Respiratory disease

Objective: To estimate the level of dispensing of oral corticosteroids (OCS) for managing asthma in Australia, with a particular focus on the cumulative dispensing of doses associated with long term toxicity (≥ 1000 mg prednisolone‐equivalent). Design: Retrospective cohort study; analysis of 10% random sample of Pharmaceutical Benefits Scheme (PBS) dispensing data. Participants, setting: People aged 12 years or more treated for asthma during 2014–2018, according to dispensing of controller inhaled corticosteroids (ICS). Main outcome measures: Number of people dispensed OCS for managing asthma during 2014–2018; proportion who were cumulatively dispensed at least 1000 mg prednisolone‐equivalent. The secondary outcome was the number of people dispensed at least 1000 mg prednisolone‐equivalent during 2018, stratified by inhaler controller dose and use. Results: 124 011 people had been dispensed at least two prescriptions of ICS during 2014–2018 and met the study definition for asthma, of whom 64 112 (51.7%) had also been dispensed OCS, including 34 580 (27.9% of the asthma group) cumulatively dispensed 1000 mg prednisolone‐equivalent or more. Of 138 073 people dispensed OCS at this level, 68 077 (49%) were patients with airway diseases. Dispensing of diabetes and osteoporosis medications was more common for people cumulatively dispensed 1000 mg prednisolone‐equivalent or more. During 2018, 4633 people with asthma using high dose ICS controllers were dispensed 1000 mg prednisolone‐equivalent or more, for 2316 of whom (50%) controller use was inadequate. Conclusions: Cumulative exposure to OCS in Australia reaches levels associated with toxicity in one‐quarter of patients with asthma using ICS. Cumulative dispensing of potentially toxic OCS amounts often accompanies inadequate inhaler controller dispensing. Better approaches are needed to improve adherence to controller therapy, improve outcomes for people with asthma, and to minimise the use and toxicity of OCS.

Mark Hew · Vanessa M McDonald · Phil G Bardin · Li Ping Chung · Claude S Farah · Amanda Barnard · Mark S Cooper · Peter G Gibson · John W Upham

Objective: To evaluate associations between exposure during early life to mine fire smoke and parent‐reported indicators of respiratory and atopic illness 2–4 years later. Design, setting: The Hazelwood coalmine fire exposed a regional Australian community to markedly increased air pollution during February – March 2014. During June 2016 – October 2018 we conducted a prospective cohort study of children from the Latrobe Valley. Participants: Seventy‐nine children exposed to smoke in utero, 81 exposed during early childhood (0–2 years of age), and 129 children conceived after the fire (ie, unexposed). Exposure: Individualised mean daily and peak 24‐hour fire‐attributable fine particulate matter (PM2.5) exposure during the fire period, based on modelled air quality and time‐activity data. Main outcome measures: Parent‐reported symptoms, medications use, and contacts with medical professionals, collected in monthly online diaries for 29 months, 2–4 years after the fire. Results: In the in utero exposure analysis (2678 monthly diaries for 160 children exposed in utero or unexposed), each 10 μg/m3 increase in mean daily PM2.5 exposure was associated with increased reports of runny nose/cough (relative risk [RR], 1.09; 95% CI, 1.02–1.17), wheeze (RR, 1.56; 95% CI, 1.18–2.07), seeking health professional advice (RR, 1.17; 95% CI 1.06–1.29), and doctor diagnoses of upper respiratory tract infections, cold or flu (RR, 1.35; 95% CI, 1.14–1.60). Associations with peak 24‐hour PM2.5 exposure were similar. In the early childhood exposure analysis (3290 diaries for 210 children exposed during early childhood, or unexposed), each 100 μg/m3 increase in peak 24‐hour PM2.5 exposure was associated with increased use of asthma inhalers (RR, 1.26; 95% CI, 1.01–1.58). Conclusions: Exposure to mine fire smoke in utero was associated with increased reports by parents of respiratory infections and wheeze in their children 2–4 years later.

Gabriela A Willis · Kate Chappell · Stephanie Williams · Shannon M Melody · Amanda Wheeler · Marita Dalton · Shyamali C Dharmage · Graeme R Zosky · Fay H Johnston

Australian clinicians need to be able to recognise, diagnose, manage and appropriately refer patients affected by COVID-19

Irani Thevarajan · Kirsty L Buising · Benjamin C Cowie

To the Editor: The National Disability Insurance Scheme (NDIS) is one of the largest health reforms in Australia's history.1 The scheme aims to give people with a disability choice and control over their daily lives.2 It is designed to operate as nation‐wide disability “markets” from which services can be “purchased”.2 NDIS participants are allocated a budget from which they purchase the services they require. The NDIS is very different from our previous disability models, which saw people receiving standardised services from a more limited number of government and not‐for‐profit organisations, and a less decentralised workforce. The NDIS is a visionary reform; however, we are now seeing that it is also designed to spread an epidemic such as coronavirus disease 2019 (COVID‐19) to thousands of people with a disability. The NDIS has created a “gig economy” within the disability services sector. Individuals are paid for discrete services, from showering and feeding, to social support activities, to household tasks. This means as many as ten different carers entering a participant's home, performing a care service, and then moving on to another home. The workforce is now predominantly casual, and there are growing numbers of self‐employed.3 This structure is primed to spread infection because: large numbers of carers are moving between homes; carers are not paid if they do not perform care tasks, which deters people from self‐isolating; and much of the workforce is disparate and there is no central registry, which makes it difficult to provide new information such as hygiene practices to all people. Unfortunately, many people who are part of the NDIS have comorbidities,4 making them vulnerable to COVID‐19 by both physiology and system design. Previous research has raised concerns about the readiness of the workforce to handle complex disability under normal circumstances, let alone in the context of a pandemic.5 While government agencies are working to communicate hygiene practices with NDIS participants, challenges such as personal protective equipment shortages and high worker motility need to be addressed. Otherwise, the health care system will need to ready itself for a disproportionate number of people with disability.

