Infectious diseases

To the Editor: Health care workers are at occupational risk of contracting coronavirus disease 2019 (COVID‐19) and may act as vectors of transmission. The guidelines from the Department of Health prioritise health care workers as a risk group for diagnostic testing.1,2 After confirmation of diagnosis, in addition to resolution of symptoms, polymerase chain reaction (PCR) negativity on at least two consecutive respiratory specimens collected 24 hours apart and at least 7 days after symptom onset was required before health care workers were permitted to return to work.1,2 Since 10 March 2020, there have been 11 health care workers managed at our hospital diagnosed with mild COVID‐19 not requiring hospitalisation, with repeated specimens tested by PCR (Box). All patients with COVID‐19 assessed and managed at the Austin Hospital were prospectively included in a clinical database approved by the Austin Health Human Research Ethics Committee (database reference number: CD 20002). The median time from PCR positivity to the second negative swab was 32.5 days (range, 11–53 days). None of these health care workers received any specific antiviral or immunomodulatory treatment. Our current understanding of the viral kinetics in COVID‐19 is incomplete. Pharyngeal viral shedding is very high early in the course of illness3 and may be prolonged.4 However, nucleic acid detection cannot differentiate between infectious and non‐infectious virus. In a study of nine patients with mild COVID‐19, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was not recoverable by culture after day 8 of illness despite high viral loads by PCR.3 In another contact tracing study, there were no secondary cases in the group that was exposed after 6 days.5 These findings suggest that infectivity and transmissibility is low after the initial illness. In Australia, although there was allowance for the return to work of health care workers with prolonged PCR positivity, this was predicated on rounds of testing in what was assumed to be a “small proportion of people”.1,2 Culture for viable virus is not readily available. The findings in our cohort indicate that persistent positivity is the norm and is in line with international studies.4 Current guidelines for health care workers’ return to work appear conservative, with significant workforce implications if outbreaks were to occur in health care settings. Further studies are urgently required to determine the infectivity in patients with prolonged SARS‐CoV‐2 viral shedding to find a balance in policy that benefits health care workers, hospitals and patients. Box – Health care workers with mild coronavirus disease 2019 (COVID‐19) Patient number Age (years) Sex Duration of symptoms (days) Number of swabs collected after first positive swab Days between first PCR positive swab and second negative swab* 1† 62 Male 10 5 42 2 20 Female 5 5 34 3 24 Female 1 5 32 4 32 Female Patient asymptomatic 5 33 5 56 Male 23 3 na‡ 6 26 Female 8 6 43 7§ 62 Female 28 7 53 8 50 Female 12 2 11 9 35 Female 11 2 13 10¶ 52 Female 14 3 21 11 55 Female Unable to ascertain 2 23 na = not applicable; PCR = polymerase chain reaction. * Of two consecutive negative swabs. † Patient with asthma. ‡ The last collected specimen from patient 5 was PCR positive 11 days after initial positive specimen. The nucleic acid detection assay used was the AusDiagnostics Coronavirus Typing (8‐well) assay. This is a multiplex‐tandem PCR assay that employs two rounds of amplification. The cycle take‐off value for the last positive specimen on patient 5 was 23 cycles in the second round of amplification. § Patient with hypertension. ¶ Patient with rheumatoid arthritis.

