Respiratory disease

The median age of patients with pandemic influenza H1N1 2009 infection was reported as 20–25 years in initial case series from Europe and the United States. This has been lowered to 13 years in the US after testing of more patients, but this may reflect differential increased testing of school-aged children as part of the pandemic response. The median age of patients with seasonal influenza A(H1N1) infection identified through sentinel surveillance in Western Australia and Victoria in 2007–2008 was 18 and 22 years, respectively. For pandemic influenza H1N1 2009 infection, the median age of the first 244 patients identified in WA was 22 years, and median age of the first 135 patients identified through sentinel surveillance in Victoria was 21 years. Other comparisons of the epidemiological features of pandemic and seasonal influenza are difficult because much less laboratory testing is done for seasonal than for pandemic influenza. While early surveillance data indicated co-circulation of both pandemic and seasonal strains in WA and Victoria, more recent data from both states indicate an increasing predominance of pandemic influenza. If the evolving pandemic allows, we should take advantage of the increased testing being conducted for pandemic influenza to learn more about the real impact of laboratory-confirmed seasonal influenza.

Heath A Kelly BSc, MB BS, MPH · Kristina A Grant BSc · Simon Williams BSc(Hons) · James Fielding BSc(Hons), MAppEpidemiol · David Smith MB BS, FRCPA, FACPM

We present the first six cases of H1N1 influenza 09 (confirmed by a polymerase chain reaction test from nasopharyngeal swabs) in patients requiring admission to intensive care in Australia (in three hospitals in the north-western suburbs of Melbourne). These cases highlight the small but significant risk of life-threatening respiratory failure associated with H1N1 influenza 09 infection. Clinical recordsPatient 1A 28-year-old obese woman (body mass index [BMI], 57 kg/m2) presented to the emergency department (ED) with a history of 5 days of sore throat, lethargy and myalgias, and a clear chest x-ray, followed by 2 days of dyspnoea, productive cough, and pleuritic chest pain. She was febrile (40°C), and had tachypnoea (respiratory rate, 36 breaths/min) and hypoxia (oxygen saturation measured by pulse oximetry [Spo2], 87% on 15 L/min oxygen via face mask). Her admission chest x-ray showed widespread alveolar infiltrates. She had a normal white cell count (WCC) of 6.3 × 109/L, but an elevated serum C-reactive protein (CRP) level of 221 mg/L (reference ranges shown in Box 1). She was admitted to the intensive care unit (ICU) and, after a brief trial of non-invasive ventilation (NIV), was intubated and treated with mechanical ventilation (MV) with a fraction of inspired oxygen (Fio2) of 1.0 and positive end-expiratory pressure (PEEP) of 20 cm H2O for the first 24 hours to maintain an Spo2 > 89%. She was treated with inotropes for septic shock and with renal replacement therapy for acute renal failure. Therapy with oseltamivir in addition to empiric broad-spectrum antibiotics was commenced. Bacterial cultures of blood, urine and tracheal aspirate were negative. The result of a test for urine pneumococcal antigen was negative. The patient was successfully weaned from ventilatory support on Day 14. Patient 2A previously well 24-year-old man (BMI, 22 kg/m2) was admitted to a regional hospital with a 1-week history of dry cough, fever, headache, abdominal pain, and vomiting. Thirty-six hours later, he was transferred to a metropolitan hospital because of worsening dyspnoea and hypoxia (Spo2, 88% on 15 L/min oxygen via face mask). He had tachycardia (110 beats/min), tachypnoea (respiratory rate, 34 breaths/min) and was febrile (39.9°C). He had a normal WCC (4.2 × 109/L) but an elevated CRP level (256 mg/L). A chest x-ray showed unilateral lobar consolidation. He was transferred to the ICU and treated with oseltamivir, broad-spectrum antibiotics, and NIV with an Fio2 of 1.0. After 96 hours, his hypoxia remained severe (partial pressure of arterial oxygen [Pao2] to Fio2 ratio, < 100), another chest x-ray showed bilateral alveolar infiltrates, and he was intubated and MV was commenced with an Fio2 of 1.0 and high-level PEEP (20 cm H2O) for several days. Bacterial cultures and urine pneumococcal antigen test results were negative. Oseltamivir therapy was continued for 7 days, and MV for 15 days. Patient 3A 26-year-old obese man (BMI, > 40 kg/m2) with a history of mild asthma presented after 2 days of nausea without vomiting, and no fever or cough. On the day of admission, he developed shortness of breath. He was found to be hypoxic (Spo2, 90% on an Fio2 of 1.0) with bilateral pulmonary infiltrates showing on a chest x-ray. His WCC was 5.6 × 109/L and CRP level was 137 mg/L. Therapy with broad-spectrum antibiotics and oseltamivir was commenced. He was intubated, and MV was commenced with an Fio2 of > 0.6 and high-level PEEP (15 cm H2O); the patient was successfully extubated after 10 days. Patient 4A previously well 41-year-old man (BMI, 30 kg/m2) presented with a 7-day history of cough, coryza, malaise, back pains and rigors. On the day of presentation, he became febrile (39.6°C) and developed tachypnoea (respiratory rate, 45 breaths/min) and severe hypoxia (Spo2, 84% on 10 L/min oxygen via face mask). His chest x-ray showed widespread pulmonary infiltrates. He had a WCC of 4.4 × 109/L and a CRP level of 166 mg/L. He was intubated in the ED and MV was commenced, and he was given oseltamivir and broad-spectrum antibiotics. He remained severely hypoxic (requiring an Fio2 of > 0.8) for 10 days, and was treated with MV in the prone position and inhaled nitric oxide. His condition gradually improved, and he was extubated on Day 13. Patient 5A 60-year-old man presented to hospital with an exacerbation of his severe chronic obstructive pulmonary disease (COPD). He also had severe peripheral and coronary vascular disease. On examination, he had tachypnoea (respiratory rate, 36 breaths/min) but no fever. He had no prodrome of coryza or myalgias, and a chest x-ray showed mild bibasal opacities. His WCC was elevated (11.4 × 109/L), but his CRP level was 12 mg/L. He was admitted to the respiratory ward and treated with oseltamivir, broad-spectrum antibiotics, and NIV. Two days later he was intubated, and MV was commenced for hypercapnic respiratory failure. Bacterial cultures were negative. His hypoxia was mild (requiring an Fio2 of < 0.5), but he required MV for 14 days. Patient 6An 18-year-old pregnant woman presented with a 4-day history of cough, fever, and persistent vomiting without diarrhoea. Oseltamivir therapy for possible H1N1 influenza infection was discussed with the patient, but not administered. After intravenous rehydration, she was discharged home, but she returned several hours later in premature labour. Her WCC was 8.2 × 109/L but her CRP level was high (90 mg/L). She was given steroids for fetal lung immaturity and transferred to a tertiary obstetric/neonatal hospital. Twenty-four hours after delivering a 26-week live infant, she developed hypoxic respiratory failure with tachypnoea (respiratory rate, 35 breaths/min) and bilateral pulmonary infiltrates. She required a high level of inspired oxygen therapy (Fio2, 0.6) by face mask, and monitoring in the ICU. The mother, but not her baby, had a positive polymerase chain reaction (PCR) test result for H1N1 influenza 09, and both were treated with broad-spectrum antibiotics and oseltamivir. DiscussionSince the emergence of the novel H1N1 influenza 09 (human swine influenza) in North America and Mexico in mid April, the number of confirmed cases has increased to over 55 000 across 105 countries.1 While most individuals will experience a mild clinical illness (coryza, fever, cough and myalgias), there have been 238 reported deaths (0.4%).2 A Centers for Disease Control and Prevention (CDC) report in May provided details of the 30 patients who were hospitalised in California, of whom six required admission to an ICU and four required MV.3 At the time of writing, there have been 3912 confirmed cases of H1N1 influenza 09 in Australia.2 Most reported illness has been mild, but 268 patients (6.9%) have been hospitalised, over 25 (0.6%) have been admitted to ICUs, and five deaths (0.1%) have been reported. Here, we presented the first six cases of H1N1 influenza 09 (confirmed by PCR test from nasopharyngeal swabs) in which patients required admission to intensive care in Australia. Admissions were to three hospitals in the north-western suburbs of Melbourne. These cases highlight the small but significant risk of life-threatening respiratory failure associated with H1N1 influenza 09 infection. All patients experienced a rapid (but reversible) decline in respiratory function, with most requiring complex respiratory support. The age distribution of these patients is consistent with other reports, and lower than that seen in previous influenza seasons.4,5 Four of the six cases we report had risk factors, including asthma, chronic lung disease, smoking, obesity, and pregnancy; these risk factors were similar to those identified in the CDC reports.3 Patients 2 and 4 had no identifiable risk factors. There are several possible explanations for the acute respiratory failure observed in these patients. Early onset of respiratory failure with widespread pulmonary infiltrates (Patient 3) suggests primary viral pneumonitis, whereas the delayed onset of fever with lobar signs (Patient 2) and pleurisy (Patient 1) suggest secondary bacterial pneumonia. A cytokine-mediated acute lung injury may also explain the late appearance of diffuse pulmonary infiltrates (Patients 4 and 6). The absence of a severe prodrome in Patient 5 suggests an exacerbation of the patient’s COPD. With the number of cases of H1N1 influenza 09 infection likely to increase, it is anticipated that further cases of severe respiratory failure associated with this influenza will be seen. Based on the cases reported here and other reports, we offer the recommendations shown in Box 2. A high index of suspicion that respiratory failure may ensue is warranted in patients who have risk factors5 or present with tachypnoea (respiratory rate, > 24 breaths/min) and/or hypoxia (Spo2, < 95% on supplemental oxygen), and early referral to hospital is warranted. Youth and prior good health do not preclude the possibility of severe respiratory failure. The Victorian Department of Human Services currently recommends nasopharyngeal swabs for a PCR test for influenza A in patients admitted to hospital with suspected influenza. Empiric therapy with antiviral agents (oseltamivir or zanamivir)5 should be considered in addition to antibiotic treatment for community-acquired pneumonia pathogens, in consultation with an infectious diseases specialist. Patients with suspected H1N1 infection should be isolated, preferably in a negative pressure isolation room.6,7 Where possible, antiviral filters applied to the expiratory limb of the ventilator circuit may further reduce the risk to health care staff. Oseltamivir (Tamiflu) and zanamivir (Relenza) reduce viral replication and shedding, and may reduce the risk of more severe illness. Their safety in pregnancy has not been investigated (Category B1 for use in pregnancy), but without treatment there may be a greater risk of premature labour (Patient 6).5,8 Increasing resistance to oseltamivir has been reported in other strains of currently circulating influenza A viruses, but, as yet, not in the H1N1 influenza 09 lineage.9,10 Any patient with respiratory distress or severe hypoxia (requiring an Fio2 of > 0.5) and pulmonary infiltrates on chest x-ray should be referred to an intensive care specialist for further assessment. Mechanical ventilation for these patients is complex, and requires expertise and specialised equipment. We used restrictive tidal volumes (6 mL/kg ideal body weight), high PEEP (15–20 cm H2O), pressure-limited modes of ventilation, alveolar recruitment manoeuvres, inhaled nitric oxide, and restrictive fluid therapy with apparent success. This is consistent with ventilation strategies used by others,11 and in keeping with strategies described by the Acute Respiratory Distress Syndrome (ARDS) Clinical Network.12 Extracorporeal oxygenation therapy has recently been used in other cases (G J D, personal communication). Based on the available data, we would not recommend NIV as the mainstay of respiratory support. The four patients who were given a trial of NIV in this series all required intubation and MV. This is consistent with published data for ARDS and pneumonia.13 NIV temporarily improves oxygenation and reduces the work of breathing, but does not necessarily alter the course of the disease.14 The need for NIV is an indication of severe disease and the likelihood of intubation and MV. For the most part, H1N1 influenza 09 is a benign disease, but it may lead to severe respiratory complications in a small proportion of patients. In our series, prompt diagnosis and intensive therapy was associated with favourable outcomes. 1 Reference ranges for white cell count and C-reactive protein level Reference range White cell count (WCC) 4–11 ×109/L C-reactive protein (CRP) < 5 mg/L 2 Summary of clinical recommendations for managing patients with possible H1N1 influenza 09 infection Maintain a high index of suspicion of possible respiratory failure in patients with risk factors such as asthma, smoking, pregnancy, obesity or chronic medical conditions.2,4 Refer patients to hospital if they have hypoxia (oxygen saturation measured by pulse oximetry [Spo2], < 95%) and/or tachypnoea (respiratory rate, > 24 breaths/min) or pulmonary infiltrates. Institute respiratory and contact precautions, including personal protective equipment.2,4-6 Conduct polymerase chain reaction tests for H1N1 influenza A in patients admitted to hospital with suspected influenza. Start antiviral therapy early; its benefits in pregnant mothers may outweigh the risks.4,7 Refer patients for intensive care unit assessment if a fraction of inspired oxygen (Fio2) of > 0.5 or oxygen at a rate of > 10 L/min is required to maintain the Spo2 at > 92%. Non-invasive ventilation is unlikely to improve the outcome; consider intubation and mechanical ventilation. Complex mechanical ventilation strategies are often required.