Gemma Carey

Tetrahydrocannabinol‐containing (THC) products with vitamin E additives are implicated in the pathogenesis of EVALI Electronic cigarettes, or e‐cigarettes, are battery‐powered devices that heat liquids containing nicotine and other chemicals in order to produce vapour.1 “Vaping” is the act of inhaling the vapour produced by an e‐cigarette.1 First marketed in 2005, e‐cigarette use is viewed by many as less harmful than traditional cigarette smoking, and championed as a strategy for smoking cessation.1,2,3 A detailed discussion of e‐cigarette use in smoking cessation is available in the United States Surgeon General's 2020 report, and is beyond the scope of this article; however, the report states that “there is presently inadequate evidence to conclude that e‐cigarettes, in general, increase smoking cessation”.2 Thus far, no e‐cigarette product for the therapeutic purpose of smoking cessation has been submitted to Australia's Therapeutic Goods Administration for safety evaluation or approval. Vaping in the US was initially associated with nicotine‐containing solutions. However, it is important to note that nicotine or nicotine salts may no longer be the only active ingredient in vaping solutions.1,4,5 In particular, unregulated vaping solutions or “home‐brew” products that contain tetrahydrocannabinol (THC) oil, or cannabinoids, can be obtained in the US.4,6 Vaping solutions come in a wide range of flavours, many designed to appeal to adolescents.1,2 Indeed, e‐cigarette manufacturers have used celebrity endorsements and social media‐based marketing campaigns to target adolescents, and these strategies appear to have been highly successful.1,2 There has been significant uptake of vaping among tobacco‐naive high school students, particularly in the US, where it is estimated that one in four high school students are current e‐cigarette users;7 moreover, in 2019, 14% of year 12 students reported vaping cannabis in the preceding 30 days.8 Between 2011 and 2018, e‐cigarette use increased among US high school students from 1.5% to 20.8%, even when traditional cigarette use declined from 15.8% to 8.1%.9 Consequently, from 2017 to 2018, overall use of tobacco products (traditional and e‐cigarettes combined) increased from 19.6% to 27.1%.9 In contrast, e‐cigarettes use among adults in the US has remained largely stable at 8.1 million e‐cigarette users (3.2%).10 It is possible that for young non‐smokers, e‐cigarettes may normalise smoking and serve as a gateway to nicotine dependency and traditional cigarette smoking, although this is strongly debated.1,9 In 2016, the Australian National Drug Strategy Household Survey reported that e‐cigarette use within the 12–17 and 18–29 years age brackets was about 7.1% and 16% respectively.11,12,13 The 2017 Australian secondary students’ alcohol and drug survey found that 13% of students had used an e‐cigarette at least once.14 Of the 2410 students who used an e‐cigarette, 48% reported that they had never smoked a traditional tobacco cigarette before using an e‐cigarette.14 E‐cigarettes may be perceived by young people as “a cool new gadget” and “safer than smoking”.1 Unfortunately, it has become abundantly clear that the use of illicitly sourced e‐cigarettes can be dangerous.10 In 2019, disturbing reports emerged of an acute and, for some, deadly outcome from vaping.15 Across the US, e‐cigarette users began to be admitted to hospitals with acute respiratory failure. In August 2019, the first fatality was documented in Illinois, while 200 other cases across 22 states were under investigation by the Centers for Disease Control and Prevention (CDC).15 This epidemic has spread very rapidly. There have been over 2800 hospitalised cases reported from every US state and territory and a total of 68 deaths.16 Patients were predominantly male (66%) and under 35 years of age (76%).6 [Correction added on 2 July 2020 after first online publication: Information has been updated on the second last sentence.] The CDC has termed this new disease “e‐cigarette or vaping product use‐associated lung injury” (EVALI)17 and has proposed four obligatory criteria for its diagnosis: use of an e‐cigarette (“vaping”) in the 90 days before symptom onset;18 pulmonary infiltrates or ground glass opacities on x‐ray or computed tomography scan; absence of pulmonary infection (defined by negative respiratory viral panel, negative influenza polymerase chain reaction, negative urinary pneumococcal antigen and sputum culture including Legionella, and bronchoalveolar lavage [BAL] culture); and no evidence of an alternative plausible diagnosis such as a cardiac disease or a neoplastic process.17,18 Patients with EVALI typically present with both respiratory (dyspnoea, cough, fever) and gastrointestinal (nausea, vomiting, diarrhoea, abdominal pain) symptoms.15,19 Usually, there is no prior history of respiratory disease. Diagnosis may be challenging, as EVALI can mimic infective pneumonia and gastrointestinal symptoms may sometimes precede respiratory symptoms.15 Respiratory failure may be severe enough to require invasive ventilation and intensive care support.15,19 Imaging findings include ground glass opacities on chest imaging,20 suggesting diffuse lung injury with bronchiolitis obliterans and cryptogenic organising pneumonia.19 Pathologically, limited lung biopsies have shown acute lung injury, acute fibrinous pneumonitis and diffuse alveolar damage.21 “Foamy” or lipid‐laden macrophages are often seen, suggestive of lipoid pneumonia.15 Aetiology and pathophysiology of EVALI: reasons for its recent emergence Careful epidemiological investigation has revealed two key findings explaining the recent emergence of EVALI after more than a decade of e‐cigarette use. Firstly, 80% of hospitalised patients with EVALI have admitted to using THC vaping products.6 Eighty‐four per cent of the reported THC products were acquired via informal channels and were probably manufactured outside of regulated facilities.15 The CDC identified “Dank Vapes” — a group of largely counterfeit THC‐containing products — as the most commonly reported THC brand across the US and used by 56% of patients with EVALI admitted to hospital.6 In contrast, only 13% of hospitalised patients with EVALI reported exclusive use of nicotine‐containing products; however, traces of THC were found in BAL samples.6,19 There may be unreliable self‐reporting and it is possible that the nicotine e‐cigarettes may have been contaminated by black‐market THC additives. Most patients reported using combination products containing either THC, cannabidiol or nicotine.6 Secondly, there is mounting evidence that a specific additive to vaping solutions — vitamin E acetate — played a major role in the 2019 EVALI outbreak.19,20 It is hypothesised that vaping the vitamin E acetate oil causes direct lung injury and lipoid pneumonia.21 Supporting this, BAL fluid from 51 patients from 16 states diagnosed with EVALI yielded vitamin E acetate in 94% (48/51) of the BAL samples.19 In an analysis of the THC‐containing e‐cigarette products used by 12 patients, vitamin E acetate was found in products from 11 patients.19 It is likely that this substance was added as a diluent or filler, and this practice appears to be a very recent development.19 The same chemical analysis performed on THC e‐cigarette products seized in 2018 did not find vitamin E acetate.19 Current evidence shows that THC‐containing products with vitamin E acetate additives are implicated in the pathogenesis of EVALI.21 Given the outbreak has only manifested in the past 18 months, it is likely that the addition of these substances into e‐cigarette solutions is a very recent occurrence. The CDC outlines three broad tenets for treating suspected EVALI: cover possible infective agents with empiric broad‐spectrum antibiotics; administer systemic steroids (optimal dose unknown); and provide best supportive care with oxygen therapy and close monitoring.15,17,20 In mild to moderate cases, the decision to start steroids can be delayed until culture results exclude or identify potential infectious pathogens.17 In severe cases, systemic corticosteroids should be given early due to the potential life‐threatening nature of EVALI.20 There have been reports of progressive ventilatory failure despite administration of high dose steroids (methylprednisolone 1 mg/kg), with patients requiring extracorporeal membrane oxygenation.20 So far, there are no confirmed reports of EVALI in Australia. Unlike in the US, nicotine‐containing liquids are illegal in Australia and can only be obtained on medical prescription for personal use.11 The sale of e‐cigarettes to people aged under 18 years is also illegal.11 In practice, however, a 2015 survey of Australian e‐cigarette use found that 90% of users purchased e‐cigarettes and liquids from unregulated online stores.11 Even legal nicotine‐free liquids sold in Australia have been found to contain traces of nicotine and other toxic substances, with no regulation of products.22 Most Australian e‐cigarette users are therefore vulnerable to the possibility of potentially dangerous substances being added to solutions, as has occurred in the US. Conclusion Vaping THC oil contaminated with vitamin E acetate is linked with severe lung injury and death. With more than 2800 cases of EVALI reported and 68 deaths, e‐cigarettes are definitely not risk‐free. Australian clinicians should maintain vigilance and ask every patient about e‐cigarette use. Adults using nicotine‐containing e‐cigarettes as an alternative to cigarette smoking should not revert to tobacco smoking.2 A reasonable and precautionary strategy is to advise patients that little is known about the long term effects of e‐cigarettes, and also to inform users that severe lung disease and death have occurred mainly with unregulated solutions. We recommend further research and ongoing field monitoring of e‐cigarette usage patterns in Australia.