Kyra YL Chua · Natasha E Holmes · Jason Kwong

Cancer immunotherapy during the COVID‐19 pandemic presents management challenges from immune‐related toxicities, requiring careful patient selection The coronavirus disease 2019 (COVID‐19) pandemic has led to fundamental re‐evaluation of the benefits versus risks of treatment in oncology. Immunotherapy has had an expanding presence in oncology, becoming a primary systemic treatment option in diseases such as melanoma, lung, urothelial, renal, and head and neck cancers. Immune checkpoint inhibitor (ICI) therapy, namely anti‐programmed cell death protein 1 (anti‐PD‐1), anti‐programmed cell death ligand 1 (anti‐PD‐L1) and anti‐cytotoxic T‐lymphocyte‐associated protein 4 (anti‐CTLA‐4) antibodies, halt the negative regulatory checks of T lymphocytes, thus activating the immune response against tumours. Patients with cancer receiving these treatments are faced with a unique set of treatment‐related toxicities driven by an autoimmune mechanism. An association between immune‐related adverse events (irAEs) and severe COVID‐19 has been raised during the current outbreak. In particular, an overlap in the physiological insult from immunotherapy‐mediated pneumonitis and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐related interstitial pneumonia is hypothesised.1 Both conditions may present with lung parenchymal changes, and their coexistence may potentially aggravate the underlying interstitial inflammatory infiltrate and diffuse alveolar damage, leading to a common final pathway of respiratory failure. Pre‐existing lung pathology is expected to be a risk factor for COVID‐19 pneumonia, with higher incidence in patients with lung cancer and smokers.2 Whether prior thoracic radiation may have an impact on outcomes from COVID‐19 pneumonia is unknown. Parallels have been drawn between the cytokine storm driving COVID‐19‐associated acute respiratory distress syndrome and cytokine release syndrome as a complication following T cell‐engaging therapies, such as chimeric antigen receptor T cell and CD3‐based bispecific T cell engager therapies. It is known that interleukin (IL)‐6, IL‐10 and interferon (IFN)‐γ are key drivers behind cytokine release syndrome. Elevated circulating IL‐6 levels have been observed in patients with COVID‐19‐associated pneumonia.3 Patients with severe COVID‐19 have significantly higher circulating levels of pro‐inflammatory cytokines, including IL‐1B, IL‐6, IL‐8 and IL‐10, compared with milder cases of COVID‐19;3 and elevated IL‐6 has been shown to be a predictor of mortality risk. Patients with immune‐related toxicity have higher levels of 11 circulating cytokines, such as G‐CSF, GM‐CSF, IFN‐α‐2, IL‐1a, IL‐1B, IL‐2 and IL‐12,4 with some but incomplete overlap with the cytokine milieu seen in severe COVID‐19 cases.3 The outcomes of COVID‐19 in patients with cancer treated with immunotherapy remain under investigation, with some2,5 but not all6 studies suggesting a more severe outcome. In a multicentre study from China involving 105 patients with cancer infected with SARS‐CoV‐2, 6% received anti‐PD‐1 therapy within 40 days of COVID‐19 symptom onset and experienced increased risk of death and critical symptoms.2 Another series of 423 cancer patients with SARS‐CoV‐2 infection from New York City also reported that treatment with ICI therapy within 90 days was a predictor for admission to hospital and for severe respiratory illness, defined as the requirement for high flow oxygen supplementation or mechanical ventilation.5 Of interest, even after exclusion of patients with lung cancer, the ICI group experienced worse outcomes, inferring that the ICI therapy itself conferred inferior COVID‐19 outcomes without the confounding effect of lung cancer, which had been shown as an independent predictor of poor prognosis in COVID‐19. However, an interim analysis of the first 200 patients from the Thoracic Cancers International COVID‐19 Collaboration (TERAVOLT) registry of patients with thoracic malignancies did not observe a worse outcome among the 37% of patients receiving ICI therapy (23% ICI alone and 14% ICI plus chemotherapy), with data collection ongoing.6 Dual checkpoint inhibitor (anti‐CTLA4 with anti‐PD1 antibody) therapy has achieved high response rates in a number of cancer types,7,8 but is associated with greater incidence and severity of treatment‐related toxicity compared with monotherapy.7 This has several implications. Firstly, differentiating between immune‐mediated pneumonitis and COVID‐19‐associated