers were elevated: C-reactive protein level, 92 mg/L (RR, < 8 mg/L); and erythrocyte sedimentation rate, 17 mm/h (RR, 8–12 mm/h). Results of a full blood examination were within normal limits. Chest x-ray showed a diffuse bilateral reticulonodular infiltrate, and a high resolution computed tomography (HRCT) scan showed changes consistent with hypersensitivity pneumonitis (Box 1). Mushroom worker’s lung was diagnosed and the patient was admitted for observation and oxygen administration. Corticosteroid treatment was not administered. Respiratory function tests showed a borderline restrictive ventilatory defect, with moderately impaired transfer factor for carbon monoxide diffusion (TLco) (Box 2). During 4 days of observation, there was an improvement in oxygenation, his fever abated, and C-reactive protein levels fell to 15 mg/L. He was discharged home and advised not to return to work. Over the next 4 months, with ongoing avoidance of workplace exposure, ventilatory function, gas transfer and vital capacity improved significantly, and the abnormalities seen on HRCT scan partly resolved, with persistence of tiny centrilobular nodules (Box 1). Precipitin testing for antibodies to A. bisporus was not available. Precipitin testing for antibodies to Micropolyspora faeni (a fungus of compost, hay and grain), done at the 1-month review, gave negative results. Case 2A 40-year-old man, an ex-smoker, who had worked in the spawning shed for 6 years, had experienced 3 months of non-productive cough, fatigue, exertional dyspnoea and weight loss. His working day in the spawning shed started at 6 am, with onset of symptoms usually occurring around midday. He presented on two occasions to another hospital after a full day’s work complaining of dyspnoea, cough, chest tightness, myalgias and fever. At the first of these two presentations, resting Spo2 (oxygen saturation measured by pulse oximetry) was mildly reduced at 93%. Results of a full blood examination showed neutrophilia (9.4 × 109/L; RR, 2.0–8.0 × 109/L), and the C-reactive protein level was 13.5 mg/L. No abnormalities were seen on chest x-ray. He was diagnosed with a respiratory tract infection, prescribed antibiotics and discharged. His symptoms abated during a period of sick leave, but recurred 2 hours after returning to work in the spawning shed. On presenting to our outpatient clinic, 9 days after his last work exposure, he reported that his cough and fever had abated, but exertional dyspnoea persisted. Spirometry tests showed no abnormality, but TLco was impaired at 22.8 mL·min-1·mmHg-1 (58% predicted). Serum precipitin testing for M. faeni gave negative results. HRCT scan of the chest showed subsegmental air-trapping on expiratory scans and subtle patchy ground-glass opacities in both lower lobes (Box 3). After 4 months of avoiding further exposure, he noted no recurrence of symptoms, slow improvement in exercise tolerance, and improved gas transfer. DiscussionMushroom cultivation in Australia is a large agricultural industry, employing over 2500 people,2 yet mushroom worker’s lung has not previously been reported in the Australian medical literature, nor to an occupational lung disease notification scheme.3 It is likely that there is considerable under-recognition of this condition, as it is estimated that 5%–15% of those exposed to the causative antigens may develop hypersensitivity pneumonitis.4 In the largest cross-sectional study of workers at an Agaricus mushroom farm, 20% of those heavily exposed to organic dust reported experiencing symptoms consistent with mushroom worker’s lung.5 Unfortunately, with no thorough epidemiological studies, specifically cohort studies, it is not possible to estimate the true incidence of respiratory disease in mushroom farm workers. Several outbreaks of mushroom worker’s lung have been reported in the international literature since the 1950s. Workers with high exposure to organic dust from mushroom compost, such as spawners and compost handlers, are commonly affected and hence the more specific term “mushroom compost worker’s lung” is occasionally used.1,6 In this form of mushroom worker’s lung, M. faeni (currently known as Saccharopolyspora rectivirgula of the class Thermoactinomycetes), which is present in mushroom compost, is the most commonly implicated allergen.1,5,7 Organic dust from mushroom compost consists of a vast array of microorganisms and organic antigens; failure to demonstrate precipitins to