Maitri Munsif · Mark Hew · Eli Dabscheck

COVID‐19 ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management “This disease is still too strange to us, and there are too many doubts”, says Dr Ling Qin (LQ), after reviewing more than 400 patients with coronavirus disease 2019 (COVID‐19) pneumonia in Wuhan Union Hospital, China. COVID‐19 is a novel disease. We are familiar with acute respiratory distress syndrome (ARDS); however, when it occurs as part of COVID‐19, it has different features and there remain unanswered questions. So if someone has COVID‐19 ARDS, how does it compare and contrast with ARDS from other causes? To answer this question we provide a summary of the published literature (based on a PubMed search using the terms “COVID‐19” and “ARDS”, 17 April 2020) and current clinical experience from managing patients with COVID‐19 ARDS in Singapore (SHP) and Wuhan (LQ). Severe COVID‐19 represents viral pneumonia from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection leading to ARDS. Its manifestations can be viewed as a combination of the two processes, namely viral pneumonia and ARDS. COVID‐19 is a novel disease recognised initially in Wuhan, China, in December 2019, and is now pandemic. It is likely caused by zoonotic spillover of a β‐coronavirus type 2b that is now transmitted between humans. Along with the other serious coronavirus infections of severe acute respiratory syndrome and Middle East respiratory syndrome, which also cause ARDS, COVID‐19 represents an ongoing global threat as this virus family has the potential to mutate and infect non‐immune populations. Australia's living guidelines provide the latest recommendations and evidence.1 Diagnosis SARS‐CoV‐2 infection can be confirmed by positive detection of viral RNA in nasopharyngeal secretions using a specific PCR test. COVID‐19 illness can be confirmed by a consistent clinical history, epidemiological contact, and a positive SARS‐CoV‐2 test. COVID‐19 ARDS is diagnosed when someone with confirmed COVID‐19 infection meets the Berlin 2012 ARDS diagnostic criteria2 of (i) acute hypoxaemic respiratory failure; (ii) presentation within 1 week of worsening respiratory symptoms; (iii) bilateral airspace disease on chest x‐ray, computed tomography (CT) or ultrasound that is not fully explained by effusions, lobar or lung collapse, or nodules; and (iv) cardiac failure is not the primary cause of acute hypoxaemic respiratory failure. ARDS is underdiagnosed in intensive care settings.3 ARDS develops in 42% of patients presenting with COVID‐19 pneumonia, and 61–81% of those requiring intensive care.4 COVID‐19 ARDS follows a predictable time course over days, with median time to intubation of 8.5 days after symptom onset in Singaporean patients.5 This is similar to previous reports where ARDS developed at day 8 or 9 after symptom onset. It is therefore important to monitor patients for the development of ARDS as their COVID‐19 infection progresses. Respiratory rate and SpO2 are two important parameters for judging patients’ clinical condition and allowing early recognition of ARDS. A patient who fits any one of the following conditions may have severe disease and require further evaluation: respiratory rate ≥ 30 breaths/min; SpO2 ≤ 92%; and PaO2/FiO2 ≤ 300 mmHg. Blood tests can also be helpful. In Singapore, it was noted that raised C‐reactive protein levels and blood neutrophil counts along with lymphopenia were more common in patients requiring invasive mechanical ventilation for COVID‐19 ARDS.5 Lung pathology ARDS causes diffuse alveolar damage in the lung. There is hyaline membrane formation in the alveoli in the acute stage, and this is followed by interstitial widening and by oedema and then fibroblast proliferation in the organising stage. COVID‐19 ARDS causes the typical ARDS pathological changes of diffuse alveolar damage in the lung.6,7 As patients move through the course of their illness, the longer term outcomes of ARDS are being reported, with lung fibrosis appearing as part of COVID‐19 ARDS.8,9 A study reported that 17% of patients had fibrous stripes in chest CT scans,9 and considered that the fibrous lesions may form during the healing of pulmonary chronic inflammation or proliferative diseases, with gradual replacement of cellular components by scar tissues. Thrombosis Pulmonary thrombosis is common in sepsis‐induced ARDS. Coagulation dysfunction appears to be common in COVID‐19, and is detected by elevated D‐dimer levels. In fatal cases there is diffuse microvascular thrombosis, suggesting a thrombotic microangiopathy, and most deaths from COVID‐19 ARDS have evidence of thrombotic disseminated intravascular coagulation.10 This may explain some of the atypical or unexpected manifestations seen in the lung, such as dilated pulmonary vessels on chest CT, and episodes of pleuritic pain. Vascular enlargement is rarely reported in typical ARDS, yet was seen in most cases of COVID‐19 ARDS.9 Mortality COVID‐19 ARDS appears to have worse outcomes than ARDS from other causes. The intensive care unit and hospital mortality from typical ARDS are 35.3% (95% CI, 33.3–37.2%) and 40.0% (95% CI, 38.1–42.1%), respectively.3 For COVID‐19 ARDS, mortality ranged between 26% and 61.5% if ever admitted into a critical care setting, and in patients who received mechanical ventilation, the mortality can range between 65.7% to 94%.4 Risk factors for poor outcomes include older age; presence of comorbidities such as hypertension, cardiovascular disease and diabetes mellitus; lower lymphocyte counts; kidney injury; and raised D‐dimer levels. Death from COVID‐19 ARDS is due to respiratory failure (53%), respiratory failure combined with cardiac failure (33%), myocardial damage and circulatory failure (7%), or death from an unknown cause.4 Radiology The radiology of ARDS is distinctive, yet COVID‐19 pneumonia appears to have unique features. This likely results from the co‐occurrence of viral pneumonia and ARDS, and allows radiologists to be fairly specific in diagnosing COVID‐19 pneumonia. The most discriminating features for COVID‐19 pneumonia in China compared with viral pneumonia in the United States included a peripheral distribution of opacification (80% v 57%; P < 0.001), frosted glass opacities (91% v 68%; P < 0.001), and vascular thickening or enlargement (58% v 22%; P < 0.001).11 These imaging features appear to be typical for COVID‐19 pneumonia and can be helpful in early screening of highly suspected cases and in evaluation of the severity and extent of disease. As COVID‐19 lung disease progresses, the lesions are more likely to be bilateral, lower lung predominant and multifocal. They often have the appearance of rounded opacities, termed “COVID balls”. With the development of ARDS, the extent of lung involvement increases, and there is a consolidative component.12 The opacities resolve with recovery from COVID‐19;13 however, with ARDS, the lesions increase in their extent and density, and evolve to fibrotic bands. Ventilation The strategy of breathing support is very important in treating COVID‐19 ARDS, as is the case with typical ARDS caused by other pathogens.14 The key elements are: use oxygen by nasal cannulae to achieve SpO2 > 92%; use of high flow nasal oxygen is controversial and highly dependent on the treatment location; avoid non‐invasive ventilation; prone ventilation appears to be beneficial; and consider extracorporeal membrane oxygenation for rescue. Because of concerns about viral transmission to other patients and health care workers,15 the use of high flow nasal oxygen and non‐invasive ventilation (such as bi‐level positive pressure ventilation) for COVID‐19 ARDS is highly dependent on the health care setting. Australian COVID‐19 guidelines1 strongly recommend against the use of high flow nasal oxygen in emergency departments, but provide a strong recommendation for its use in negative pressure single rooms. Non‐invasive ventilation may be used in negative pressure rooms with appropriate viral transmission precautions.1 Clinical experience has found inconsistent benefit from non‐invasive ventilation and there is concern about aerosol generation and increased risk of viral transmission. Prone ventilation appears to be beneficial for COVID‐19 ARDS.1 Placing a person in prone position promotes more homogenous aeration of the lung in ARDS and can improve oxygenation. While prone ventilation is used in only about 16% of patients with typical ARDS,3,16 in COVID‐19 it is being used successfully earlier in the course of ARDS, and suggested use is for > 12 hours per day.16 Venovenous extracorporeal membrane oxygenation can be used as rescue for mechanically ventilated adults with COVID‐19 and hypoxaemia that persists despite optimised ventilation, use of rescue therapies and prone ventilation. Among critically ill patients treated in Wuhan, prone ventilation and extracorporeal membrane oxygenation treatment were not found to be as effective as for ARDS caused by other pathogens. Possible reasons include: COVID‐19 pneumonia was still progressing and was not under control; lung lesions were not completely gravity‐dependent under ultrasound, so the effect of the prone position was limited; the patient's immune status was not restored, and a secondary hospital‐acquired infection worsened the condition; and when case numbers are high from the epidemic, the management mode and human resource arrangement of the isolation wards still need to be discussed and strengthened. Anecdotal observations in Singapore (SHP) and investigations in the Netherlands17 suggested that patients ventilated for COVID‐19 ARDS tended to have plateau pressures < 30 cmH20 and driving pressures < 15 cmH20 despite high oxygen requirements. The lung protective ventilation strategy used in typical ARDS involves a low tidal volume (6 mL/kg) and higher positive end expiratory pressure targets. For COVID‐19 ARDS, a change to more generous tidal volume targets allowing up to 8 mL/kg and lower positive end expiratory pressure levels is suggested to prevent patient self‐inflicted lung injury. Adjunct treatment In typical ARDS, continuous neuromuscular blocking agents, high dose corticosteroids and recruitment manoeuvers were the most frequently used adjunctive therapies. In COVID‐19 ARDS, the evidence for systemic steroids is still scarce and they are only recommended in patients with concomitant shock which has been unresponsive to vasopressors. There are concerns that steroids may increase viral shedding and possibly lead to a higher mortality rate. Antiviral therapy Many patients with COVID‐19 receive antiviral or immunosuppressive therapy. In Australia, the National COVID‐19 Clinical Evidence Taskforce1 recommends administering antiviral medications or other disease‐modifying treatments in the context of clinical trials. Singapore was using empiric lopinavir–ritonavir plus subcutaneous interferon‐β 1b initially, but is now randomising patients to receive remdesivir. In Wuhan, a broad range of antiviral and immune therapies are being used. All patients also received treatment with Chinese medicine. COVID‐19 ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management. Research programs such as the Medical Research Future Fund 2020 Respiratory Medicine Clinical Trials Research on COVID‐19 grant opportunity are required to answer the important questions that remain about therapies for COVID‐19 ARDS.