pneumonia can be difficult due to similarities in clinical and radiological features. Earlier in the pandemic, there were concerns that this may cause delays in initiation of corticosteroids, which is the standard management of irAEs. However, emerging evidence for potential benefit of dexamethasone in severe cases of COVID‐199 reduces concerns for its empirical use in cases where immune‐mediated pneumonitis is a differential diagnosis. Secondly, patients with severe irAEs, such as immune‐mediated pneumonitis requiring intensive care support may face a health system already strained by demand from COVID‐19 cases. Finally, severe irAEs require treatment with high dose corticosteroid and, at times, additional immunosuppressive agents, such as infliximab and mycophenolate. To avoid rebound of the irAEs, corticosteroids are weaned over 6–8 weeks, subjecting patients to prolonged immunosuppression that can predispose them to opportunistic and nosocomial infections.10,11 This has the potential to add further burden to the health care system. The impact of cancer immunotherapy on microbial infection in general is not fully understood. A retrospective study of patients with metastatic melanoma receiving immunotherapy (mainly ipilimumab, an anti‐CTLA4 antibody) reported a 7.3% incidence of serious infections due to a variety of bacterial, viral, fungal or parasitic infections requiring hospitalisation or parenteral antimicrobials.10 Nonetheless, the study of this interaction is complex, with the receipt of corticosteroids for irAEs and having diabetes as a comorbidity10,12 associated with an increased risk of infection in patients with cancer receiving ICI therapy. Furthermore, immune checkpoint blockade can reactivate tuberculosis and viral infections. There are case reports of acute tuberculosis developing in patients with cancer receiving immunotherapy, without concurrent corticosteroid therapy.13 At least three of five cases were suspected to represent reactivation of latent tuberculosis, which may be directly mediated through PD‐1 inhibition driving an exaggerated immune response to tuberculosis infection. Another consideration for patients with cancer receiving immunotherapy is influenza vaccination during the COVID‐19 pandemic. While there is currently no vaccine specifically against COVID‐19, many health authorities encourage the uptake of influenza vaccination to reduce the concurrent burden from influenza illnesses, particularly for nations approaching winter facing the seasonal influenza period. Controversy surrounds whether influenza vaccination in patients receiving cancer immunotherapy heightens the risk of irAEs.14 Numerous retrospective series support the safety of inactivated influenza vaccine in recipients of anti‐PD‐1 monotherapy, with no increase in irAEs observed.15 Reassuringly, influenza vaccination had no adverse impact on the anticancer effect of ICI therapy.14,15 However, there may be heightened concerns for influenza vaccination in combination immunotherapy (anti‐PD‐1 with anti‐CTLA‐4) recipients, as they are more prone to irAEs, including rarer, but potentially fatal, complications such as immune‐mediated myocarditis. This potential concern for influenza vaccination in recipients of combination ICI can leave this patient population more vulnerable from influenza infection. For patients taking monotherapy ICI, current evidence supports the safety and efficacy for influenza vaccination. There are guidelines addressing the use of cancer immunotherapy in the COVID‐19 era.16,17 These call for careful considerations on the use of dual checkpoint inhibitor therapy depending on the local prevalence of community transmission and the capacity of the local health service to cope with demand.16 On a practical note, this requires individual patient risk–benefit assessment. Patient factors such as age, smoking and comorbidities (eg, diabetes and chronic obstructive pulmonary disease) may affect their recovery from irAEs and affect the outcomes from concomitant COVID‐19. Tumour factors for consideration include the burden and biology of disease. Combination immunotherapy may be justified, for example, in a young patient with metastatic melanoma with high disease burden and/or intracranial metastases. This is in contrast to a patient with underlying comorbidities who has low volume disease and/or disease characteristics, such as underlying B‐Raf proto‐oncogene (BRAF) V600K mutation or desmoplastic melanoma subtype, associated with higher likelihood of response to