Melissa A Kaufman MB BS · Graeme J Duke MD, FJFICM, FANZCA · Forbes McGain FJFICM, FANZCA · Craig French FJFICM, FANZCA · Craig Aboltins MB BS, FRACP · Gary Lane FRACP, MMed(ClinEpi), MQIHC · Geoff A Gutteridge FJFICM, FANZCA

Extracorporeal membrane oxygenation (ECMO) is a technique that involves oxygenation of blood outside the body, and provides support to selected patients with severe respiratory or cardiac failure. The two major ECMO modalities are venoarterial and venovenous. Data from several randomised trials support the use of ECMO in neonatal respiratory failure, and a recent randomised controlled trial of ECMO in adults has produced encouraging results. The evidence base for ECMO use in cardiac disease is developing, but progress has been slowed by considerations of clinical equipoise and evolving indications for ECMO. Advancing ECMO technology and increasing experience with ECMO techniques have improved patient outcomes, reduced complications and expanded the potential applications of ECMO. Awareness of the indications and implications of ECMO among doctors managing patients with severe but potentially reversible respiratory or cardiac failure may help facilitate better communication between health care teams and improve patient recovery.

Steven J Lindstrom MB BS(Hons), BMedSc(Hons) · Vincent A Pellegrino MB BS, FRACP, FJFICM · W Warwick Butt MB BS, FRACP, FJFICM

With the recent outbreak of swine influenza, the world may be facing this century’s first influenza pandemic. In Mexico, around 2000 patients have been hospitalised with respiratory illness and almost 150 people have died. Several other countries have reported smaller numbers of suspected and confirmed cases of swine influenza. This 2009 influenza A virus is a strain of the H1N1 subtype, and appears to be a human–avian reassortment swine virus influenza. It is likely that sustained human-to-human transmission of swine influenza has occurred, at least in Mexico. Despite there being so many hospitalised patients in Mexico, cases outside Mexico have demonstrated a mild influenza-like illness, with only one fatality to date. In contrast to the 1918 influenza pandemic, we now have a more robust public health system, with widespread global networks; vaccines can be developed rapidly; and there are antiviral medications to which the swine influenza A(H1N1) virus is sensitive. Many resources have been invested in pandemic preparedness programs in the health care and public health systems in Australia over the past few years.

Sanjaya N Senanayake MB BS, MAppEpid, FRACP

A 6-week old infant who had been conceived through in-vitro fertilisation (IVF) presented with a skin lesion and enlarged lymph nodes, and developed severe respiratory distress. Mycobacterium tuberculosis was identified; his mother was the only potential source identified. To our knowledge, this is the first case of congenital tuberculosis after IVF reported in Australia and the second worldwide. It highlights the importance of adequate screening during investigation of infertility and the difficulties in diagnosing congenital tuberculosis. Clinical recordsA 29-year-old Bosnian woman, who had migrated to Australia 8 years earlier, conceived through in-vitro fertilisation (IVF). Her baby, a boy, was born at 28 weeks’ gestation by emergency caesarean section for fetal distress in labour. His mother made an uneventful recovery after the delivery. The baby’s birthweight was 1154 g (50th percentile), and neonatal assessment was consistent with gestational age. He developed mild respiratory distress syndrome and required a short period of endotracheal intubation and artificial ventilation, from which he was successfully weaned. He had several significant problems during the early neonatal period, including prolonged neonatal jaundice (which required repeated episodes of phototherapy), hypothyroidism (serum thyroid-stimulating hormone, 9.2 mU/L; reference range, 0.30–5.00 mU/L) and right-sided Erb palsy. At 6 weeks of age, while still in hospital, the infant developed a 1 cm brown–pink macular lesion on the left side of the neck, and was noted to have an enlarged (1.5 cm) left axillary lymph node. Empirical antistaphylococcal therapy was introduced without any apparent effect. Biopsy of the lymph node was planned, but before this could be performed, the lymph node became acutely more enlarged, and the infant’s condition deteriorated rapidly. He developed severe respiratory distress and required re-intubation. A large mediastinal lymph node mass was noted on chest x-ray and magnetic resonance imaging (Box 1), and bronchoscopy showed extrinsic compression of the trachea and bronchi at the level of the carina. Excision biopsy of the axillary lymph node showed necrotising granulomatous inflammation, and acid-fast bacilli were identified on Ziehl–Neelsen and auramine–rhodamine staining. Mycobacterium tuberculosis was identified in lymph node tissue and endotracheal aspirates by polymerase chain reaction (PCR) and culture. M. tuberculosis was not identified in cerebrospinal fluid, blood or gastric aspirate by PCR or culture. Empirical treatment with isoniazid, rifampicin, ethambutol and pyrazinamide was commenced, along with prednisolone, and the infant’s condition stabilised, then improved. Abdominal ultrasound examination did not show features of a primary complex in the liver. The M. tuberculosis isolate was sensitive to all first- and second-line agents. The baby developed moderate neutropenia after 4 weeks of therapy, which resolved after discontinuation of ethambutol; pyrazinamide was ceased after 12 weeks of therapy. After 4 months of therapy, further left axillary and cervical adenopathy was noted. The largest node was about 1 cm in diameter and fluctuant. The nodes settled spontaneously without excision or treatment change. The infant experienced two episodes of wheezing associated with clinical features of viral upper respiratory tract infection (at 8 and 10 months into the course of antituberculous therapy, respectively). Chest x-rays on each occasion did not show evidence of mediastinal node enlargement. His recovery was otherwise uncomplicated, and he completed a planned 12 months of therapy. The child’s mother had no significant medical history apart from infertility. Infertility investigations had included ultrasound, hysteroscopy and diagnostic laparoscopy. A uterine curettage (as part of the work-up for infertility) 5 years before the pregnancy had shown “granulomas” in the endometrium (Box 2), but stains for acid-fast bacilli were negative. Culture for M. tuberculosis had not been performed at the time. Following the diagnosis of tuberculosis (TB) in her child, an interferon-gamma release assay (IGRA [QuantiFERON-TB Gold, Cellestis, Melbourne, Vic]) was performed, and gave a positive result. Chest x-ray revealed old fibrotic changes in the right upper lung, but no evidence of active tuberculous disease. She was prescribed antituberculous medication. Extensive contact tracing was performed. The father and all close contacts of the baby during his stay in the neonatal unit (including 118 health care workers, 20 neonates and 32 relatives) were screened with an IGRA or tuberculin skin test, and positive results were followed up with chest x-ray. No other cases of active TB were found, suggesting that the index patient did not acquire TB postnatally, but had congenital tuberculosis. DiscussionThis is the first case of congenital TB after IVF reported in Australia, and to our knowledge only the second case reported in the literature.1 This case suggests two valuable lessons: the importance of considering congenital TB in babies who develop a suggestive clinical illness in the first weeks of life, and the need for accurate assessment for and exclusion of TB in women proceeding to IVF. Congenital TB is a rare condition, with around 350 cases reported in the literature.2-10 The fetus can be infected by direct spread through the umbilical cord, by aspiration or swallowing of infected amniotic fluid, or by direct contact with maternal genital lesions during delivery.11 TB can be difficult to recognise in infants as symptoms may be non-specific and easily mistaken for more common neonatal illnesses, such as bacterial sepsis or congenital viral infections.12 Symptoms usually present 2–3 weeks after birth, and the disease can quickly progress to dissemination and death if not promptly treated. In 1994, criteria for diagnosis of congenital TB were revised.3 They comprise documentation of tuberculous lesions in the infant and one or more of the following: lesions in the first weeks of life; a primary hepatic complex or caseating granuloma; documented tuberculous infection of the endometrium or placenta; or exclusion of the possibility of postnatal transmission by investigation of close contacts. Our patient met the criteria for congenital TB: he had tuberculous lesions in early life; his mother had documented granulomas of the endometrium; and extensive contact tracing found no evidence of transmission to the child from other close contacts. Confirmation of endometrial TB in the mother, by repeat endometrial biopsy with PCR and culture for TB, would have been ideal, but would not have altered management in either the mother or the neonate. Thus, it was elected to treat the mother on the basis of the neonate’s culture results, rather than subject her to another procedure. Globally, there has been a slow decline in the incidence of TB; but this is more than offset by population growth, with the number of new cases worldwide increasing between 2005 and 2006 from 9.1 to 9.2 million (an increase of 0.6%). Increases occurred in the African, Eastern Mediterranean, European and South-East Asian regions.13 In Australia, the total number of TB cases reported in 2006 was 1201 (5.8 cases per 100 000 population). The incidence varies dramatically between populations in Australia, with 0.9 cases per 100 000 population in the non-Indigenous population, climbing to 20.1 per 100 000 population in those born overseas.14 Within the group born overseas, incidence ranges from 2.0 per 100 000 population for those born in the United Kingdom to 405 per 100 000 population for those born in Somalia.14 Genital TB is a major cause of infertility in women belonging to high-risk groups, causing up to 17% of cases of infertility.15 Its incidence is increasing in Western continents. Twenty-nine cases of genitourinary TB were reported in Australia in 2006 (2.5% of all reported cases of TB).14 In Australia, it is estimated that one in every 60 babies is conceived through IVF .16 As IVF is a useful treatment for infertility caused by TB, it can be expected that in the future more women with TB as a cause of their infertility will present for IVF. It is therefore imperative that women from high-risk groups undergo evaluation for and exclusion of TB. Investigations should include an IGRA or tuberculin skin test. If either gives a positive result, expert opinion should be sought to determine the need for more invasive investigations, such as endometrial biopsy. If an endometrial biopsy reveals granuloma, it is imperative that the specimen be sent for PCR and culture for TB, even in the absence of acid-fast bacilli. Consultation with an infectious diseases physician or clinical microbiologist is then warranted. In summary, this case highlights the fact that TB should be considered and excluded in high-risk women undergoing IVF, and that TB should be considered in ill neonates who have a poor response to conventional antibiotic therapy. 1 Magnetic resonance imaging scan of a 6-week old infant A scan showing multiple enlarged lymph nodes in the mediastinum measuring up to 13 mm (right paratracheal, subcarinal and right hilum) and in the axillae (largest on the left) and cervical area. 2 Section of endometrium from the infant’s mother A section of endometrium sampled 5 years before the infant’s birth showing a granuloma. (Image courtesy of Dr John Rees, Southern Health Pathology Department, Melbourne, Vic.)