Peter G Gibson · Ling Qin · Ser Hon Puah

All countries must increase medical capabilities and adopt a concerted whole-of-government approach to combat COVID-19

Ray Junhao Lin · Tau Hong Lee · David CB Lye

Investment is urgently needed in repurposed drugs which could ease the burden of the COVID-19 pandemic

Jennifer H Martin · Nikola A Bowden

Advice for clinicians managing patients with cancer during the pandemic

Robert Weinkove · Zoe K McQuilten · Jonathan Adler · Meera R Agar · Emily Blyth · Allen C Cheng · Rachel Conyers · Gabrielle M Haeusler · Claire Hardie · Christopher Jackson · Steven W Lane · Tom Middlemiss · Peter Mollee · Stephen P Mulligan · David Ritchie · Myra Ruka · Benjamin Solomon · Jeffrey Szer · Karin A Thursky · Erica M Wood · Leon J Worth · Michelle K Yong · Monica A Slavin · Benjamin W Teh

To the Editor: On 11 March 2020, the World Health Organization declared COVID‐19 a pandemic. Australia has enacted public health measures to reduce the number and severity of cases.1 These measures, alongside disease burden, profoundly impact the health care system. However, the place of medical students in the COVID‐19 response is unclear. The gravity of the COVID‐19 crisis has led governments to take drastic measures. The graduation of over 10 000 Italian final year students has been expedited to supplement the overburdened workforce.2 In the United Kingdom, the Medical Schools Council has encouraged prioritising qualification of final year students to support the over‐encumbered National Health Service.2 Medical Deans Australia and New Zealand recognises the value of final year medical students, releasing a statement outlining appropriate roles.3 These involve routine aspects of care independent of the COVID‐19 response, in various clinical settings with which students are already familiar. Moreover, with clinical placements being disrupted, senior students may gain valuable practical exposure aligned with course requirements. Considering the noted mental health effects of COVID‐19,4 student contributions may relieve the burden on professional staff while alleviating any sense of helplessness, improving the mental wellbeing of students and staff alike. Importantly, medicine embodies altruism and humanity, with many students undertaking the vocation for this reason. As imminent doctors, senior medical students may therefore feel impassioned to contribute to the COVID‐19 response. Involving students, however, is not without risk. With the reported asymptomatic infectious period, expanding the workforce elevates infection risk. Exposure to patients with COVID‐19 should therefore be minimal. Further, the risk of litigation is pertinent as students are less experienced than professional staff. Responsibilities should be within capabilities, under supervision and institutional medico‐legal protection. Lastly, additional work hours may impede formal medical education; academic penalties should not be levied, on‐the‐job learning should be duly acknowledged, and accessibility of course materials should be maximised. Indeed, medical student involvement should be implemented following principles developed by key stakeholders.3,5 Extraordinary times call for extraordinary measures. With appropriate legal, operational and training safeguards, senior medical students have a role in the COVD‐19 response if they desire.

Jim H‐S Wang · Sarah Tan · Kyle Raubenheimer

To the Editor: The advent of coronavirus disease 2019 (COVID‐19) has generated an unparalleled level of interest from the medical and non‐medical community. As clinician‐scientists, we watch in astonishment at the exponential growth of academic publications in journals. In January 2020, PubMed saw a sharp rise in the number of publications related to COVID‐19, which continues to grow (Box). We could not help but wonder if this has generated a race to publish. Of course, publishing is crucial to help confront one of the most devastating global health issues of the century. However, it is well recognised that external pressures to publish can muddle the intrinsic pursuit for scientific curiosity and excellence,1 and COVID‐19 has certainly provided the incentive for many clinicians and scientists alike to seek rapid publication. This may, unfortunately, fuel competition in the research/publishing field, which was exemplified by the concerning lack of research collaborations when humans were faced with natural disasters,2 including the 2003 severe acute respiratory syndrome coronavirus (SARS‐CoV) outbreak.3 The urgent nature of this situation means a number of preliminary studies and publications on COVID‐19 are fast‐tracked through the peer review process — or not at all — in the hope of rapidly publicising important findings, opinions and experiences. However, hastily penned observations may mislead and do more harm than good. A recent non‐peer‐reviewed publication on a preprint server likening SARS‐CoV‐2 structurally to the human immunodeficiency virus (HIV) was quickly retracted after the scientific community highlighted serious flaws in the study.4 Furthermore, a preliminary study5 supporting the use of hydroxychloroquine as a COVID‐19 treatment prompted a flurry of off‐label use and media attention. The study was later criticised as being too small and biased, and provided insufficient evidence to recommend its use.6 In summary, rapid publishing allows extensive dissemination of knowledge and sharing of experiences; yet the astute clinician needs to keep an open mind and analyse what is being published, for this cannot take the place of rigorous scientific evaluation and best clinical practice. This is a challenging time in the academic world and COVID‐19 will, no doubt, test our abilities to untangle the vast range of literature available. Box – Monthly and cumulative published articles on coronavirus disease 2019 (COVID‐19)* * We conducted an online search in PubMed and included all articles with the terms “coronavirus”, “COVID‐19”, “COVID” and/or “SARS‐CoV‐2”. The information is correct as of 30 April 2020.