single‐agent anti‐PD‐1/anti‐PD‐L1 therapy. Current guidelines recommend ICI monotherapy to be delivered at increased dosing intervals, such as nivolumab four times per week and pembrolizumab six times per week.16 These approved alternate schedules have been shown to maintain therapeutic efficacy, while advantageous in reducing patient attendance at health care facilities, potentially reducing exposure and community transmission of COVID‐19. The timing of immunotherapy cessation in patients is another consideration. A number of trials in metastatic non‐small cell lung cancer had a 2‐year treatment duration for immunotherapy in responding patients.18 Data on metastatic melanoma support that cessation of anti‐PD‐1 after at least 6 months of therapy in patients achieving complete response can be feasible without adversely affecting outcome.19 Selection of patients with cancer suitable to stop immunotherapy may further reduce these patients’ hospital visits and may potentially reduce the chance of acquiring COVID‐19. There are international efforts to collate the clinical experience of COVID‐19 in patients receiving cancer immunotherapy.6 These registries will provide a valuable resource for further areas of research, such as assessing the impact of irAEs on COVID‐19. The data will also improve our understanding of the outcomes in this patient population to aid management decisions and counsel patients. Research on potential biomarkers of disease severity may also assist in patient triage. In this rapidly evolving area, it is helpful for practising clinicians to maintain current knowledge through regularly updated resources (Box). In summary, the increased role of ICI therapy in oncology calls for consideration of the impact of their use during the COVID‐19 pandemic. While these agents are not directly immunosuppressive, as with cytotoxic chemotherapy, ICI‐associated toxicities pose diagnostic and therapeutic challenges for management in the setting of a COVID‐19 outbreak. Overlapping clinical and radiographic features in immune‐mediated pneumonitis and COVID‐19‐associated pneumonia may cause diagnostic difficulties at initial presentation. Severe irAEs requiring corticosteroids and prolonged immunosuppression may predispose patients to opportunistic infections. Furthermore, there is a possibility of worse outcomes in the setting of COVID‐19 with underlying immune‐mediated pneumonitis and damaging inflammatory response from immune checkpoint blockade. Practical measures, namely prolonging treatment interval and careful patient selection for combination ICI therapy, may help minimise harm. Box – Practice points for cancer immunotherapy during the coronavirus disease 2019 (COVID‐19) pandemic Judicious use of combination anti‐CTLA-4 and anti‐PD-1/anti‐PD-L1 immunotherapy in patients requiring high tumour response rate with good organ functional reserve. Combination checkpoint therapy is associated with higher rate for immune‐related toxicities (eg, pneumonitis), which may potentially have an adverse impact on outcomes in patients with COVID‐19 Use of approved dosing schedule with longer duration between treatments (eg, nivolumab every 4 weeks, pembrolizumab every 6 weeks) Individualised assessment for pausing or cessation of immunotherapy in patients with controlled low disease burden Rapid assessment and COVID‐19 testing for patients receiving cancer immunotherapy who have clinical presentations with overlapping features for COVID‐19 and immune‐related adverse events Prevention of co‐infections: seasonal influenza vaccination for patients taking single‐agent immune checkpoint inhibitor (the use in combination checkpoint recipients should be individualised). Pneumocystis jirovecii prophylaxis for patients receiving prolonged corticosteroid therapy for immune‐mediated toxicities Maintain current knowledge through professional journals, dynamic resource links (examples below) and webinars sharing clinical knowledge and experience internationally: ▸ Clinical Oncology Society of Australia (https://www.cosa.org.au/publications/covid‐19-updates/articles/) ▸ American Society of Clinical Oncology (https://www.asco.org/asco-coronavirus‐information) ▸ European Society for Medical Oncology (https://www.esmo.org/covid‐19-and‐cancer/covid‐19-full‐coverage) ▸ Journal of Thoracic Oncology (https://www.jto.org/content/covid19) anti‐CTLA‐4 = anti‐cytotoxic T‐lymphocyte‐associated protein 4; anti‐PD‐1 = anti‐programmed cell death protein 1; anti‐PD‐L1 = anti‐programmed cell death ligand 1.