Rhonda L Stuart MB BS, FRACP, PhD · Anthony Lewis MB BCh, MMed(Microbiology), FRACP · C Andrew Ramsden FRCP, FRCPCH, FRACP · Richard R Doherty MB BS, FRACP

The challenge of providing a multidisciplinary response to complex health problems A developmental disability is a neurological abnormality having its onset in childhood that is associated with long-term neurological and developmental deficits (for example, spastic quadriplegic cerebral palsy). Although the degree of physical and intellectual disability varies greatly, people with a severe developmental disability often have very limited mobility, are dependent on caregivers for their daily needs, and usually have several concomitant medical problems. Because of their complex health needs, consensus is growing that multidisciplinary clinics provide the optimal setting for assessment and management of patients with a developmental disability. Life expectancy is significantly reduced in people with developmental disabilities compared with the general population.1-3 Review of the causes of death of people with a disability living in state-funded supported accommodation in New South Wales shows that respiratory disease accounts for about 40% of deaths (Kelly Savage, NSW Ombudsman, personal communication). Similar findings have been reported from Victoria and the United Kingdom.2,3 Multiple factors contribute to the increased mortality in this group. Gastro-oesophageal reflux disease is common in people with severe developmental disability,4,5 with or without intellectual disability, and is an important comorbidity in individuals with incoordinate swallowing. Respiratory disease, often secondary to recurrent aspiration, is also common and under-recognised. Malnutrition caused by reduced food intake (related to swallowing difficulties) frequently accompanies neurological impairment. Previous studies from our group6 identified profound levels of protein energy malnutrition, severe disturbance of body composition, and almost universal osteoporosis in subjects with spastic quadriplegic cerebral palsy. Seizure activity can also compromise food intake. Orthopaedic problems such as joint contractures, hip dislocation and kyphoscoliosis further contribute to limited mobility and may exacerbate lung disease. Kyphoscoliosis also poses technical challenges for surgical procedures, such as gastrostomy device insertion and fundoplication. The interrelationships of these conditions clearly require the coordinated input of several disciplines. However, there have been no clinical trials attesting to the efficacy of multidisciplinary clinics in improving patient outcomes in this group of patients. We recently reported our experience with 452 adults and children with severe developmental disability, most of whom had cerebral palsy.7 These patients were seen at tertiary referral dysphagia–nutrition multidisciplinary clinics at Westmead Hospital and the Children’s Hospital at Westmead in NSW between 2001 and 2006. The treating teams included a developmental paediatrician–physician, paediatric gastroenterologist, clinical nurse coordinator, speech pathologist, dietitian, and paediatric physiotherapist. Patients ranged in age from 7 months to 53 years; 90% were wheelchair-dependent and 60% had epilepsy. Among other things, we found that: 90% of patients had dysphagia; three-quarters of the children and half of the adults were malnourished due to inadequate food intake; 60% of the total clinic population reported respiratory symptoms; and half of the patients undergoing upper endoscopy had reflux oesophagitis, and 66% of patients undergoing computed tomography scans of the chest had chronic suppurative lung disease. In our series, simple interventions such as dietary advice, change of food consistencies, appropriate positioning during feeding and sleeping, use of proton-pump inhibitors, and implementation of a chest management plan were effective for many patients. However, a significant number of patients required gastrostomy with or without fundoplication for nutritional rehabilitation and to control gastro-oesophageal reflux and pulmonary aspiration. Improving the quality of life of the person with a developmental disability is the primary goal of management. Quality of life of the patient’s family and carers is also an important consideration when formulating management plans. Studies of children with a severe level of disability suggest that gastrostomy tube insertion has a positive impact on quality of life for both the children and their caregivers.8 However, the news is not all positive. Studies of caregivers’ attitudes to health professionals indicate that the way the health system dealt with their child with a disability was seen as a significant negative factor in the carer’s quality of life.9 Caregivers describe problems such as a lack of information, communication difficulties with health professionals, and lack of experience and expertise in managing the complex health needs of patients with a disability. Many of the medical problems described here are relatively easy to diagnose, and most respond to simple interventions, but they are often overlooked or undertreated in the general medical system. Interventions include treatment of nutrient deficiencies, management of reflux oesophagitis, saliva management, strategies to reduce episodes of aspiration pneumonia, and active management of chronic suppurative lung disease. Seizure control can also be problematic and may require regular specialist review. Coordination and provision of satisfactory health care to this population is a challenge to the health system, especially as these patients often present acutely to already overcrowded emergency departments.10 There are few specialist multidisciplinary clinical services in Australia for people with a developmental disability and complex health needs. Training opportunities in disability medicine are few outside of paediatrics, where developmental paediatrics is an essential component of paediatric training. Specific expertise and support services are often not available, and care may be significantly compromised in the adult health system. Communication barriers, lack of up-to-date medical records, difficulty doing a simple examination or routine investigations, and confusion about consent for even simple interventions all conspire to challenge the system to provide optimal care. These problems can be compounded by preconceived ideas about the quality of life of a person with a disability. Many of the problems confronting people with a developmental disability and complex health needs, and their carers attempting to access health services, need to be addressed. Increased awareness of their needs, improved education and training of health professionals, and the development of multidisciplinary clinics and support services are basic requirements to improve their health status.

Edward V O’Loughlin MD, FRACP · Helen M Somerville MB BS, MPaed · Ernest R Somerville MB BS, FRCP, FRACP

Indigenous Australians die of asthma at more than three times the rate of the rest of the nation The recently released Australian Centre for Asthma Monitoring (ACAM) report Asthma in Australia 2008 focuses attention on several important and novel findings about asthma among Indigenous Australians (see Box).1 This is the third report in the 2-yearly series from ACAM, and brings together analyses of routinely collected national data, including data from Australian Bureau of Statistics national health surveys, and current information from published articles. Asthma is clearly identified in the report as a prevalent health problem in the Indigenous population. It is one of the two most common causes of hospitalisation of Indigenous Australians, second only to renal dialysis.2 It is also the second most common self-reported long-term illness among Indigenous Australians, and the mortality rate due to asthma among Indigenous Australians is 3.2 times that of other Australians.1 However, in contrast to the attention given to other medical conditions over-represented among Indigenous Australians, such as cardiovascular disease and diabetes mellitus, disproportionately little attention is given to respiratory disease, including asthma. In contrast to lower prevalence rates reported in the past,3,4 the prevalence of asthma among Indigenous Australians (16.5%) is now higher than among other Australians (10.2%), particularly in adults older than 35 years and those living in urban locations.1 Furthermore, the report shows that the prevalence of asthma in Indigenous adults older than 55 years is higher than the prevalence seen in children. This is in stark contrast to the data for other Australians and from other countries, which show the prevalence of asthma to be higher in children than in adults. We can only speculate about the reasons, but these may include the cumulative effects of three factors: life-long exposure to pulmonary toxicants, such as tobacco smoke and infections; uncertainty among Indigenous Australians about the nature of the disease and of the diagnosis (probably a very significant factor, particularly in the very young and the elderly); and long-term undertreatment of asthma. Uncertainty about the diagnosis is an issue as most of the prevalence data are based on self-reported questionnaire data from the National Aboriginal and Torres Strait Islander Health Survey 2004–05,5 and are not confirmed by clinical examination. Although this survey was conducted on a representative sample of Indigenous people (respondents totalled 10 439), with oversampling in remote communities, there remains a need for well conducted epidemiological studies of asthma and wheezing illness in urban, rural and remote Aboriginal populations that include objective measures, such as results of lung function and airway hyper-responsiveness tests. The problems of smoking and poor access to high-quality health care for Indigenous Australians are well known and similar to those affecting minority groups in many other affluent countries.6 Indigenous Australians have very high rates of smoking, a particular concern in relation to asthma. Intrauterine and postnatal exposure to environmental tobacco smoke has serious implications for lung health in young children, especially the many who suffer frequent wheezing illness and persistent lower respiratory tract symptoms. Concurrent smoking and asthma are associated with accelerated lung function decline, and the report highlights the very serious lung-health consequences of the high smoking rates in Indigenous Australians, for children and adults. Chronic obstructive pulmonary disease (COPD) and lung cancer are other important adverse lung outcomes largely attributable to smoking. Hospitalisation rates for asthma are disproportionately high among Indigenous Australians, as are rates of absences from work or school because of asthma. This occurs despite rates of possession of asthma action plans among Indigenous patients (24.9%) being similar to those among other Australians (22.5%).1 A possible explanation is the underuse of appropriate medications and devices. Indigenous Australians are less likely to use inhaled preventer medications for asthma. Studies in different regions of Australia, from the Australian Capital Territory to northern Queensland, have confirmed high levels of parent-reported asthma and symptoms such as wheeze in Indigenous children compared with other children, and relative underuse of preventive treatments for asthma.7,8 However, Indigenous adults, especially those older than 55 years, have high overall usage of medications for airway disease.1 Indigenous people with asthma also have a high prevalence of comorbid conditions that may complicate the management of asthma; in particular, comorbid heart disease, cerebrovascular disease and diabetes mellitus are likely to affect asthma management.1 Furthermore, Indigenous Australians report poorer quality of life than other Australians with asthma, suggesting asthma has a more serious impact in the Indigenous community than in the non-Indigenous community.1 These data and other findings described in Asthma in Australia 2008 have important implications for setting priorities and selecting initiatives to promote lung health in Indigenous communities. A start should be made with research into and implementation of more effective and tailored interventions to minimise tobacco use, particularly in settings where high levels of exposure have such deleterious consequences for healthy lung growth, and aggravating effects on respiratory symptoms in children with wheezing illness. Once symptoms are present, further attention is required to ensure that Indigenous Australians receive optimal care for their asthma, particularly to improve inhaler use and maintenance of long-term medication regimens. There are difficulties in accurately diagnosing the cause of airway symptoms such as cough and wheeze in young children. As diagnosis drives the management of asthma, it is important to conduct research into and promote accurate diagnosis of asthma and related conditions, such as chronic suppurative lung disease and bronchiolitis and, in older people, COPD. In remote Indigenous communities, asthma-like symptoms may be the presenting features of these other respiratory conditions in both children and adults.9 Reasons for the high prevalence and morbidity of wheezing illness and asthma, particularly in the very young (younger than 1 year of age) and older Indigenous people, are not known, and require research and clinical attention. The high rate of hospitalisations for asthma, more than twice that of other Australians, suggests there is a need for careful and systematic investigation to develop interventions most likely to benefit the Indigenous community. These are needed to help improve the quality of medical care and preventive strategies for children and adults at risk of asthma exacerbations and hospital admission. Attention to the presence of comorbidities is advocated both clinically and at a health service policy level. This may include health practitioners incorporating asthma management into cardiovascular and diabetes care plans and vice versa. To rectify the disparity in asthma and asthma-related outcomes in the Indigenous population, a complex multilevel framework10 is likely to be required, firstly to understand the reasons for this disparity, and then to develop the most appropriate strategies to overcome it. Opportunities need to be taken to significantly improve the quality of asthma-related care using culturally appropriate programs when they become available. Urgent research into and policy development for the “how to” and “what” of these programs are required. Recent data have shown the efficacy of culture-specific asthma programs compared with “usual care”.11 The Thoracic Society of Australia and New Zealand and the Australasian Sleep Association are about to release a report entitled Respiratory and sleep health in Indigenous Australians,12 and the major respiratory advocacy organisations are planning an Indigenous Lung Health Summit to consider the areas most in need of action and to prioritise new initiatives. The initiatives we have recommended here, if undertaken, would be small but important steps in reducing the health gap between Indigenous and other Australians. Asthma in Australia 2008: major findings1 Prevalence of asthma is higher among Indigenous Australians (16.5%) than it is among other Australians (10.2%). Indigenous Australians are twice as likely to be hospitalised for asthma and three times as likely to die of asthma as other Australians. Among adults, 48.2% of Indigenous Australians with asthma smoke, compared with 23.8% of other Australians with asthma. Indigenous Australians with asthma are three times as likely to have diabetes mellitus as other Australians with asthma.