Adrian YS Lee · Ming‐Wei Lin

In reply: Lee and Lin raise an important point about the need for caution in interpreting rapidly published articles in the era of coronavirus disease 2019 (COVID‐19). At the Medical Journal of Australia, we are acutely aware of the need to balance rapid dissemination of key data with the need to maintain our usual high standards of quality and accuracy. We have taken the view that in these unprecedented times, rapid sharing of information is critical, but we recognise the risk of errors this infers. In response, we have implemented a preprint and rapid review process for selected manuscripts of an urgent nature (Box). In order to minimise the risk of errors, all manuscripts are carefully reviewed by myself, our team of experienced and medically qualified editors and, where appropriate, our consultant biostatistician, before being selected for preprint in the MJA. Only where the editorial team have a high level of confidence in the validity and importance of the article will it be selected for rapid preprint publication. Before full acceptance of the manuscript to be published online and in print and, in selected cases, before we accept an article for preprint, we organise a rapid double blind peer review followed by revision in line with our usual stringent processes. In these circumstances, we endeavour to have this process completed within 7 days of preprint publication so that any errors can be quickly identified and corrected. We are very grateful to our reviewers who have been very generous in their assistance with this new process. One final check in our process on full publication is review and editing by our experienced scientific and structural editors, who meticulously check all articles for consistency, accuracy and referencing, while finessing them for readability and clarity of presentation — their expertise is invaluable in ensuring published manuscripts are presented accurately and in the best possible light. We acknowledge that contradiction and error may be inevitable during this rapidly evolving situation but would like to assure our readers that at the MJA, when errors occur, they will be rectified in a timely manner and with full transparency. While we are living in a world of rapid change, our commitment to providing Australian health and medical researchers, clinicians and policy makers with the world‐leading general medical journal they deserve stands strong. Box – MJA process for rapid publication of selected coronavirus disease 2019 (COVID‐19)‐related manuscripts* * Timing is indicative and may vary according to the complexity of the manuscript.

Nicholas J Talley

Coronavirus disease 2019 (COVID‐19) poses extraordinary challenges for health care in Australia. One of the greatest will be the pressure on hospitals to support people with severe disease. Modelling studies can provide valuable insights into the likely course of the epidemic, and can be particularly useful for anticipating resource requirements, including demand for intensive care services at the peak of the epidemic. In this report, we extrapolate the findings of the Imperial College model of the pandemic1 to the New South Wales population. We also developed a simple SEIR (susceptible–exposed/incubating–infected–removed) model to explore the effect of varying the infection reproduction number (R), which can be reduced by effective social distancing measures, on the timing of the peak of the epidemic. The two models are described in the online Supporting Information. Applying the Imperial College model, the peak demand for intensive care in NSW would be at least 6965 beds if mitigation efforts — isolation of people with confirmed COVID‐19, household quarantine of their contacts, social distancing from people over 70 years of age — are implemented, or almost eight times as many as the baseline number; without mitigation, more than three times as many ICU beds (21 283) could be required (Box 1). Applying our SEIR model to a scenario without social distancing measures (R = 2.4), the number of people requiring hospitalisation in NSW would peak at 450 per 100 000 population (35 375 beds), and the number requiring critical care at 150 per 100 000 population (11 792 ICU beds, or 1349% of baseline ICU capacity). In this scenario, viral transmission would peak during late June and ICU bed occupancy in early July. About 16% of people would be potentially infectious at this point, although a smaller proportion was modelled as exhibiting symptoms (Box 2; Supporting Information, table 3). In a scenario of increased social isolation (R = 1.6) and an assumed hospitalisation rate for people with confirmed COVID‐19 of 6.7%, case numbers would peak in early October and ICU occupancy in mid‐November; about 180 people per 100 000 population would require hospitalisation (14 150 beds) and 65 per 100 000 intensive care (5110 ICU beds, or 585% of baseline ICU capacity) (Box 2; Supporting Information, table 3). That is, the peak figures would be about one‐third the size of those in the no mitigation scenario. Sensitivity analyses in which the proportion of hospitalised patients was varied (5–15%) similarly found that increasing social isolation markedly reduced demand (Supporting Information, table 4). We have used two modelling methods to estimate peak demand for critical care services in NSW during the COVID‐19 epidemic. Both approaches identified that COVID‐19 would impose a major burden on the health care system, and the mismatch between the estimated numbers of ICU beds needed and their availability is stark. Our modelling shows the critical importance of effective COVID‐19 containment strategies, as well as the urgent need to invest in resources that support the surge capacity of critical care services in NSW. Box 1 – Estimated number of intensive care unit (ICU) beds required at the peak of the initial wave of COVID‐19 cases, applying the Imperial College model to New South Wales, by Local Health District (LHD) Mitigation strategy Population (2016)2 No mitigation Close schools, universities Case isolation Case isolation, household quarantine Case isolation, household quarantine, social distancing of people over 70 ICU beds needed per 100 000 population1 — 275 240 190 125 90 ICU beds need, by LHD Sydney 656 460 1805 1576 1247 821 591 South Western Sydney 964 342 2652 2314 1832 1205 868 South Eastern Sydney 914 021 514 2194 1737 1143 823 Western Sydney 948 584 2609 2277 1802 1186 854 Northern Sydney 914 233 2514 2194 1737 1143 823 Illawarra Shoalhaven 405 534 1115 973 771 507 365 Central Coast 335 309 922 805 637 419 302 Other LHDs 2 600 791 7152 6242 4942 3251 2341 All NSW (proportion of baseline bed number)* 7 739 274 21 283 (2435%) 18 574 (2125%) 14 705 (1682%) 9674 (1107%) 6965 (797%) * Estimated number of ICU beds prior to COVID‐19 epidemic: 874.3 Box 2 – The estimated number of patients with COVID‐19 admitted to hospital or to intensive care units (ICUs), according to a SEIR model of the epidemic * For main curves, 10% case hospitalisation rate assumed; shaded areas show range for hospitalisation rates between 5% and 15%.

Gregory J Fox · James M Trauer · Emma McBryde

Objectives: To assess the capacity of intensive care units (ICUs) in Australia to respond to the expected increase in demand associated with COVID‐19. Design: Analysis of Australian and New Zealand Intensive Care Society (ANZICS) registry data, supplemented by an ICU surge capability survey and veterinary facilities survey (both March 2020). Settings: All Australian ICUs and veterinary facilities. Main outcome measures: Baseline numbers of ICU beds, ventilators, dialysis machines, extracorporeal membrane oxygenation machines, intravenous infusion pumps, and staff (senior medical staff, registered nurses); incremental capability to increase capacity (surge) by increasing ICU bed numbers; ventilator‐to‐bed ratios; number of ventilators in veterinary facilities. Results: The 191 ICUs in Australia provide 2378 intensive care beds during baseline activity (9.3 ICU beds per 100 000 population). Of the 175 ICUs that responded to the surge survey (with 2228 intensive care beds), a maximal surge would add an additional 4258 intensive care beds (191% increase) and 2631 invasive ventilators (120% increase). This surge would require additional staffing of as many as 4092 senior doctors (245% increase over baseline) and 42 720 registered ICU nurses (269% increase over baseline). An additional 188 ventilators are available in veterinary facilities, including 179 human model ventilators. Conclusions: The directors of Australian ICUs report that intensive care bed capacity could be near tripled in response to the expected increase in demand caused by COVID‐19. But maximal surge in bed numbers could be hampered by a shortfall in invasive ventilators and would also require a large increase in clinician and nursing staff numbers.