M. faeni, as in the patients reported here, does not exclude the diagnosis of mushroom worker’s lung.1,4,8 Japanese mushroom farm workers have been reported to suffer an alarmingly high incidence of allergic respiratory disease.9,10 In a 3-year follow-up study by Tanaka et al, 40% of workers left the industry due to intolerable respiratory symptoms.10 Japanese mushroom varieties such as Hypsizygus marmoreus (Bunashimeji) are grown on wet wood dust rather than compost and release billions of spores 4–6 μm in diameter before being harvested.10,11 The inhaled mushroom spore (rather than Thermoactinomycetes) is the causative allergen in this setting, with the term “mushroom picker’s lung” used to more accurately describe the group of workers at risk of this form of mushroom worker’s lung.11 Although commercial cultivation of “exotic” mushrooms in Australia is small (1000 tonnes per year compared with 52 250 tonnes of Agaricus mushrooms), as demand for and cultivation of these mushrooms increases, employers must be aware of the significant hazard posed by these varieties when developing safe work practices.2 The most important component of identifying hypersensitivity pneumonitis is recognition of exposure to a causative antigen, reinforcing the importance of a thorough occupational history, and identification of workplace hazards (Box 4).7,12 A temporal relationship between the development of symptoms (cough, fever, chills, dyspnoea, chest tightness and malaise) 4–8 hours after the start of exposure, and an improvement during weekends or vacations, is quite indicative of this condition.4,8 Organic dust toxic syndrome, a form of inhalation fever, may be difficult to differentiate from acute hypersensitivity pneumonitis and is estimated to be 30–50 times more common.12 Organic dust toxic syndrome may result from a single heavy exposure to organic dust, and is self-limiting, with symptoms rarely exceeding 36 hours.8 Optimal management of hypersensitivity pneumonitis requires early recognition and complete avoidance of further exposure to the causative antigen;8,7,12 a change of occupation may be necessary. Although corticosteroid therapy has been shown to result in more rapid improvement in lung function and may be warranted in severely unwell patients, it has not been shown to improve long-term outcomes.9 Recurrence of acute hypersensitivity pneumonitis is more common in patients treated with steroids; this may be due to their improved sense of wellbeing and less stringent adherence to antigen avoidance.8,13 The natural history of hypersensitivity pneumonitis has been poorly described, primarily due to a lack of longitudinal studies.8 With repeated acute or chronic low-level exposure in farmer’s lung, permanent lung damage caused by pulmonary fibrosis and emphysema has been shown to occur, with associated chronic dyspnoea and permanent impairment.8,9 Even patients who remain asymptomatic may have long-term physiological sequelae.8 Australian occupational health and safety legislation describes in broad terms employers’ responsibilities to ensure every reasonable action is taken to preserve the health and safety of workers. Obligations to control hazardous non-organic substances, such as isocyanates and silica, are further described by subordinate Occupational Health and Safety (Hazardous Substances) Regulations (Vic) and the accompanying Hazardous Substances Code of Practice. Despite organic dust clearly having the potential to harm human health, the requirement to control organic dust falls outside the domain of hazardous substance legislation in Australia. Therefore, for their duty of care to be discharged, employers in the agricultural sector must demonstrate due diligence in their identification and control of all workplace hazards, including organic dust. The National Occupational Health and Safety Commission (now known as the Australian Safety and Compensation Council) has established limits for some organic dusts, such as cotton.14 However, organic dust in most agricultural settings is a complex and variable mixture of constituents, impairing the ability to set useful standards.8 Episodic high concentrations of dust exposure, rather than static ambient levels, may precipitate respiratory diseases, further increasing the difficulty of determining “safe” exposure standards. These factors impair our ability to advise employers how best to control this hazard. It is also difficult to determine what