Christine R Jenkins AM, MD, FRACP · Anne B Chang MPHTM, PhD, FRACP · Leanne M Poulos BMedSc(Hons), MPH(Hons) · Guy B Marks PhD, FRACP, FAFPHM

Guidance for clinicians on how to interpret conflicting evidence from recent studies Patients with advanced chronic obstructive pulmonary disease (COPD) have profound functional impairment and increased mortality.1 Inhaled bronchodilators, including the anticholinergic agents tiotropium bromide and ipratropium bromide, relieve symptoms and improve lung function and quality of life. Tiotropium also reduces COPD exacerbations and hospitalisations.2 Recently, the safety of anticholinergics in patients with COPD has been questioned. Based on a pooled analysis provided by the manufacturers, the United States Food and Drug Administration (FDA) alerted clinicians to an increased risk of stroke with tiotropium.3 Furthermore, a meta-analysis by Singh and colleagues4 and a nested case–control study by Lee and colleagues5 have reported an increased risk of cardiovascular events and death in patients taking inhaled anticholinergics. Two background issues are relevant. First, with once-daily tiotropium, an improvement in lung function is maintained over time, whereas the respiratory effects of ipratropium wear off within 6 hours of each dose. It is therefore likely that their physiological effects outside the respiratory system are different. Also, the potential for overuse is greater with ipratropium, when taken as needed for symptom relief. Second, the presence of COPD is itself associated with an increased risk of cardiovascular death.6 Reasons for this are incompletely understood and controversial. Furthermore, except for long-term oxygen, no medications for treating COPD clearly improve survival. A recent study suggesting improved survival with inhaler treatment was not designed to answer this question and its results require confirmation.7 The meta-analysis by Singh et al (some results of which have recently been revised in a published correction4) studied 17 randomised controlled trials in which cardiovascular events were reported and that involved 13 645 patients in whom either anticholinergics (ipratropium or tiotropium) or control therapies were used for at least 30 days.4 It included data not available in previous meta-analyses. The primary outcome was a composite of cardiovascular death, myocardial infarction or stroke. This was more prevalent in the anticholinergic group, with a relative risk of 1.60 (95% CI, 1.22–2.10) and a risk difference of 0.007 (95% CI, 0.003–0.013). The secondary outcome was all-cause mortality, which was not statistically different between the two groups (the revised value given in the correction to the original study [P = 0.05] approaches, but does not reach, statistical significance). The nested case–control study by Lee et al used national databases to identify 32 130 cases (patients with COPD who died) and 10 times that number of controls (surviving patients with COPD) in the US.5 It showed an association of ipratropium use with both all-cause mortality (odds ratio [OR], 1.11; 95% CI, 1.08–1.15) and cardiovascular death (OR, 1.34; 95% CI, 1.22–1.47). Tiotropium was not examined in this study. Coincidentally, results of the largest and longest-running randomised controlled trial of tiotropium use — the UPLIFT trial — have also recently been published.8 This was a 4-year study investigating the clinical benefit of tiotropium and decline in lung function in 5993 patients with COPD. It found that in patients treated with tiotropium, there was no increase in cardiovascular death or stroke, myocardial infarction was less frequent, and there was a non-significant trend to lower all-cause mortality. These findings are in keeping with a meta-analysis conducted in 20062 and a large population study in 2007,9 but the prospective nature of the UPLIFT study gives it greater validity. How can these very different results be explained? Methodological weaknesses and differences in study design are probably a major factor. First, cardiovascular events and strokes were not defined a priori in any of the studies, raising the possibility of inaccurate data collection. In this setting, all-cause mortality is likely to be more reliable. Second, both the UPLIFT trial and Singh et al reported very high discontinuation rates. A third methodological weakness is the presence of confounders; for example, Lee et al’s study was not able to eliminate or adjust for the crucial confounders of COPD severity and smoking status. Finally, study populations differed. In the UPLIFT study, the rate of ongoing smoking was low and the use of other concurrent COPD medication probably higher than in most of the studies analysed by Singh et al — both these factors may be cardioprotective. How does one act on this conflicting and partially flawed safety data? Regarding tiotropium specifically, no study has shown an increase in all-cause mortality. In the studies performed so far, all-cause mortality is likely to be a more robust outcome than death due to cardiovascular or respiratory causes. Even if the increase in cardiovascular events with tiotropium reported by Singh et al is correct, the size of the effect is small, and the unchanged all-cause mortality suggests that another specific cause of death has decreased. Singh et al did not report respiratory deaths, but some other studies have shown a decrease in these with tiotropium use,9 consistent with its beneficial effects on exacerbations and hospital admissions.8 The safety of ipratropium is less clear. The concerns raised by Singh et al are reinforced by Lee et al’s finding of increased all-cause and cardiovascular mortality with ipratropium use. No guidelines have yet incorporated these recent studies into their recommendations, and the FDA’s response based on its ongoing safety review is pending. In the interim, the use of tiotropium in patients with COPD is likely to be safe and beneficial. If a short-acting bronchodilator is desired, the cardiac risk profile of the patient must be considered because of the uncertain safety of both ipratropium and short-acting β2 agonists.10 Finally, the uncertainty about the safety of anticholinergics needs to be placed in the context of managing patients whose COPD presents major challenges related to their severe respiratory impairment and the increased risk of comorbidities such as lung cancer, depression and osteoporosis, as well as cardiovascular disease.

Mark J Hew MB BS, PhD, FRACP · Piersante Sestini MD · Louis B Irving MB BS, FRACP, FRACGP

A previously well 2-year-old girl presented with acute respiratory distress. After multiple investigations she was diagnosed with spontaneous chylothorax, attributed to strenuous vomiting. To our knowledge, this is the second reported case of spontaneous chylothorax occurring after the neonatal period. (MJA 2009; 190: 262-264) Clinical recordA 2-year-old child presented to her local hospital with acute respiratory distress and a 2-day history of forceful vomiting and diarrhoea. She was afebrile, with no history of cough, coryza, trauma to the chest or spine, weight loss, or lethargy. She was born at term with no perinatal complications, and was growing along the 25th percentile for weight and height. She was not dysmorphic. On examination, the patient’s temperature was 36.8°C, heart rate was 154 beats/min, respiratory rate was 67 breaths/min, and blood pressure was 96/68 mmHg. Her chest was dull to percussion, with poor air entry over the right hemithorax. The remainder of the physical examination was unremarkable. A chest x-ray (Box, A) revealed opacification of the right hemithorax with mediastinal shift to the left. An intercostal catheter (ICC) drained 900 mL of pink-stained milky fluid. Intravenous flucloxacillin and gentamicin therapy were begun for presumed empyema. She was transferred to a tertiary paediatric hospital. On arrival, the patient’s condition was stable, and she had good air entry on the right side of her chest. Pleural fluid loss from the ICC was occurring at 12 mL/kg/h. Pleural fluid analysis revealed a total cell count of 2630 × 106 cells/L with more than 80% lymphocytes, and a triglyceride level of 23.7 mmol/L (reference range [RR], <1.2 mmol/L). Spontaneous chylothorax was diagnosed. Computed tomography of the chest excluded a mediastinal mass. Tests were negative for tumour markers, including α-fetoprotein, β-human chorionic gonadotropin and urinary biogenic amines. A Mantoux test returned a non-reactive result (diameter, 0 mm). Radionuclide lymphoscintigraphy (Box, B) confirmed normal lymphatic anatomy, but also detected rapid drainage of lymph into the right side of the chest. The patient was initially managed with restriction of fat intake and a medium-chain triglyceride (MCT) diet. A 5-day culture of pleural fluid taken at Day 1 showed no growth, and antibiotics were withdrawn. The chyle loss decreased to 5 mL/kg/h after 1 week on the diet. An octreotide infusion at 5 μg/kg/h was added, and pleural fluid loss dropped to 2.5 mL/kg/h within 5 days. Blood tests on Day 8 showed a reduced immunoglobulin G level (1.2 g/L; RR, 3.2–13.4 g/L) and reduced lymphocyte count (0.51 × 109 cells/L; RR, 3.0–9.5 × 109 cells/L). Sulfamethoxazole/trimethoprim therapy was begun as prophylaxis against Pneumocystis jiroveci infection. The patient’s weight dropped from 12.1 kg before admission to 10.5 kg by Day 9. Because of continuing significant chyle loss, malnutrition and the risk of infection, surgery was performed on Day 19. Using video-assisted thoracoscopic surgery (VATS), chyle leaking above the level of the right diaphragm was detected. The region of leakage was oversewn with no attempt to isolate or ligate the thoracic duct. After surgery, there was minimal fluid loss through the ICC, and the ICC was removed 72 hours later. There was no fluid re-accumulation thereafter. A normal diet was re-introduced, and the patient was discharged home 4 days after surgery. DiscussionThis unusual case of chylothorax in a 2-year-old child had none of the previously recognised causes of chylothorax and was attributed to strenuous vomiting. To our knowledge, this is the second reported case of spontaneous chylothorax occurring after the neonatal period. Chylothorax is an uncommon cause of pleural effusion in children. Damage to the thoracic duct causes the pleural space to accumulate chyle — lymphatic fluid enriched with fat (chylomicrons) absorbed by the intestinal cells and transported into the circulation via the thoracic duct.1,2 It is well recognised in newborns as a congenital condition, or secondary to birth trauma. In childhood, it generally occurs after cardiac surgery. Other causes include neck surgery, scoliosis surgery, congenital malformations of the pulmonary or thoracic lymphatic system, and dysmorphic syndromes (Turner, Noonan and Down syndromes).2,3 Chylothorax can occur following blunt trauma to the chest, subclavian vein thrombosis or thoracic duct infiltration. Our patient had no previously recognised causes of chylothorax. Multiple investigations were undertaken to identify a cause such as malformation, infiltration or injury to the thoracic duct. On review of the medical literature (MEDLINE search, 1956–2008), one reported case of spontaneous chylothorax in a child was identified.4 Straining of the thoracic duct due to strenuous vomiting was suggested to have caused the rupture, which we consider to be the likely explanation in our case. Despite appropriate medical management, the high rate of chyle leak necessitated surgical repair. The VATS approach is worth considering early in cases of spontaneous chylothorax when the chyle leak cannot be controlled with maximal medical therapy. The diagnosis of chylothorax was straightforward in our patient. The fluid appeared milky, and the triglyceride level was extremely elevated, as was the lymphocyte count.1 The cause of the chylothorax was more difficult to ascertain. Knowledge of the anatomy of the thoracic lymphatic system is helpful in determining the site of disruption of the thoracic duct associated with right, left or bilateral chylothorax. Rupture of the thoracic duct between the diaphragm and the fifth thoracic vertebra results in accumulation of chyle in the right pleural space. In adults, lymphography has been used to define the anatomy, but is not practical in children due to difficulty cannulating lymphatics; for this reason, we used radionuclide lymphoscintigraphy instead. This showed leakage of chyle above the diaphragm on the right side. Disruption of the thoracic duct at this point was confirmed by thoracoscopy. As both our patient and the previously reported patient4 had right-sided chylothorax, the thoracic duct might be most susceptible to injury from forceful diaphragmatic contraction as it traverses the diaphragm. Hence, forceful vomiting is the most likely explanation in our patient. The management of chylothorax is the same regardless of cause, although no treatments have been subjected to a randomised controlled trial. The initial step is aspiration of pleural fluid for diagnosis. The basic principle of chylothorax management is to reduce the chyle flow in the thoracic duct while waiting for spontaneous healing. This is usually managed by a low-fat and MCT diet or, occasionally, enteric rest with total parenteral nutrition. Spontaneous healing can take weeks. MCT oil consists of triglycerides with saturated fatty acids that are 8–12 carbons in length; these are absorbed directly into the portal venous system, bypassing lymphatic drainage.5 A report on 51 children with chylothorax, aged 0–16 years (median age, 1.7 years), showed that most developed chylothorax secondary to cardiothoracic surgery (46/51), one did so after chest trauma, and four had congenital lymphatic malformation. Complete resolution of the chylothorax was achieved with a 4-week, low-fat and MCT diet in 80% of patients. Patients with congenital chylothorax or chylothorax secondary to obstruction were at higher risk of failure of medical treatment and proceeded to surgical repair.1 Octreotide, a somatostatin analogue, has recently been advocated for use in children with chylothorax that does not respond to conventional therapy.6,7 Somatostatin has a wide range of inhibitory effects on gastrointestinal and endocrine function. Its mechanism of action in treating chylothorax is unclear, but a possibility is reduction of splanchnic vascular tone, eventually leading to a decreased flow of chyle through the thoracic duct.8,9 Nevertheless, the efficacy of octreotide has not been demonstrated in a controlled trial. Although there is no clear dosage regimen, we used a continuous infusion as this was reported most often in the literature.10-13 Reduction in rate of chyle flow within 24–48 hours of treatment initiation has been reported, and the treatment appears to be safe.8,9,14 Some cases of chylothorax cannot be controlled by medical therapy, and surgery is required. There are numerous surgical approaches, including thoracic duct ligation and pleurodesis (surgical or chemical). VATS has been suggested recently, which is much less invasive than an open approach,15 and provides a superior view of the thoracic duct as it enters the thorax. In the previous report of spontaneous chylothorax in a child, ligation of the thoracic duct by VATS was also successful.4 There is no consensus on the timing of surgery, but most authors advocate 3–4 weeks of medical therapy beforehand.1,2,16 In our patient, surgery was undertaken earlier than this as spontaneous healing was considered very unlikely. Earlier surgery could reduce hospitalisation, malnutrition and risk of infection. Surgical correction is definitive and does not lead to lymph stasis because of the rich network of collateral lymphatic vessels. Chylothorax is an unusual cause of pleural effusion in children after the neonatal period and without a history of cardiothoracic surgery. Determining the cause can be challenging, thus knowledge of the thoracic duct anatomy and use of radionuclide lymphoscintigraphy can be helpful. Initial treatment involves drainage and measures to diminish chyle flow. Early surgical treatment is appropriate when medical therapy fails, and, if possible, VATS should be considered. Images used to diagnose a 2-year-old patient with spontaneous chylothorax A: On presentation, a chest x-ray showed complete opacification of the right hemithorax with mediastinal shift to the left. B: One week after admission, a lymphoscintigraphy scan showed rapid leakage of lymphatic fluid into the right hemithorax (arrowhead), suggesting significant rupture of the thoracic duct.