Edward Litton · Tamara Bucci · Shaila Chavan · Yvonne Y Ho · Anthony Holley · Gretta Howard · Sue Huckson · Philomena Kwong · Johnny Millar · Nhi Nguyen · Paul Secombe · Marc Ziegenfuss · David Pilcher

Ambient air quality in Australia is regulated by the National Environment Protection Measure (NEPM), which sets a maximum 24‐hour mean concentration of 50 μg/m3 for particulate matter less than 10 μm in diameter (PM10) and 25 μg/m3 for PM2.5. Each state and territory is required by the NEPM to annually report all breaches of this standard, including the sources of pollution.1 We analysed NEPM reports for Western Australia to identify days during 1 January 2002 – 31 December 2017 on which atmospheric particulate matter levels exceeded air quality standard levels, and classified them according to the most frequently reported sources of pollution: prescribed burns, wildfires, and other (crustal particles such as dust, wood smoke, and indeterminate). During 2008–2013, exceedances caused by smoke from prescribed burns, wildfires, and wood smoke were all recorded by the WA Department of Environment Regulation as “smoke haze”. For this period, we therefore applied a random forest algorithm, a machine learning method that uses a random sample of observations for known classifications to predict the classifications for new data.2 We included the variables month, day of the week, temperature, and pollution level as model predictors. To estimate background PM2.5 level, we obtained historical hourly values for PM10 and PM2.5 from the WA Department of Water and Environmental Regulation3 and calculated historical monthly means, excluding days on which particle levels exceeded the air quality standard. We estimated daily PM2.5 concentrations attributable to smoke events by subtracting the background PM2.5 level from measured daily values. Applying standard methods for assessing the health impact of air pollution,4 we estimated the numbers of premature deaths, hospitalisations for cardiovascular and respiratory problems, and emergency department presentations with asthma attributable to elevated PM2.5 levels. We used the value of statistical life (VSL)5 to estimate costs associated with premature mortality. The VSL is based on the willingness to pay for reduced risk of premature mortality, and does not take into account underlying health status, age, or life expectancy of individuals. Deaths associated with acute exposure to increased air pollution are more likely among people at greater risk because of advanced age or chronic illness.6 We estimated hospital service costs according to the mean cost of each episode of care as reported in the Independent Hospital Pricing Authority national cost data collection report7 and the Health Policy Analysis emergency care costing report.8 We also undertook a sensitivity analysis in which we excluded data for 2008–2013, when exceedances caused by smoke from prescribed burns, wildfires, and wood smoke were all recorded in NEPM reports as “smoke haze”. Further details on our methods, including underlying assumptions and limitations, are included in the online Supporting Information. During 2002–2017, particulate air pollution exceeded the national standard on 271 of 5844 days (4.6%), including 197 days (73%) attributable to prescribed burns or wildfires. We estimated that 41 (95% confidence interval [CI], 15–68) premature deaths, 99 (95% CI, 19–182) hospitalisations for cardiovascular problems and 174 (95% CI, 0–373) for respiratory conditions, and 123 (95% CI, 70–179) emergency department visits with asthma were attributable to elevated PM2.5 concentration (Box 1). Total estimated health costs were $188.8 million (95% CI, $68.1–311.1 million); $97.1 million (51%) was attributable to prescribed burns and $77.7 million (41%) to wildfires. Mean estimated health costs were lower on days affected by smoke from prescribed burns ($703 984; 95% CI, $254 064–$1.2 million) than those affected by wildfire smoke ($1.3 million; 95% CI, $475 000–$2.2 million), although more days were affected by prescribed burns (138) than by wildfires (59). The estimated smoke‐related costs of wildfires were highest in 2012 ($24.8 million); in many years, prescribed fires often accounted for most health‐related costs, peaking in 2017 ($24.1 million) (Box 2). In our sensitivity analysis excluding the period 2008–2013, the relative costs by source were similar (prescribed burns, 53% [$58.4 million]; wildfires, 38% [$41.6 million]; Supporting Information). Particulate matter in fire smoke is associated with adverse health outcomes,9 even at relatively low concentrations.10 Landscape fire smoke was the greatest contributor to excessive atmospheric particulate matter levels in WA during 2002–2017 and was associated with substantial health costs. Our estimates of the health impacts may be conservative, as we included only days when PM2.5 concentrations exceeded the national standard, excluding smoky days on which the air quality standard was not breached. Further, our selection of health outcomes did not encompass the total health burden attributable to smoke exposure. Our study highlights the different smoke‐related health effects and costs of infrequent severe wildfire and regular prescribed burning. While prescribed burning reduces the risk of wildfire, better understanding and incorporation into control strategies of the full health impacts of each type of fire are needed for sustainable fire management.11 Box 1 – Estimated health burden attributable to elevated PM2.5 concentrations, Western Australia, 2002–2017, by particulate matter source Outcome Estimated number of cases (95% confidence interval) Prescribed burns Wildfires Other Total Excess deaths (any cause) 21 (8–35) 17 (6–28) 3 (1–5) 41 (15–68) Hospital admissions, cardiovascular 51 (10–94) 41 (8–75) 7 (1–13) 99 (19–182) Hospital admissions, respiratory 89 (0–192) 72 (0–154) 13 (0–27) 174 (0–373) Emergency department attendances, asthma 63 (36–91) 51 (29–75) 9 (5–13) 123 (70–179) Box 2 – Estimated health costs tributable to elevated PM2.5 concentrations, Western Australia, 2002–2017, by particulate matter source