Yada Kanjanapan · Desmond Yip

To the Editor: Travel restrictions to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus that causes coronavirus disease 2019 (COVID‐19), were rapidly implemented in Australia. Despite its apparent efficacy, this proactive approach has been criticised as unscientific and in breach of the International Health Regulations. A recently published comment1 claimed that travel restrictions were implemented without supporting scientific evidence and had “been challenged by public health researchers”, citing research on Ebola and influenza. However, their interpretation is not consistent with an evidence‐based approach. When managing a novel infection, evidence‐based decision making should (i) use the best available relevant information that is generalisable to the novel infection — for example, an infection with a similar route of transmission; that is, not Ebola, but rather severe acute respiratory syndrome (SARS), influenza, and Middle East respiratory syndrome (MERS) — and (ii) clearly define the outcome of interest (eg, prevention v delay). A recent review2 of travel restrictions for emerging infectious diseases, including SARS and MERS, found only one study regarding coronaviruses. The evidence identified supports the use of air travel bans to prevent the spread of coronavirus epidemics.2 Furthermore, systematic reviews,3,4,5 including the review4 cited in the comment,1 have reported that travel restrictions delayed, but did not prevent, the spread of influenza.3,4 These delays were up to 4 months,4 and up to 10 months if implemented in combination with other local strategies.5 At the start of the COVID‐19 pandemic, this reflected the best available evidence to make evidence‐based decisions regarding travel restrictions. The evidence suggests that travel restrictions may, therefore, be used to delay and attenuate the peak in case numbers to reduce the burden on the health system, allowing for preparations to be made to better manage the outbreak. The preparation measures may include upskilling the health care workforce, building new facilities, improving access to laboratory testing and ventilators, and stockpiling personal protective equipment. This is the primary goal of travel restrictions as public health interventions. We conclude that Australia's rapid introduction of travel restrictions is consistent with an evidence‐based approach that prioritises the precautionary principle and saving lives.

Jessica Stanhope · Philip Weinstein

To the Editor: Infectious diseases physicians and microbiologists are pivotal in guiding the response to the coronavirus disease 2019 (COVID‐19) pandemic. Their involvement ranges from managing cases and coordinating local responses to establishing timely and accurate diagnostic testing.1,2 We conducted a survey of infectious diseases physicians and microbiologists in Australia and New Zealand in early March 2020 to assess the impact on workload and the perspectives of infectious diseases physicians in the pre‐pandemic period. Responses were received from 214/600 infectious diseases physicians (35.6%) and 55/310 practising microbiologists (17.7%). During February 2020, infectious diseases physicians spent a median of 27 hours (interquartile range [IQR], 17–50 h) on COVID‐19‐related activities. Microbiologists worked a median of 8 hours (IQR, 2.5–8 h) overtime per week, and nearly one‐third of infectious diseases physicians (70/214) worked late hours at least 3 days a week on COVID‐19‐related activities. While many doctors have been less busy than usual lately,3 infectious diseases physicians and microbiologists have been busier than ever. At the time of the survey, only 45% (95/212) of infectious diseases physicians agreed that the government's response was well coordinated. Similarly, only 25% (11/42) of microbiologists felt that advice from laboratory regulatory bodies was of assistance. This feedback highlights the confusion and lack of clarity that many clinicians experienced at the beginning of the pandemic. To improve coordination and response, we advocate for the establishment of a national Centre for Disease Prevention and Control.4 This Centre would need to be supported politically and financially by the federal government and all jurisdictions to be effective. Reflecting the current lack of clear data about therapeutic options for patients with COVID‐19, over three‐quarters (169, 79%) of infectious diseases physicians felt they had equipoise for a clinical trial of specific antiretroviral. We advocate for investigational agents for COVID‐19 to only be used in the context of a clinical trial.5 At this time of great challenge to the Australian and New Zealand health care systems, infectious diseases physicians and microbiologists stand with all health care professionals and members of the community. The unedited version of this article was published as a preprint on mja.com.au on 20 August 2020.