Manuel E Soto-Martinez MD · Vanessa Clifford MB BS, BA(Hons), BMedSc · Tom Clarnette MB BS, MD, FRACS(PaedS) · Sarath Ranganathan MB, MRCP, PhD · R John Massie MB BS, PhD FRACP

Pediatric respiratory medicine. 2nd ed. Lynn M Taussig, Louis I Landau, editors. Philadelphia: Mosby, 2008 (xxiii + 1118 pp). ISBN 978 0323 04048 8. If you are looking for an up-to-date encyclopaedia of paediatric chest disease, then this is it. As expected, this second edition is a substantial improvement over the first. Most of the 75 chapters are short and user friendly. The text is broken up with numerous coloured diagrams, figures, tables, x-ray images and boxed sections highlighting key points, teaching points, pitfalls and controversies. For those who want teaching resources, all images can be captured with ease directly into Powerpoint presentations via electronic access. This edition is slightly less hefty than the previous edition, largely because the references are not included in the book — however, they are accessible electronically, with direct links to MEDLINE abstracts. Most chapters are very heavily referenced (eg, Chapter 3 has over 300 references) and remarkably up to date for a multi-author textbook, including a few references from as late as 2007. Since the editors are from Western Australia and the United States, it is understandable that the majority of the expert authors are also from WA and the US. Nevertheless, all are clearly national and international authorities on their specific topics. Because there are over 130 separate authors, the style and format vary considerably. It is disappointing to see some very user “unfriendly” chapters. For example, in Chapter 35 (bacterial pneumonia) there are over 30 pages of continuous, dense text with only occasional subheadings, and illustrated with a total of only four small x-ray images. To check both content and ease of access, I tested for several of my pet topics — including “plastic bronchitis” and “genetic surfactant deficiency mimicking interstitial lung disease”. Both were readily found, comprehensively covered, and with key references included. At $190.00, the book represents outstanding value for money, given the quality of the content, the outstanding diagrams and figures, and the huge number of electronic references.

Craig M Mellis

A 51-year-old man with no known history of asbestos exposure presented with hydropneumothorax. Soluble mesothelin-related protein testing and combined positron emission tomography and computed tomography were used to diagnose malignant pleural mesothelioma. One year after radical surgery and radiotherapy, there was no clinical recurrence. Clinical recordA 51-year-old man who was born in South Africa presented with shortness of breath on exertion, increasing lethargy and a dry cough. He had never smoked. Medical history included nephritis at the age of 6 years, sinus drainage 20 years earlier, and psoriasis. He had no history of occupational or non-occupational exposure to asbestos, and had not lived near asbestos mines while in South Africa. He had not performed home renovations or building work in South Africa or Australia. After 12 months of national service in the South African Army, he worked in a plastics business in South Africa, selling perspex and acrylic products; he reported no involvement in plastics manufacturing. Since moving to Australia in 1995, he had worked in sales. A chest radiograph showed a 50% right-sided hydropneumothorax, which was confirmed by computed tomography. The pleural effusion was drained, and analysis revealed a lymphocytic exudate with no cytological evidence of malignancy. Thoracoscopic pleurodesis was undertaken, and multiple biopsy specimens were collected. These were analysed by a pathologist with special expertise in lung pathology, who reported proliferating mesothelial cells with no evidence of infiltration, probably a reactive phenomenon. The patient was discharged with a presumptive diagnosis of a reactive effusion. The patient remained well on follow-up. His lung function improved and, despite dyspnoea during exercise, he walked 20 km per week. Serial chest radiographs showed significant pleural thickening but no other abnormality. However, as the cause of the pleural effusion remained undiagnosed, the serum soluble mesothelin-related protein (SMRP) level was measured. At 2.8 nM, it was higher than the reference range (< 2.5 nM),1 suggesting malignant pleural mesothelioma (MPM). The biopsy specimens collected at presentation were reviewed, but no evidence of malignancy was found. A combined positron emission tomography/computed tomography (PET/CT) scan revealed intense tracer uptake (Box, A), suggesting MPM involving the pleura at the right lower lobe and apex, with minimal uptake in the paratracheal and subcarinal lymph nodes. Results of all other investigations (eg, full blood count, liver function tests, and measurement of creatinine and blood glucose levels) were normal. Treatment options were carefully discussed with the patient, including the absence of level 1 evidence-based data that additional surgery would prolong his survival. He elected to undergo additional surgery with an extrapleural pneumonectomy if the diagnosis of MPM was confirmed. Thoracotomy and examination of frozen sections confirmed MPM, and a radical right pleuropneumonectomy was performed. After surgery, the patient underwent adjuvant radiotherapy of the chest wall and drain sites. The patient recovered well and returned to part-time work. Some residual neuropathic pain arising from the thoracotomy scar was controlled with medication. One year after surgery, a repeat PET/CT scan showed no residual tumour or uptake of tracer in the lymph nodes (Box, B), and the SMRP level was within the reference range. He remained well 19 months after surgery. DiscussionUntil recently, MPM was a relatively rare disease, with an incidence of 1–2 cases per million per year in the general population. However, its incidence is increasing, and Australia now has the highest reported incidence in the world.2,3 The increasing incidence is explained by high asbestos use from the 1940s to the 1980s and the long latency period of this tumour.3,4 In Australia, about 90% of men with MPM have a history of occupational asbestos exposure.2 Patients usually present with pleural effusion and breathlessness, but symptoms are non-specific in many cases — particularly in the early stages of disease. MPM is difficult to diagnose in its early stages and, to date, no treatments have been shown to increase life expectancy. However, several new drugs have recently become available, and trials evaluating whether early treatment (including surgery combined with radiotherapy and chemotherapy) improves survival are underway. Ideally, early detection would allow intervention to control or eradicate the neoplasm. There is also considerable interest in the use of biomarkers to facilitate early detection of several malignancies, including MPM. SMRP is increasingly being used to detect MPM after clinical presentation5,6 and has recently been approved in the United States for diagnosis and monitoring of MPM. Our patient highlights several issues in the investigation and management of pleural effusions. First, hydropneumothorax is uncommon in middle-aged men, and malignancy should always be suspected. In addition, MPM may not always be related to asbestos exposure, hence should be considered even in its absence. Lastly, modern methods of cancer detection — including SMRP testing and PET/CT scanning — may enable early detection of MPM and improve survival. Hydropneumothorax is a consequence of a persistent pneumothorax, but is rare as a presenting feature of malignancy, particularly MPM. A literature search (using MEDLINE) for spontaneous hydropneumothorax in MPM identified few case reports in English. Most reported cases of hydropneumothorax were secondary to Boerhaave syndrome (full thickness rupture of the oesophageal wall, classically due to excessive food or alcohol consumption) or granulomatous diseases such as tuberculosis and sarcoidosis. Pleural effusions are commonly seen in clinical practice. However, despite advances in cytological techniques and application of Light’s criteria for distinguishing between exudative and transudative pleural effusions,7 diagnosis of pleural malignancy is often delayed. Closed needle biopsy is seldom used in Australia, as its sensitivity in malignant pleural effusions (particularly MPM) is low. For patients with a negative result on cytological analysis of pleural fluid, a repeat closed needle biopsy returns a positive result in only 7%8 and could seed tumour along the biopsy track. To improve sensitivity, the pleural biopsy specimen needs to be large, hence video-assisted thoracoscopic surgery (VATS) and open pleural biopsies are now the procedures of choice in suspected MPM. They also have the advantage of enabling concurrent pleurodesis. With large tissue samples, open biopsy has a sensitivity of 97% and specificity of 56% for identifying epithelial MPM.9 VATS is associated with some risks, but overall these are low. The overall incidence of postoperative complications is 10.9%, including prolonged air leak (6.7%) and recurrent pleural effusion (0.7%).10 Early pleurodesis has been shown to significantly improve quality of life in patients with MPM, and is currently recommended in the British Thoracic Society’s guidelines on the management of malignant mesothelioma.11 Mesothelin is a 40 kDa protein that is important in cell adhesion. It is a differentiation antigen, and is present on normal mesothelial cells of the pleura, peritoneum and pericardium.5 SMRPs are thought to be either cleaved peptide fragments of mesothelin, or abnormal variants of mesothelin that are unable to bind to membranes and are overexpressed in several human tumours, including MPM. Several studies have examined SMRP testing for diagnosis and monitoring of MPM.5,6,12 A recent study showed that blood SMRP level had a specificity of 95% and sensitivity of 83% in identifying patients with MPM.6 However, an elevated SMRP level can also occur in metastatic disease, especially ovarian cancer, pancreatic cancer and adenocarcinomas, and its use for screening in the absence of symptoms is unproven.12 PET/CT scanning is a new technique that has been shown to be useful in patients with MPM for predicting survival and evaluating response to chemotherapy.13,14 However, few data are available on its use as a diagnostic tool. In 28 patients with suspected MPM, PET/CT imaging was compared with VATS and surgical biopsies. Fluorodeoxyglucose-PET imaging was sensitive (91%) and highly specific for malignancy (100%), although the activity of some epithelial MPMs was close to the threshold of abnormality.15 MPM may not have been suspected in our patient without SMRP testing. His relatively young age and excellent fitness allowed him to opt for radical surgery and radiotherapy, which, although not proven in controlled studies, offered him hope of long-term survival. Further follow-up is needed to confirm the outcome. Improving survival in MPM is currently being evaluated in an international collaborative controlled study, the Mesothelioma and Radical Surgery trial, which includes a trial centre at St Vincent’s Hospital in Sydney. New biomarkers such as SMRP and techniques such as PET/CT may enable selection of patients for surgery in the early stages of disease and offer hope of cure in MPM. Positron emission tomography/computed tomography images of a 51-year-old man before and after treatment of mesothelioma A: Before treatment, increased tracer uptake is visible in the apex of the right lower lobe, extending into the oblique and horizontal fissures (arrow). B: One year after radical surgery and radiotherapy, no abnormal tracer uptake is visible.