can reasonably be expected of employers as far as monitoring is concerned. Urgent research has been called for in this area by the American Thoracic Society.8 Employers in agricultural industries should demonstrate awareness of the hazard of organic dust, and aim to reduce exposure levels using the “as low as reasonably practicable” (ALARP) principle. Mushroom farm workers specifically should be educated about the risk of developing hypersensitivity pneumonitis and be advised of the symptoms and warning signs.5 1 Lung imaging — Patient 1 A: High resolution computed tomography (HRCT) scan of the chest of Patient 1 at presentation showing small, ill-defined centrilobular ground-glass nodules < 5 mm in diameter. Scans of the lower zones (not shown) revealed more confluent areas of ground-glass opacity, without discrete nodules. B: Repeat HRCT scan performed 1 month later (1 month without workplace exposure) showing significant improvement, but with persistence of tiny centrilobular nodules, particularly in the upper zones. 2 Respiratory function tests — Patient 1 Normal range Time since exposure (percentage of mean predicted value) Tests Presentation 1 month 4 months FEV1 (L) > 3.34 3.24 (76%) 4.50 (107%) 4.54 (108%) FVC (L) > 4.27 4.11 (78%) 5.17 (99%) 5.51 (105%) FEV1/FVC (%) > 72% 79% 87% 82% TLco (mL·min-1·mmHg-1) > 30.3 19.8 (53%) 26.8 (72%) 32.7 (88%) VA (L) > 5.8 5.3 (78%) 6.4 (95%) 6.9 (104%) FEV1 = forced expiratory volume in 1 second. FVC = forced vital capacity. TLco = transfer factor for carbon monoxide diffusion. VA = alveolar volume. 3 Lung imaging — Patient 2 High resolution computed tomography scan of Patient 2 at presentation, showing normal upper lobes (A) and patchy, centrilobular ground-glass opacities, with expiratory subsegmental air- trapping at the lung bases (B, C). This is a non-specific pattern, compatible with hypersensitivity pneumonitis. 4 Occupational causes of hypersensitivity pneumonitis — disease and source of exposure9,12 Farmer’s lung: mouldy hay, grain; compost Bagassosis: mouldy sugarcane Mushroom worker’s lung: mushroom compost, mushroom spores Ventilation pneumonitis: humidifier, air conditioner Machine operator’s lung: contaminated metal working fluids Humidifier lung: ultrasonic cool-mist humidifiers Floor finisher’s lung: mouldy wood floors Malt worker’s lung: mouldy malt dust (brewing) Compost lung: compost Tobacco worker’s lung: mouldy tobacco Sequoiosis: contaminated red-wood dust Wood worker’s lung: mouldy wood dust Wood trimmer’s disease: mouldy wood trimmings Wine grower’s lung: mouldy grapes Suberosis: mouldy cork dust Cheese worker/washer’s lung: cheese mould Salami worker’s lung: salami seasoning Saxophonist’s lung: mouldy saxophone reed Bird fancier/breeder/handler’s lung: pigeon, duck, chicken, turkey, parrot Furrier’s lung: cat hair, fur dust Laboratory worker’s lung: laboratory rat or gerbil urine Oyster shell lung: shell dust Tobacco grower’s lung: tobacco dust Coffee worker’s lung: coffee bean dust Tea grower’s/worker’s lung: tea leaves Streptomyces hypersensitivity pneumonitis: contaminated fertiliser Detergent worker’s disease: detergent

Ryan F Hoy MB BS · Jeffrey J Pretto BAppSc, GDBI, CRFS · David van Gelderen MB BCh, FRANZCR · Christine F McDonald MB BS, PhD, FRACP

Clinical record A 23-year-old woman presented to the emergency department with acute radicular lower back pain that became apparent when she was lifting books. She had normal blood pressure and 100% oxygen saturation breathing room air, but her heart rate was 110 beats/min and she had a temperature of 38.4°C. Inexplicably, she was discharged with a diagnosis of mechanical back pain. She presented again 2 days later with back pain, increasing shortness of breath, vomiting, myalgia, fever and sweating. She had also developed a dry cough and anterior pleuritic chest pain. There was an erythematous lesion on her left elbow. She and other family members had a history of recurrent furunculosis. When examined on admission, the patient was tachycardic (heart rate, 160 beats/min), hypotensive (blood pressure, 80/50 mmHg) and hyperpnoeic (respiratory rate, 32 breaths/min), with an oxygen saturation of 100% on a non-rebreather mask with oxygen flow at 15 L/min. She was febrile, with a temperature of 38.2°C, and had a furuncle on her left elbow. She had tenderness in the right upper quadrant; the spleen was not palpable. There was midline and left paraspinal tenderness over T8/9. There