Nicolas Borchers Arriagada · Andrew J Palmer · David MJS Bowman · Fay H Johnston

It is imperative that we prepare for the worst, and that we do it now As the Editor‐in‐Chief of the MJA, I'm in the very privileged position of being among the first to critically evaluate early and emerging data forwarded to the Journal. I can also talk to experts around the world because of my medical and academic links. In January 2020, early on in what is now the SARS‐CoV‐2 pandemic, I remember seeing the first data on the outbreak of COVID‐19 in China, the estimated R0 values, and the initial models of exponential spread. Evidence from past outbreaks provides many lessons, including the importance of public health responses going very hard and very early, well before all the epidemiologic data are in.1,2 I therefore watched with increasing alarm that, despite early warnings from the World Health Organization, the initial responses of many governments around the world were limited and slow. I remember when I first saw the disturbing Imperial College modelling for the United Kingdom and the United States, including the different impacts of mitigation and suppression strategies in terms of hospital deaths from COVID‐19.1 In Australia, the messages have yet to fully sink in. On 26 March we published a new model of COVID‐19‐related mortality and hospital admissions, validated against Italian data.3 The model is simple and grim; it describes a hypothetical Australian hospital admitting new cases of confirmed COVID‐19 infection day after day, assuming that one in 20 patients require intensive care for 10 days, and that the COVID‐19 community case load increases by 20% each day. From day 15 — about the time when it is expected that available ICU beds run out — mortality steadily increases, as has happened in Italy. Those familiar with outbreak modelling know how complex such models can be and how many unknowns need to be imputed, especially early in a new outbreak; some employ supercomputers for their calculations, and can take months or years to build their model. Further, the predictive validity of complex models in an outbreak may not apply in other locations because human behaviour is complex and unpredictable.4,5 For this reason, simple models may be more robust; at least early on, when they matter most.6 Many have spoken out about the public health measures needed to slow the spread of SARS‐CoV‐2, and bolder action has recently been taken in Australia and elsewhere; those medical leaders who have stepped up and the political leaders who have heeded their advice early enough will have helped save lives. The next wave of heroes will soon emerge as frontline clinicians in hospitals care for patients during the COVID‐19 surge. At the time of writing (26 March), major preparations are underway to increase ICU bed and ventilator capacity, and personal protective equipment (PPE) is being donned to protect staff. According to current COVID‐19 surge modelling, however, it won't be enough. The health workers who will be on the COVID‐19 frontline and manage the sickest patients will need our greatest support, every single one of them. We will need to ensure that PPE stocks are not wasted and that they are replenished quickly, a clear government priority supported by the suspension of non‐urgent elective surgery announced by the federal government. I hope that manufacturers will be directed to produce everything we need, and quickly; we would re‐tool factories in wartime and not rely alone on private companies to step up (although some have). Some may dislike the wartime analogy, but it resonates with me. We will need to work together to support our medical teams. For families with two health professionals and dependents, we should not place both carers at high risk of exposure and severe disease. This will not be a straightforward rostering task, particularly outside major hospitals and in rural Australia. We need a statewide, and preferably a national plan; closing our internal borders must not impede sensible rostering and medical team deployment. Training needs to ramp up for all staff, and consist of more than simple online videos. We need a clear plan if PPE runs low or out. And we need clear triage rules about which patients should be ventilated if beds run short; health professional leaders and the community must together discuss the complex medical and ethical problems involved, and guidance needs to be finalised as soon as possible. Mental health support will be important, as post‐traumatic stress disorder will be a serious risk for ventilated patients and for staff; I suggest resting staff as much as possible now so that they are healthy, physically and mentally, when they are really needed. We will also require our health system leaders to understand that at a time like this every hospital should have a strict command and control structure led by senior clinicians and health professionals, with a designated clinician leader; bureaucrats primarily concerned with finances and political considerations must move to the sidelines. The Australian Health Practitioner Regulation Agency (AHPRA) is working to determine the role of medical students in this hour of need. Those close to graduating could play direct clinical roles under close supervision if they volunteered, but we need to start upskilling them now if this is to be worthwhile; it takes time to transition from being a medical student to a fully functioning, safe and competent intern. Doctors are being recalled from retirement in the UK and parts of Australia. I hope that this strategy will not be needed, as it places the most vulnerable in the profession in the wrong place. We must also protect staff financially and professionally. The indemnity implications for doctors required to work outside their scope of usual practice are unclear and must be resolved quickly. I am a gastroenterologist, and I am fully prepared to work on COVID‐19 wards or fill gaps in non‐COVID wards if required. But what if I make mistakes? And if I die, will insurance cover my family? The MJA has stepped up to play its part in meeting this crisis, including ultra‐rapid review of SARS‐CoV‐2 manuscripts and pre‐print publication of unedited papers, to ensure that the newest data and viewpoints are available as soon as possible. In addition, all SARS‐CoV‐2 articles will be fully accessible without fee. Our medical and structural editors are working from home, carefully reviewing every submission, but the MJA will continue to publish as usual in these extraordinary times. The ultra‐rapid review and publication model entails a risk of error, but sharing important information too slowly is a much greater hazard. We will transparently correct and update the preprints if appropriate, and we will of course apply our usual high standards of review and editing to refine them before we publish their final versions online and in print. Models matter, even if they are imperfect representations of the real world.7 While the projections reported in this issue3 may represent a worst case scenario and may not come to pass, it is better that we prepare for the worst, and now. Over the coming months it's going to take courage, brains, and a concerted and unified effort by the medical profession and other health professionals to manage SARS‐CoV‐2. Let's not leave anyone behind.

Nicholas J Talley

Objectives: To describe the first isolation and sequencing of SARS‐CoV‐2 in Australia and rapid sharing of the isolate. Setting: SARS‐CoV‐2 was isolated from a 58‐year‐old man from Wuhan, China who arrived in Melbourne on 19 January 2020 and was admitted to the Monash Medical Centre, Melbourne from the emergency department on 24 January 2020 with fever, cough, and progressive dyspnoea. Major outcomes: Clinical course and laboratory features of the first reported case of COVID‐19 (the illness caused by SARS‐CoV‐2) in Australia; isolation, whole genome sequencing, imaging, and rapid sharing of virus from the patient. Results: A nasopharyngeal swab and sputum collected when the patient presented to hospital were each positive for SARS‐CoV‐2 (reverse transcription polymerase chain reaction). Inoculation of Vero/hSLAM cells with material from the nasopharyngeal swab led to the isolation of SARS‐CoV‐2 virus in culture. Electron microscopy of the supernatant confirmed the presence of virus particles with morphology characteristic of viruses of the family Coronaviridae. Whole genome sequencing of the viral isolate and phylogenetic analysis indicated the isolate exhibited greater than 99.99% sequence identity with other publicly available SARS‐CoV‐2 genomes. Within 24 hours of isolation, the first Australian SARS‐CoV‐2 isolate was shared with local and overseas reference laboratories and major North American and European culture collections. Conclusions: The ability to rapidly identify, propagate, and internationally share our SARS‐CoV‐2 isolate is an important step in collaborative scientific efforts to deal effectively with this international public health emergency by developing better diagnostic procedures, vaccine candidates, and antiviral agents.

Leon Caly · Julian Druce · Jason Roberts · Katherine Bond · Thomas Tran · Renata Kostecki · Yano Yoga · William Naughton · George Taiaroa · Torsten Seemann · Mark B Schultz · Benjamin P Howden · Tony M Korman · Sharon R Lewin · Deborah A Williamson · Mike G Catton

Objectives: To assess the efficacy of corticosteroid treatment of patients with coronavirus disease 2019 (COVID‐19). Design, setting: Observational study in the two COVID‐19‐designated hospitals in Wuhu, Anhui province, China, 24 January – 24 February 2020. Participants: Thirty‐one patients infected with the severe acute respiratory coronavirus 2 (SARS‐CoV‐2) treated at the two designated hospitals. Main outcome measures: Virus clearance time, length of hospital stay, and duration of symptoms, by treatment type (including or not including corticosteroid therapy). Results: Eleven of 31 patients with COVID‐19 received corticosteroid treatment. Cox proportional hazards regression analysis indicated no association between corticosteroid treatment and virus clearance time (hazard ratio [HR], 1.26; 95% CI, 0.58–2.74), hospital length of stay (HR, 0.77; 95% CI, 0.33–1.78), or duration of symptoms (HR, 0.86; 95% CI, 0.40–1.83). Univariate analysis indicated that virus clearance was slower in two patients with chronic hepatitis B infections (mean difference, 10.6 days; 95% CI, 6.2–15.1 days). Conclusions: Corticosteroids are widely used when treating patients with COVID‐19, but we found no association between therapy and outcomes in patients without acute respiratory distress syndrome. An existing HBV infection may delay SARS‐CoV‐2 clearance, and this association should be further investigated.

Lei Zha · Shirong Li · Lingling Pan · Boris Tefsen · Yeshan Li · Neil French · Liyun Chen · Gang Yang · Elmer V Villanueva