Emma L O’Lone · Eun-Kee Park · Alessandra Sandrini · Gerald B Fogarty · Deborah H Yates

A 69-year-old man presented with a 3-week history of intermittent interscapular dull ache, complicated by small volume haemoptysis. Contrast-enhanced computed tomography of the thorax showed no evidence of pulmonary embolism, but demonstrated a well circumscribed lesion, 10 mm in diameter, in the right bronchial tree (Figure, A), leading to suspicion of a neoplasm. Using flexible bronchoscopy, we successfully removed a whole macadamia nut (Figure, B) that was obstructing the bronchus intermedius at the level of the right middle lobe orifice. Additional history obtained after the procedure revealed an aspiration event 3 weeks before admission. The patient reported having tripped while walking upstairs and concurrently eating a handful of macadamia nuts, resulting in a coughing spell that lasted the better part of the night.

Stefan Buchholz · George R Rudan

Chronic neonatal lung disease (CNLD) is defined as a supplemental oxygen requirement beyond 36 weeks’ postmenstrual age, with more severely affected infants requiring oxygen beyond a full-term-equivalent age. Low-flow supplemental oxygen facilitates discharge from hospital of infants with CNLD who develop hypoxia in air. There is a lack of data on the most appropriate minimum mean target oxygen saturation (Spo2) level. Reflecting a variety of clinical practices and infant comorbidities (frequency of oxygen desaturation, presence of pulmonary hypertension, retinopathy of prematurity, and adequacy of growth), the minimum mean target range for Spo2 during overnight oximetry should be 93%–95%. The effect of supplemental oxygen on carbon dioxide retention should be considered before deciding on an oxygen flow. Most infants with CNLD are not ready for discharge until their supplemental oxygen requirement is ≤ 0.5 litres per minute delivered through a nasal cannula. The safety of short-term disconnection from supplemental oxygen should be assessed before discharge. Assessment of oxygenation during sleep with continuous overnight oximetry or polysomnography is recommended when weaning infants from supplemental oxygen. Discontinuation of oxygen therapy is based on clinical assessments and documentation of adequate oxygenation in room air. There is limited objective evidence on which to base recommendations.

Dominic A Fitzgerald MB BS, PhD, FRACP · R John H Massie MB BS, PhD, FRACP · Gillian M Nixon MB ChB, MD, FRACP · Adam Jaffe MD, FRCPCH, FRACP · Andrew Wilson MB BS, PhD, FRACP · Louis I Landau MD, FRACP · Jacob Twiss MB ChB, FRACP · Greg Smith MB ChB, FRACP · Claire Wainwright MB BS, MD, FRACP · Margaret Harris MB ChB, FRACP

A 50-year-old man presented with cough, wheeze, intermittent haemoptysis and progressive dyspnoea. He had no relevant past history. On examination, he was hypoxic but haemodynamically stable. Results of routine blood tests, including full blood count, urea and electrolyte levels, and erythrocyte sedimentation rate, were within normal ranges. Pulmonary function tests confirmed severe airway obstruction and diffusion impairment. A chest x-ray revealed multifocal areas of nodularity and consolidation in both lungs (Figure, A). A computed tomography scan showed thickening and calcification of the bronchial walls with multiple cavities and nodules throughout both lungs (Figure, B). A virtual bronchoscopy revealed irregular narrowing of the right main bronchus (Figure, C; arrows), and a bronchial biopsy confirmed pulmonary amyloidosis (light-chain type). Pulmonary amyloidosis occurs in three forms: tracheobronchial (the most common, which is limited to central airways and which this case exemplifies), diffuse and adenopathy-associated.1 Nearly all cases are of the light-chain type.2 Treatment is difficult and controversial; repeated bronchoscopic resection is conventional,3 but the role of external beam radiotherapy in tracheobronchial amyloidosis has also been described.4

Kshitij Mankad · Michael J Darby

To the Editor: I have read every issue of the Journal since graduating in 1953. In my opinion, one of the best articles I’ve seen is Dawn DeWitt’s story, “I went to work with a ‘cold’ ...”.1 Dr DeWitt’s dilemma mirrors that of the average doctor precisely. Her “solution” gives us a good dose of commonsense that we seldom hear. In my time as a general practitioner, I have given thousands of doses of influenza vaccine; but I have never had the flu or pneumonia shot myself (nor has my wife — a registered nurse). I took 2 weeks off duty in 1971 with a “cold”, when I simply flaked out on the floor. A corneal transplant and transurethral resection of the prostate were done while “on vacation”. Luckily, I no longer have the dilemma of whether or not to go to work when I am sicker than my patients, but I will have the flu shot this week anyway. Thanks Dawn.

John F Knight AM

To the Editor: We note with interest the recent commentary by Cretikos et al on the predictive value of a high respiratory rate for adverse outcomes.1 We wish to provide empirical evidence from Australian patients with pneumonia in support of their view that simple clinical parameters are good predictors of adverse outcomes. We examined data from a prospective cohort of consecutive patients presenting to the Royal Melbourne Hospital Emergency Department with radiologically confirmed, community-acquired pneumonia between 2003 and 2006.2 In an earlier study of a subset of these patients,3 we found that hypotension and tachypnoea were strongly associated with death and/or the need for respiratory/inotropic support (odds ratios, 8.0 and 3.5, respectively). In the full cohort (n = 740), we examined factors associated with either admission to the intensive care unit (ICU) or mortality (106 patients were in one of these two categories). Respiratory rate was documented in 712 patients (96%). A combination of tachypnoea (≥ 24 breaths/min) and/or hypotension (systolic blood pressure ≤ 90 mmHg) had similar predictive value for the risk of ICU admission and/or death to the recommended system of risk stratification, the Pneumonia Severity Index (PSI)4 (Box). The combination of respiratory rate and systolic blood pressure performed better than either sign alone in ruling out at-risk patients if both were normal (ie, a high negative predictive value), although almost a quarter of patients with either clinical sign had adverse outcomes. The PSI is based on 20 individual clinical and laboratory parameters, and evidence suggests that it is poorly documented in patients’ records.5 Our data relate to patients with community-acquired pneumonia from a single centre and thus have limited statistical power for making comparisons. However, they suggest that these two routinely measured clinical parameters can be used to stratify patients at risk of adverse outcomes at the time of presentation. We support efforts to incorporate simple clinical indicators into systems that can identify seriously unwell patients early in the course of illness. Summary statistics for tachypnoea, hypotension and PSI class as predictors of ICU admission and/or death from community-acquired pneumonia* Number of patients Sensitivity Specificity PPV NPV RR ≥ 24 breaths/min 712 82% (73%–89%) 48% (44%–52%) 22% (18%–26%) 94% (91%–96%) RR ≥ 27 breaths/min 712 70% (60%–78%) 67% (63%–71%) 27% (22%–32%) 93% (90%–95%) RR ≥ 24 breaths/min and/or systolic BP ≤ 90 mmHg 713 93% (86%–97%) 45% (41%–49%) 23% (19%–27%) 97% (94%–99%) PSI class IV or V† 740 90% (82%–95%) 49% (45%–53%) 22% (19%–27%) 97% (94%–98%) BP = blood pressure. ICU = intensive care unit. NPV = negative predictive value. PPV = positive predictive value. PSI = Pneumonia Severity Index. RR = respiratory rate. * Figures in parentheses represent 95% CIs calculated using the exact binomial distribution. † Severe pneumonia.