was no tampon in situ. Initial investigations showed a predominantly neutrophilic leukocytosis (18.4 × 109 cells/L [reference range (RR), 3.5–11 × 109 cells/L]); coagulopathy (prothrombin time, 20 s [RR, 9–14 s]; activated partial thromboplastin time, 40 s [RR, 25–38 s]); thrombocytopenia (platelet count, 59 × 109/L [RR, 140–400 × 109/L]); renal dysfunction (urea level, 14.2 mmol/L [RR, 3–8 mmol/L]; creatinine level, 172 μmol/L [RR, 50–100 μmol/L]); and an elevated serum troponin I level (1.4 μg/L [RR, < 0.2 μg/L]). A chest x-ray showed bilateral multilobar consolidation. Initial therapy included large-volume fluid resuscitation, a noradrenaline infusion, intravenous hydrocortisone and empirical intravenous antibiotics (3.1 g ticarcillin/clavulanate, 400 mg gentamicin and 500 mg azithromycin, within 50 minutes of arrival). Subsequently 2 g dicloxacillin was administered intravenously. The patient required intubation and mechanical ventilation 6 hours after admission, due to markedly deteriorating respiratory function. At this time, arterial blood gas results measured with the patient on 100% oxygen were: pH, 7.13 (RR, 7.35–7.45); partial pressure of carbon dioxide (Paco2), 52 mmHg (RR, 35–45 mmHg); Pao2, 237 mmHg (RR, 75–100 mmHg); base deficit, –12.3 mmol/L (RR, –3 to 3 mmol/L); and bicarbonate, 16 mmol/L (RR, 22–33 mmol/L). A computed tomography scan revealed multiple small areas of airspace opacification in a perivascular distribution, as well as bilateral extensive lower-lobe consolidation. Nine hours after admission, in view of worsening shock, drotrecogin alpha (activated protein C) and vasopressin were commenced. Despite a high-dose infusion of noradrenaline and adrenaline, the patient’s circulatory status continued to deteriorate. Staphylococcus was grown from initial blood cultures after 14 hours, and intravenous vancomycin 1000 mg was administered. Sixteen hours after admission, the patient had an episode of ventricular tachycardia, which reverted to sinus rhythm after a single precordial thump. However, ventricular tachycardia recurred and progressed to asystole. The patient died 17 hours after presentation, despite resuscitation. Subsequently, methicillin-resistant S. aureus (MRSA) was grown from blood cultures, endotracheal aspirates, and furuncle swabs and biopsies. The organism was sensitive to erythromycin, clindamycin, gentamicin, tetracycline, ciprofloxacin and vancomycin. Isolates were typed using a real-time polymerase chain reaction method based on single nucleotide polymorphisms (SNP) of the core genome and the presence or absence of variable genes, including the gene for Panton–Valentine leukocidin (pvl).1 All isolates had an SNP and variable gene profile characteristic of the Queensland clone (ST93-MRSA-IV) of community-associated MRSA (CA-MRSA), including the presence of pvl. Queensland clone CA-MRSA was also isolated from nose swabs subsequently collected from three family members, two of whom had suffered from recurrent furunculosis. Postmortem examination showed that the principal pathology lay in the lungs and myocardium. The lungs showed multiple foci of bronchopneumonia, many coalescing to form extensive areas of lobar pneumonia. However, the most striking feature seen on histology was involvement of the pulmonary vasculature by staphylococcal septicaemia. Staphylococci had invaded the walls of multiple blood vessels, producing a florid vasculitis with subsequent secondary thrombosis of the involved vessels (Figure). This process involved both large and small vessels to such an extent that a lethal degree of bilateral arterial thrombosis had developed. The larger thrombosed vessels were obvious at macroscopic examination of lung slices. Multiple small thrombi were seen on microscopy. The myocardium showed focal abscesses containing staphylococcal colonies. Adjacent myocardial fibres showed necrosis, which correlated with the patient’s raised troponin level. The other organs of the body were remarkably free of sepsis, the spleen was normal, and the spinal column showed no evidence of osteomyelitis. A furuncle on the left elbow was confirmed. Virulent strains of methicillin-resistant Staphylococcus aureus (MRSA) have recently emerged in community settings around the world (including many parts of Australia)2 and are causing community-acquired infection with increasing frequency.3 Most of the virulent strains carry the genes for producing Panton–Valentine leukocidin (PVL), a potent necrotising toxin. They most commonly cause primary skin and soft tissue infections such as furuncles and abscesses, but can also give rise to severe invasive conditions, including necrotising pneumonia.4 While uncommon, necrotising pneumonia is associated with a high mortality rate. In Australia, two major strains of PVL-positive, community-associated MRSA (CA-MRSA) are currently circulating: the Queensland (QLD) clone and the south-west Pacific (SWP) clone. Currently, these strains predominate among CA-MRSA in Queensland, New South Wales and the Australian Capital Territory, while in other states, PVL-negative strains are more common.2 Lessons from practice A history of recurrent furunculosis in a patient or in family members may precede severe Staphylococcus aureus sepsis, including necrotising pneumonia. Patients with recurrent infection due to S. aureus should be tested for persistent nasal carriage. Treatment aimed at eradication could be considered. The prevalence of virulent strains of community-associated methicillin-resistant S. aureus (CA-MRSA) is increasing in many parts of Australia. Knowledge of local prevalence would be valuable in guiding empirical treatment. In communities where CA-MRSA is prevalent, suspected severe sepsis due to S. aureus should be treated with a combination of vancomycin and one of dicloxacillin, flucloxacillin or cephalothin until culture and susceptibility results are available. Necrotising pneumonia due to PVL-positive S. aureus is often rapidly fatal, as in the case described here. A study by Gillet et al recorded a mortality rate of 37% within 48 hours of presentation.5 A significant association with preceding furunculosis was also noted. Most cases occurred in otherwise healthy children and young adults. A recently reported fatal case of CA-MRSA necrotising pneumonia in an Indigenous person was also in a previously healthy young adult.6 The patient in our case had a history of recurrent furunculosis and a furuncle on her elbow at presentation, both commonly caused by PVL-positive S. aureus. Two family members had also suffered from recurrent furunculosis. All isolates from the patient and from nose swabs of three family members belonged to the QLD clone. QLD and SWP clones are frequently sensitive to numerous non-β-lactam antimicrobials.2 Agents such as clindamycin and cotrimoxazole may be used to treat mild-to-moderate CA-MRSA infections such as furunculosis, depending on the organism’s susceptibility.7 Agents that act against protein synthesis (and therefore toxin production) have a theoretical advantage in the treatment of toxin-related infectious syndromes, but good clinical studies in this area are lacking. The use of clindamycin for treating invasive CA-MRSA infections is supported by one retrospective study in children.8 Linezolid, a new agent also active against protein synthesis, has been shown to be superior to vancomycin, but only in complicated skin and soft tissue infections.9 Use of one of these agents, perhaps in combination with established anti-staphylococcal antibiotics, is worthy of prospective study. The current national recommendation for treating suspected MRSA pneumonia is to administer vancomycin together with a β-lactam antibiotic (dicloxacillin, flucloxacillin or cephalothin) until susceptibility data are known.7 The severity of this case and rapidity of progression make it unlikely that more appropriate antibiotic therapy would have led to survival. Indeed, azithromycin, which was administered soon after admission, is active against erythromycin-sensitive strains of S. aureus. Nevertheless, early optimum antimicrobial treatment will give the best chance of survival. The possibility of MRSA pneumonia should be considered in the context of severe community-acquired pneumonia, particularly in children or young adults, and especially if there is evidence of preceding staphylococcal infection, such as folliculitis or furunculosis. Histological section of the patient’s lung at autopsy The section shows confluent staphylococcal bronchopneumonia with invasion of vessels in the lungs, producing a florid vasculitis (arrow). Secondary thrombosis is occluding the pulmonary vascular system. (Haematoxylin–eosin stain; original magnification × 100)

David C Risson MB BS, BVSc · Enda D O’Connor MB BCh, MRCP(Irl), FJFICM · Roger W Guard FRCPA · Jacqueline M Schooneveldt MAppSci, MASM, GCM · Graeme R Nimmo FRCPA, FASM, MPH