Editor’s note: This is an update of a Letter to the editor originally published as a preprint on 16 March 2020 (https://www.mja.com.au/journal/2020/212/8/covid-19-precautions-easier-said-done-when-patients-are-homeless). To the Editor: Implementation of advice to the public and general practitioners on minimising the risk of COVID‐19 exposure and transmission is immensely difficult for people experiencing homelessness and for the health services working with them. Yet this is a population group more vulnerable to infection than most.1 The elevated risk factors for COVID‐19 are substantial, as people experiencing homelessness have a much higher prevalence of comorbidity and chronic disease compared with people of the same age who are housed.2 To illustrate further, among the 4000 active patients seen by Homeless Healthcare (Australia's largest specialist homelessness GP practice based in Perth), nearly all patients have comorbidities, 13% have chronic respiratory conditions, 79% smoke (associated with poorer lung health and risk) and 8% have diabetes (associated with supressed immunity). There are parallel calls in Australia and the United Kingdom for clearer government guidance as to how the precautionary measures can be applied in homeless populations. There are a myriad of challenges to this, both for people who are homeless themselves and for those providing health care to this vulnerable population group. These challenges include: Regular hand washing and hygiene (and accessing soap or sanitiser and bathrooms in order to do this) is extremely problematic if living on the street. Self‐isolation by staying at home if you feel unwell and suspect having symptoms is impossible if you do not have a home to live in. Reducing face‐to‐face health service contact is being advocated to GPs and health services in Australia and the UK. The Australian Government has just announced Medicare rebates for bulk‐billed telephone consultations,3 but this is problematic for people who are homeless without a phone. Similarly, technological solutions such as video or virtual consultations are digitally prohibitive for people without a home let alone a computer. Outreach health services are among the most effective ways of enabling people who are rough sleeping to access health care.4 Homeless Healthcare, for example, runs clinics at drop‐in centres and crisis accommodation settings and has nurses out on the streets each day and doing home visits to those recently housed. However, implementing the use of personal protective equipment is difficult in these settings, and in the absence of primary care outreach, emergency department presentations are likely to escalate. Cancelling outreach GP clinics and other outreach services for this population to reduce exposure risks would have severe unintended consequences. If risk factors for COVID‐19 or patients with COVID‐19 are untreated in this highly susceptible population, the mortality risk is high.1 Moreover, many people will not receive critical treatment for other medical conditions, such as depot medications for psychotic illness and, as articulated in a recently published article, “lockdowns and disease containment procedures might also be deleterious to the mental health of people experiencing homelessness, many of whom have fears around involuntary hospitalisation and incarceration”.1 The higher risks of COVID‐19 for people experiencing homelessness and, consequently, for those working closely with them present an enormous challenge that has no easy answers. As new precautionary measures are being announced daily, it is critical that further marginalisation for this group is not an unintended consequence.

Lisa J Wood · Andrew P Davies · Zana Khan

Weather conditions conducive to extreme bushfires are becoming more frequent as a consequence of climate change.1 Such fires have substantial social, ecological, and economic effects, including the effects on public health associated with smoke, such as premature mortality and exacerbation of cardio‐respiratory conditions.2,3 During the final quarter of 2019 and the first of 2020, bushfires burned in many forested regions of Australia, and smoke affected large numbers of people in New South Wales, Queensland, the Australian Capital Territory and Victoria. The scale and duration of these bushfires was unprecedented in Australia. We undertook a preliminary evaluation of the health burden attributable to air pollution generated by bushfires during this period. Using standard methods for assessing the health impact of air pollution,4 we estimated the numbers of excess deaths, hospitalisations for cardiovascular and respiratory problems, and emergency department presentations with asthma in NSW, Queensland, the ACT and Victoria between 1 October 2019 and 10 February 2020 that could be attributed to bushfire smoke exposure. We estimated population exposure to particulate matter less than 2.5 μm in diameter (PM2.5) for the regions of NSW, Queensland, the ACT and Victoria for which publicly available air quality monitoring data were available (for about 90% of the total population of these states). Data were obtained from the NSW Department of Planning, Industry and Environment,5 the Queensland Department of Science,6 ACT Health,7 and the Environmental Protection Agency Victoria.8 We defined bushfire smoke‐affected days as days on which the 24‐hour mean PM2.5 concentration exceeded the 95th percentile of historical daily mean values for individual air quality stations. We estimated daily mean PM2.5 levels by Statistical Area Level 2 (SA2), using station level data whenever at least one monitoring station was within 100 km of the SA2 centroid, and applying inverse distance weighting.9 Published population and health data from the Australian Bureau of Statistics,10,11 the Australian Institute of Health and Welfare,12,13,14,15 and the NSW Ministry of Health were used.16 We quantified health outcomes by combining baseline incidence rates12,13,14,15 for each health outcome with daily exposure data and applying the relevant exposure–response risk coefficients for each outcome.17,18 We also conducted sensitivity analyses with different PM2.5 thresholds for defining bushfire smoke‐affected days. Further methodological details, including underlying assumptions and limitations, are included in the online Supporting Information. Our analysis of publicly available aggregated data did not require ethics approval. During the study period, PM2.5 concentrations exceeding the 95th percentile of historical daily mean values were recorded by at least one monitoring station in the study area on 125 of 133 days (Box 1). We estimated that bushfire smoke was responsible for 417 (95% CI, 153–680) excess deaths, 1124 (95% CI, 211–2047) hospitalisations for cardiovascular problems and 2027 (95% CI, 0–4252) for respiratory problems, and 1305 (95% CI, 705–1908) presentations to emergency departments with asthma (Box 2). Applying lower thresholds for defining bushfire smoke‐affected days (no threshold, 90th percentile of historical values) did not markedly alter our findings; a higher threshold (99th percentile) reduced the estimates by about 20%. The highest population‐weighted PM2.5 exposure level, 98.5 μg/m3 on 14 January 2020 (Box 1), exceeded the national air quality 24‐hour standard (25 μg/m3)19 and was more than fourteen times the historical population‐weighted mean 24‐hour PM2.5 value of 6.8 μg/m3. We have estimated the excess health burden during 19 weeks’ continuous fire activity in the states most severely affected by smoke. Our estimates are based on air quality data from monitoring stations in the four eastern states — that is, we did not include data for smoke from all extreme fires in Australia during the study period — and we did not attempt to estimate health effects for which exposure–response relationships are less well characterised, such as primary health care attendances and ambulance calls. Detailed epidemiological analysis of more comprehensive exposure estimation and empirical health data will provide more complete information about the harms attributable to the severe air pollution associated with these unprecedented fires, but our findings indicate that the smoke‐related health impact was substantial. Smoke is just one of many problems that will intensify with the increasing frequency and severity of major bushfires associated with climate change. Expanded and diversified approaches to bushfire mitigation and adaptation to living in an increasingly hot and fire‐prone country are urgently needed.20 Box 1 – Population‐weighted PM2.5 levels, New South Wales, Queensland, the Australian Capital Territory and Victoria, 1 October 2019 – 10 February 2020* * Data by state are included in the online Supporting Information. Box 2 – Estimated health burden attributable to bushfire smoke, Queensland, New South Wales, the Australian Capital Territory and Victoria, 1 October 2019 – 10 February 2020 Outcome Estimated number of cases (95% confidence intervals) Queensland New South Wales Australian Capital Territory Victoria Total Excess deaths (any cause) 47 (17–77) 219 (81–357) 31 (12–51) 120 (44–195) 417 (153–680) Hospital admissions, cardiovascular 135 (25–246) 577 (108–1050) 82 (15–149) 331 (62–602) 1124 (211–2047) Hospital admissions, respiratory 245 (0–513) 1050 (0–2204) 147 (0–308) 585 (0–1227) 2027 (0–4252) Emergency department attendances, asthma 113 (61–165) 702 (379–1026) 89 (48–131) 401 (217–586) 1305 (705–1908)

Nicolas Borchers Arriagada · Andrew J Palmer · David MJS Bowman · Geoffrey G Morgan · Bin B Jalaludin · Fay H Johnston

The lung will tolerate the challenges of low gravity and decompression stress during lunar exploration, but dust may be the major challenge

G Kim Prisk

The increasing age and obesity rates of the Australian population are contributing to the higher prevalence of patients with obstructive sleep apnoea presenting for surgery

Nicolette R Holt · Glenn Downey · Matthew T Naughton

Medicare criteria may hinder timely diagnosis and treatment of patients

David R Hillman

National reporting for all age groups is needed to accurately determine the full burden of disease

Hannah C Moore · Christopher C Blyth

National population-level analysis provides valuable insights into severe RSV-associated disease

Gemma L Saravanos · Meru Sheel · Nusrat Homaira · Aditi Dey · Edward Brown · Han Wang · Kristine Macartney · Nicholas J Wood