Allen C Cheng · James F Black · Kirsty L Buising

To the Editor: Cretikos et al make a strong case for routinely recording patients’ respiratory rate (RR) in acute wards.1 In a prospective study designed to evaluate the prognostic value of RR in acutely hospitalised patients aged over 75 years, we analysed data from all admissions to a single 14-bed acute-care geriatric unit between 15 May and 15 November 2007. Clinical data were recorded on admission and blood tests were performed the next morning. The Charlson score was used to assess comorbidity.2 Features of the 195 admissions during the study period (13 patients were admitted twice) are reported in the Box. The main reasons for admission were falls (15%), left ventricular failure (11%), pneumonia (11%), cancer complications (9%), pyelonephritis (7%) and stroke (5%). Twenty-nine patients died in hospital, including six from cancer complications, five from pneumonia, four from pyelonephritis and four from left ventricular failure. Based on univariate logistic regression analysis at the 0.05 significance level, the following variables were predictive of death during hospitalisation: being male (odds ratio [OR], 2.42, Wald test P = 0.03); increased Charlson score (OR, 1.50 for each additional point between 3 and 13; P < 0.001); decreased systolic blood pressure (OR, 6.71 for systolic blood pressure < 100 mmHg; P =0.004); abnormal heart rate (< 60 beats/min or > 100 beats/min) (OR, 3.63; P = 0.003); increased RR (OR, 1.81 for each additional 5 breaths/min between 14 and 44; P < 0.001); abnormal blood sodium level (< 137 mmol/L or > 143 mmol/L) (OR, 2.82; P = 0.01) and raised C-reactive protein level (OR, 2.67 for C-reactive protein level > 45 mg/L; P = 0.02). After multivariate logistic regression analysis with stepwise backward elimination, the only remaining factors that were significant predictors of death during hospitalisation were Charlson score (OR, 1.53 for each additional point between 3 and 13; P < 0.001) and RR (OR, 1.83 for each additional 5 breaths/min between 14 and 44 breaths/min; P < 0.001). RR on admission was associated with an area under the ROC (receiver operating characteristic) curve of 0.73 (95% CI, 0.64–0.82) for the prediction of death during hospitalisation. An RR of ≥ 20 breaths/min had a sensitivity of 97% (95% CI, 80%–100%), a specificity of 28% (95% CI, 21%–35%) and a negative likelihood ratio of 0.12 (95% CI, 0.02–0.82) for prediction of death during hospitalisation. Only one patient (admitted for stroke) with an RR of < 20 breaths/min at admission died in hospital. Higher RR cut-off values increased specificity but reduced sensitivity. For instance, an RR of ≥ 30 breaths/min had a specificity of 90% (95% CI, 84%–94%), but a sensitivity of 38% (95% CI, 21%–58%), leading to a positive likelihood ratio of 3.68 (95% CI, 1.93–7.04) for prediction of death during hospitalisation. In conclusion, besides comorbidity (Charlson score), RR was the most useful predictor of death in acutely hospitalised patients aged over 75 years. Our results extend the evidence base promoting regular documentation of RR in acute-care departments.1 Features of the 195 admissions to the acute-care geriatric unit between May and November 2007 Age (years) 85 (81–91)* Women 123 (63%)† Charlson score 6 (5–8)* Dementia 88 (45%)† Body temperature (°C) 37.0 (36.8–37.5)* Systolic blood pressure (mmHg) 136 (120–152)* Heart rate (beats/min) 80 (70–92)* Respiratory rate (breaths/min) 20 (20–25)* Serum sodium level (mmol/L) 140 (137–143)* Serum creatinine level (μmol/L) 91 (76–120)* Serum protein level (g/L) 65 (59–70)* Serum C-reactive protein level (mg/L) 36 (12–108)* Blood haemoglobin level (g/L) 115 (100–125)* White blood cell count (× 109/L) 8.3 (6.3–11.5)* * Median (interquartile range). † Number of admissions (%).

Olivier Steichen · Gilles Grateau · Eric Bouvard

To the Editor: The concept that respiratory rate (RR) is a key vital sign is hardly new,1 but it is being re-emphasised.2,3 The recent article by Cretikos et al3 highlights the diagnostic relevance of a raised RR for serious adverse events. The authors make sensible recommendations regarding the need to educate hospital staff about the importance of measuring patients’ RR. However, they do not specify how this rate should be measured. Indeed, most textbooks of general medicine, and even respiratory medicine, fail to provide guidance on this or to define an abnormal rate. A widely used book on clinical examination4 suggests measuring RR while feeling the pulse, and quotes a normal (adult) resting range of 16–25 breaths/min, but no source for this information is provided. There are few reports of true normal resting RR measurements obtained by covert observation. Respiratory physiologists have long known that RR commonly increases and becomes more regular as soon as a subject becomes aware of the measurement. This is especially so if a mouthpiece is in place. Rates as low as 8 breaths/min may be seen at rest, and the normal adult range quoted by physiologists is 11–14 breaths/min.5 Bradypnoea is usually defined as a rate less than 8 breaths/min and tachypnoea as a rate greater than 18–20 breaths/min. There is no gold standard method for accurate measurement of RR in clinical practice. Of course, when patients are being monitored, particularly with a nasal cannula, it should be easy to obtain the rate. Oximetry is not a surrogate measure of RR, although it is often easier to record. Inductance bands around the chest provide a simple non-invasive way to measure RR. In addition to the absolute rate, an irregular and erratic rate is of concern. In settings in which formal monitoring is not being conducted, RR is the one “vital” sign that must be assessed when the patient is resting quietly, unaware of its measurement, and not conversing with staff. Duplicate measurements should be made over an interval of at least 1 minute. An RR of over 20 breaths/min, particularly if irregular, is noteworthy. Tachypnoea is intimately linked with the sensation of breathlessness, and hence the patient’s respiratory sensations should be assessed. In some patients with a normal RR at rest, marked tachypnoea may be precipitated by mild exertion, such as walking a few paces.

Simon C Gandevia · David K McKenzie

Consensus recommendations for managing bronchiectasis in Indigenous children and adults living in rural and remote regions were developed during a multidisciplinary workshop and were based on available systematic reviews. Successful diagnosis, management and prevention of bronchiectasis in Indigenous Australians requires access to comprehensive health care services, as well as improved housing, education and employment and reduced poverty levels. Diagnosis of bronchiectasis requires a chest high-resolution computed tomography scan. Children who have bronchiectasis symptoms but non-diagnostic scans are described as having chronic suppurative lung disease (CSLD), rather than bronchiectasis. Untreated CSLD may progress to bronchiectasis. Chronic wet cough (> 4 weeks) or recurrent wet cough (> 2 episodes/year) are important but often under-reported symptoms. Bronchiectasis is suspected when chronic cough is excessively prolonged (> 12 weeks) or if a chest radiographic abnormality persists despite appropriate therapy. Intensive treatment aims to improve symptom control and quality of life while preserving lung function and reducing acute exacerbation frequency. Antibiotics should be prescribed for acute infective episodes according to culture results of respiratory secretions, local susceptibility patterns and clinical severity. Patients not responding promptly to oral antibiotics should be hospitalised for more intensive treatment. Ongoing care requires regular primary health care and specialist review, including monitoring for complications and comorbidities. Corticosteroids, bronchodilators and mucoactive agents may be used in individual cases, but routine use is not recommended. Physiotherapy and exercise should be encouraged, nutrition optimised, environmental pollutants (including tobacco smoke) avoided, and immunisations maintained.

Anne B Chang MPHTM, PhD, FRACP · Keith Grimwood MB ChB, FRACP, MD · Graeme Maguire MB BS, FRACP · Paul T King MB BS, FRACP, PhD · Peter S Morris MB BS, FRACP, PhD · Paul J Torzillo MB BS, FRACP

Objective: To determine whether a 5-day course of oral prednisolone is superior to a 3-day course in reducing the 2-week morbidity of children with asthma exacerbations who are not hospitalised.Design, setting and participants: Double-blind randomised controlled trial of asthma outcomes following a 5-day course of oral prednisolone (1 mg/kg) compared with a 3-day course of prednisolone plus placebo for 2 days. Participants were children aged 2–15 years who presented to the emergency departments of three Queensland hospitals between March 2004 and February 2007 with an acute exacerbation of asthma, but were not hospitalised. Sample size was defined a priori for a study power of 90%.Main outcome measures: Difference in proportion of children who were symptom-free at Day 7, as measured by intention-to-treat (ITT) and per-protocol analysis; quality of life (QOL) on Days 7 and 14.Results: 201 children were enrolled, and there was an 82% completion rate. There was no difference between groups in the proportion of children who were symptom-free (observed difference, 0.04 [95% CI, − 0.09 to 0.18] by ITT analysis; 0.04 [95% CI, − 0.17 to 0.09] by per-protocol analysis). There was also no difference between groups in QOL (P = 0.42). The difference between groups for the primary outcome was within the equivalence range calculated post priori.Conclusion: A 5-day course of oral prednisolone confers no advantage over a 3-day course for children with asthma exacerbations who are not hospitalised.Trial registration: Australian Clinical Trials Registry ACTRN012605000305628.

Anne B Chang MPHTM, PhD, FRACP · Ronald Clark PhD, FRACP · Theo P Sloots BSc, PhD · David G Stone FRACP · Helen L Petsky BN · Donna Thearle BN · Anita A Champion BPharm · Coralie Wheeler BN · Jason P Acworth FRACP

Two children with advanced lung disease underwent successful cadaveric bilateral lobar lung transplantation, using lungs “cut down” from deceased adult donors — the first reported use of the technique in Australia. This approach, while it cannot address the lack of donor organs, may enable us to redress any size bias limiting paediatric lung transplantation. Clinical recordsPatient 1A previously healthy 9-year-old girl presented in early 2007 with an upper respiratory tract infection that progressed over 10 days to respiratory failure, requiring intubation and ventilation with high inspiratory pressures. Subsequent tracheal aspirates were positive for Mycoplasma (by polymerase chain reaction), with consistent serological results (antibody titres, 1 : 640). Computed tomography of the chest demonstrated widespread bronchiectasis (Box 1, A). Although she was extubated 6 weeks after initial presentation, she remained in hypercapnic respiratory failure (Pco2, 80 mmHg), requiring continuous oxygen supplementation (5 L/min) and bilevel non-invasive positive-pressure ventilation (BiPAP). She was listed for lung transplantation in May 2007, but, given the severity of her lung disease and in the absence of appropriately matched donor organs, the transplant team gave early consideration to cadaveric bilateral lobar transplantation using an adult “oversized” donor. This was performed in August 2007. Patient 2A 13-year-old girl with cystic fibrosis was referred for consideration of lung transplantation. She had been diagnosed with cystic fibrosis at birth (Δ508 homozygous, without liver, sinus or diabetic sequelae), and over the preceding 2 years developed progressive bronchiectasis (Box 1, B), necessitating supplemental oxygen and initiation of nocturnal BiPAP. She was initially listed for either lung transplantation or heart–lung transplantation; however, after 9 months of progressive respiratory failure (Pco2 increased to 46 mmHg; forced expiratory flow in 1 second [FEV1], 16%; forced vital capacity [FVC], 28% predicted), the transplant team considered cadaveric bilateral lobar transplantation, which was performed in September 2007. Surgical procedure and clinical courseBoth children underwent cadaveric bilateral lobar transplantation as described by Starnes and colleagues1 for living-related lung transplantation. Briefly, the donor right lower lobe was resected, and the right upper and middle lobes were implanted, the anastomosis being performed at the right main bronchus. On the left, the inferior pulmonary vein, interlobar artery distal to its lingular branch, and bronchus were transected, and the lower lobe removed. Size mismatch was compensated for by seating the donor bronchus inside the recipient bronchus, while pulmonary vessel mismatch was taken up in the suture lines. Neither patient required cardiopulmonary bypass, and resected lobes were not used further. Following surgery, both children were established on an internationally standardised immunosuppression regime, comprising prednisolone, tacrolimus and mycophenolate mofetil.2 Both patients made a good postoperative recovery, with short intensive care unit stays. Patient 1 required a longer inpatient stay for treatment of pneumonia. Neither patient developed allograft rejection, and lung function gradually improved (Box 2). Both patients were discharged to their respective tertiary hospitals for continuing follow-up. Both patients were well and without complication at follow-up 10 and 9 months postoperatively, respectively. DiscussionTo our knowledge, these are the first reported cases of cadaveric bilateral lobar transplantation in Australia. They demonstrate its efficacy as a means of reducing waiting-list mortality for paediatric lung transplantation recipients. Lung transplantation is now an established treatment for patients with severe end-stage lung or pulmonary vascular disease. Despite attempts to increase organ donation worldwide, the number of patients requiring lung transplantation far exceeds the availability of donor lungs. In Australia, this is of particular concern for children awaiting appropriate size-matched donor organs.3 Review of the Australian and New Zealand Organ Donation Registry between 2002 and 2006 revealed that very few lungs are retrieved from paediatric donors younger than 14 years (26/497 lung donors).4 The number of children with severe lung disease warranting consideration of lung transplantation, both globally and in Australia, is, fortunately, very small. The most recent data from the International Society for Heart and Lung Transplantation show that only 65 paediatric lung transplantations were performed worldwide in 2005.2 However, of concern is that waiting-list mortality is greater for children than for adults — a worrying trend as fewer paediatric lung transplantations have been performed per annum, while adult lung transplantation numbers have increased.5 In Australia during 2006, 181 donor lungs were offered for lung transplantation, with only seven paediatric donors contributing, all of whom were aged 6–14 years (Ross Pettersson, Australian and New Zealand Cardiothoracic Organ Transplant Registry and Heart Transplant Data Manager, St Vincent’s Hospital, Sydney, NSW, personal communication). Despite an active policy of utilising “extended” donor organs (eg, from older donors or donors with previous cancer, smoking or aspiration history) wherever possible, only 30%–50% of available lungs are actually suitable for transplantation,6 further diminishing the number of available donor lungs, which is low by international standards.7 In the absence of appropriately size-matched organs, children from our institution have died while on the waiting list (2/9 listed in 2000–2007); after reviewing the 2007 donor referrals, it became apparent that the children described here would most likely have died while waiting. Minimising paediatric waiting-list mortality requires consideration of non-traditional donor sources, such as live donors, who have been used in small numbers in the United States and Japan.8 The technique involves a bilateral lobar transplantation, typically taking one lobe from each of two larger, usually related, adult donors. Outcomes for living-donor bilateral lobar transplantation are similar to cadaveric lung transplantation, but there are significant ethical and technical issues with such an approach, and a potential 300% mortality rate. The number of these procedures being performed is declining.5 To our knowledge, no centre presently offers this service in Australia. In adults, cadaveric lungs have been cut down to facilitate lung transplantation where size mismatch between donor and recipient could prevent transplant.9 Typically, this involves non-anatomical “lung shaving” or anatomical lobar resection. Rarely is this a bilateral extensive procedure, given the potential complications, including persistent air leaks, airway stenoses and stump dehiscence. Lobar transplantation is not specific to lung transplantation and has become common practice in liver transplantation; lessons may be learned from these experiences.10 Paediatric lobar transplantation has not been widely performed outside of the living-related scenario, but despite the additional surgical complexity, outcomes have proven comparable to cadaveric lung transplantation.8,9 Starnes and colleagues’ work suggests our two patients can be expected to ultimately achieve near-normal lung function,11 and their total lung capacity will increase as they grow.12 Cutting down cadaveric adult donor lungs for use in paediatric recipients raises ethical and practical issues about removing donor lungs from an already insufficient adult pool. Should lungs that might “perfectly” match an adult be cut down for a paediatric patient? Is a child more deserving than an adult? Our approach to reducing waiting-list mortality is to perform transplantation on recipients with the most severe lung disease at the first opportunity, and both these children satisfied that criterion. In conclusion, our cases illustrate the difficulty experienced by many centres in acquiring an adequate number of donor lungs to service the needs of the paediatric lung transplantation waiting list. Using cut-down adult donor lungs had a good outcome in both our patients. Such an approach is likely to expand the donor pool available for children needing lung transplantation, thereby reducing the high waiting-list mortality experienced by this age group. 1 Computed tomography scans of the two patients’ lungs before transplantation A: Patient 1 had cysts and lung destruction after Mycoplasma infection (arrows). B: Patient 2 had severe cystic fibrosis-related bronchiectasis (arrows). 2 Clinical course after cadaveric bilateral lobar transplantation in two children Patient ICU days Hospital days Respiratory infection in first 3 months Biopsy (ISHLT grade) 30 days 90 days 180 days FEV1 (% pred) FVC (% pred) FEV1 (% pred) FVC (% pred) FEV1 (% pred) FVC (% pred) 1 2 27 Pseudomonas, Staphylococcus A0 0.89 (40%) 0.90 (37%) 1.02 (46%) 1.33 (54%) 1.26 (55%) 1.81 (78%) 2 2 11 Staphylococcus A0 1.12 (72%) 1.27 (71%) 1.17 (75%) 1.45 (81%) 1.11 (63%) 1.66 (94%) ICU = intensive care unit. ISHLT = International Society for Heart and Lung Transplantation. FEV1 = forced expiratory flow in 1 second. pred = predicted. FVC = forced vital capacity.

Dominic T Keating MD, MRCPI · Glen P Westall FRACP, PhD · Silvana F Marasco MS, FRACS · Jacquie H Burton DipAppSci(Nursing), BN, GradDipPaed · Mark R Buckland MB BS, FANZCA · Colin F Robertson MSc(Epi), MD, FRACP · Trevor J Williams MB BS, FRACP, MD · Gregory I Snell MB BS, FRACP, MD

Objectives: To use community pharmacy medication records to identify patients whose asthma may not be well managed and then implement and evaluate a multidisciplinary educational intervention to improve asthma management.Design, setting and participants: We used a multisite controlled study design. Forty-two pharmacies throughout Tasmania ran a software application that “data-mined” medication records, generating a list of patients who had received three or more canisters of inhaled short-acting β2-agonists in the preceding 6 months. The patients identified were allocated to an intervention or control group. Pre-intervention data were collected for the period May to November 2006 and post-intervention data for the period December 2006 to May 2007.Intervention: Intervention patients were contacted by the community pharmacist via mail, and were sent educational material and a letter encouraging them to see their general practitioner for an asthma management review. Pharmacists were blinded to the control patients’ identities until the end of the post-intervention period.Main outcome measure: Dispensing ratio of preventer medication (inhaled corticosteroids [ICSs]) to reliever medication (inhaled short-acting β2-agonists).Results: Thirty-five pharmacies completed the study, providing 702 intervention and 849 control patients. The intervention resulted in a threefold increase in the preventer-to-reliever ratio in the intervention group compared with the control group (P < 0.01) and a higher proportion of patients in the intervention group using ICS therapy than in the control group (P < 0.01).Conclusions: Community pharmacy medication records can be effectively used to identify patients with suboptimal asthma management, who can then be referred to their GP for review. The intervention should be trialled on a national scale to determine the effects on clinical, social, emotional and economic outcomes for people in the Australian community, with a longer follow-up to determine sustainability of the improvements noted.

Bonnie J Bereznicki BPharm(Hons) · Gregory M Peterson BPharm(Hons), PhD, MBA · Shane L Jackson BPharm(Hons), PhD · E Haydn Walters DM, FRCP, FRACP · Kimbra D Fitzmaurice BPharm · Peter R Gee BPharm(Hons)

To the Editor: My attention was drawn to the Snapshot of an apical lung hernia published in the Journal last year.1 Persons with emphysematous hypertrophic lungs are often found to have clinically discernible supraclavicular swellings (Box). The finding of these swellings is a surprisingly common sign that is little remarked upon in clinical descriptions. These swellings are the bullous expansions of the apices of the lungs. Supraclavicular swelling in patients with emphysematous hypertrophic lungs A woman (A) and a man (B) with visible supraclavicular swellings.

George R Crowe

To the Editor: Parasitic infections of the respiratory tract are rare causes of haemoptysis in Western communities, and are often clinically indistinguishable from pulmonary tuberculosis.1 We report a case of a 19-year-old Burmese factory worker who presented to our outpatients department with a history of haemoptysis for 4 years. He was born in Myanmar (Burma) and lived in Malaysia for 2 years before migrating to Australia. He had no past history of significance, and denied having any contacts with tuberculosis. He was a non-smoker and was taking no regular medications. His haemoptysis started in Myanmar, but increased in frequency after he migrated to Australia. He coughed up both fresh and old blood mixed with some sputum, and complained of weight loss of 6 kg, intermittent chest pain and headaches. He had no fever, night sweats, shortness of breath, dysuria, or gastrointestinal or neurological symptoms. He appeared well, and findings of a general physical examination were unremarkable. Chest x-rays from before this presentation, which included migrant screening x-rays, were normal, but his most recent chest x-ray revealed a round lesion posteriorly. A computed tomography scan organised by the patient’s general practitioner showed an area of consolidation at the base of his left lung, not typical of tuberculosis which was the primary suspect in this case. Blood tests showed a raised white cell count of 14. 5 × 109/L (reference range [RR], 4.0–11.0 × 109/L) with a neutrophil count of 11.33 × 109/L (RR, 2.0–7.5 × 109/L) and an eosinophil count of 0.51 × 109/L (RR, 0.04–0.4 × 109/L), an erythrocyte sedimentation rate of 44 mm/h (RR, 1–10 mm/h) and C-reactive protein level of 20 mg/mL (RR, < 5 mg/mL). The result of a QuantiFERON-TB Gold test for tuberculosis was negative. Attempts to obtain sputum samples were unsuccessful, and the patient underwent a bronchoscopy that revealed white milky mucous secretions within the lower lobe of the left lung, where a bronchial lavage was performed. Microscopy of bronchial washings revealed the presence of parasitic structures consistent with Paragonimus westermani (Box 1). Therapy with praziquantel was initiated at a dose of 1200 mg orally, twice daily for 2 days. His condition improved quickly and, on review in the outpatients department 4 weeks later, he had no clinically or radiologically evident recurrence of infection. Paragonimiasis is a common endemic infection in South-East and East Asia, particularly in India, China, Japan and the Philippines. Humans acquire the infection by eating raw or undercooked crayfish and freshwater crab, in which the metacercariae encyst. Once the organisms reach the duodenum, they excyst, penetrate the gut wall, and travel through the peritoneal cavity as immature flukes. They then migrate through the diaphragm and pleural space to reach the lungs, where they form adult worms.2 Early after infection, pleuritic chest pain may develop, in some cases accompanied by a pneumothorax or pleural effusion. Later, with invasion of the lung parenchyma, low-grade fever, cough or streaky haemoptysis may develop. Once the adult worms inhabit the lungs, usually after 2 months, recurrent haemoptysis becomes the cardinal symptom.3 Pulmonary paragonimiasis is most commonly misdiagnosed as tuberculosis, owing to many similarities in the clinical pictures of the two infections (Box 2).4,5 In a patient from a known endemic area, differential diagnoses should be considered and every effort should be made to obtain sputum samples or bronchial washings to distinguish between these two conditions. Serological tests are available if sputum or washings cannot be obtained. 1 Paragonimus westermani eggs detected on microscopy of bronchial washings 2 Similarities in the clinical pictures of paragonimiasis and tuberculosis Both are endemic in the same areas Neither responds to standard antibiotics Both produce chronic symptoms Symptoms of both include: Haemoptysis Weight loss Pleural effusion Chest pain

Murad G Ibrahim · Richard Bunter · Stanley Rajasooriar · Francis Thien

A 79-year-old man presented with painless dysphagia. Results of an oesophagogastroduodenoscopy were unremarkable. A dynamic videofluoroscopic examination was diagnostic, revealing hypertrophic cervical osteophytes indenting the hypopharynx and oesophagus. The osteophytes were also seen on a lateral cervical spine radiograph (Box). The dysphagia responded to dietary modification. Although cervical osteophytes are seen in 20%–30% of the geriatric population, they are an unusual (and treatable) cause of dysphagia. Dysphagia occurs because of mechanical blockage as well as inflammation of the peripharyngeal and peri-oesophageal tissue. As enlarged cervical osteophytes may be an incidental finding, it is important to exclude other potential causes, such as neoplasm.1,2 Lateral radiograph of the cervical spine showing multiple enlarged anterior and bridging cervical osteophytes, with the most prominent bridging osteophyte between the C4 and C5 vertebrae (arrow).

Shoaib Faruqi · Muthu Thirumaran · Parry Blaxill