On behalf of the Australasian Society for Infectious Diseases Clinical Research Network

Introduction: Coronavirus disease 2019 (COVID‐19) is a contagious disease that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Health care workers are at risk of infection from aerosolisation of respiratory secretions, droplet and contact spread. There are a number of procedures that represent a high risk of aerosol generation during cardiothoracic surgery. It is important that adequate training, equipment and procedures are in place to reduce that risk. Recommendations: We provide a number of key recommendations, which reduce the risk of aerosol generation during cardiothoracic surgery and help protect patients and staff. These include general measures such as patient risk stratification, appropriate use of personal protective equipment, consideration to delay surgery in positive patients, and careful attention to theatre planning and preparation. There are also recommended procedural interventions during airway management, transoesophageal echocardiography, cardiopulmonary bypass, chest drain management and specific cardiothoracic surgical procedures. Controversies exist regarding the management of low risk patients undergoing procedures at high risk of aerosol generation, and recommendations for these patients will change depending on the regional prevalence, risk of community transmission and the potential for asymptomatic patients attending for these procedures. Changes in management as a result of this statement: This statement reflects changes in management based on expert opinion, national guidelines and available evidence. Our knowledge with regard to COVID‐19 continues to evolve and with this, guidance may change and develop. Our colleagues are urged to follow national guidelines and institutional recommendations regarding best practices to protect their patients and themselves. Endorsed by: Australian and New Zealand Society of Cardiac and Thoracic Surgeons and the Anaesthetic Continuing Education Cardiac Thoracic Vascular and Perfusion Special Interest Group.

Joanne F Irons · Warren Pavey · Jayme S Bennetts · Emily Granger · Elli Tutungi · Aubrey Almeida

Fit testing of respirators is recommended to ensure proper fit for individual health care workers and is required to comply with respirator standards

Adrian Regli · Britta S Ungern‐Sternberg

As we face a second wave of the pandemic, mobility data may assist government public health action

Lucinda Adams · Robert J Adams · Tarun Bastiampillai

Objectives: To assess catch‐up vaccination of older children and adolescents during the first two years of the “No jab, no pay” policy linking eligibility for federal family assistance payments with childhood vaccination status. Design, setting, participants: Cross‐sectional analysis of Australian Immunisation Register data on catch‐up vaccination of children aged 5 to less than 7 years before (January 2013 – December 2014; baseline) and during the first two years of “No jab, no pay” (December 2015 – December 2017), and of children aged 7 to less than 10 years and young people aged 10 to less than 20 years (“No jab, no pay” period only). Main outcomes: Catch‐up vaccination rates for measles–mumps–rubella vaccine second dose (MMR2), by age group, Indigenous status, and socio‐economic status; catch‐up vaccination of children aged 5 to less than 7 years (third dose of diphtheria–tetanus–pertussis vaccine [DTPa3], MMR1), before and after introduction of “No jab, no pay”. Results: The proportion of incompletely vaccinated children aged 5 to less than 7 years who received catch‐up DTPa3 was higher under “No jab, no pay” than during the baseline period (15.5% v 9.4%). Of 407 332 incompletely vaccinated people aged 10 to less than 20 years, 71 502 (17.6%) received catch‐up MMR2 during the first two years of “No jab, no pay”, increasing overall coverage for this age group from 86.6% to 89.0%. MMR2 catch‐up activity in this age group was greater in the lowest socio‐economic status areas than in the highest status areas (29.1% v 7.6%), and also for Indigenous than for non‐Indigenous Australians (35.8% v 17.1%). MMR2 catch‐up activity in 2016 and 2017 peaked mid‐year. Conclusions: Linking family assistance payments with childhood vaccination status and associated program improvements were followed by substantial catch‐up vaccination activity, particularly in young people from families of lower socio‐economic status.

Brynley P Hull · Frank H Beard · Alexandra J Hendry · Aditi Dey · Kristine Macartney

To the Editor: Torda and colleagues1 highlight the impact of the coronavirus disease 2019 (COVID‐19) pandemic on medical education, which has prompted the rapid shift to online teaching for medical students. We need to ensure that these recent changes in medical education are thoughtfully blended with the reintroduction of face‐to‐face teaching when it occurs. Before integrating these changes, it is critical we reflect and review three key elements: Preparing students: blended learning, where online learning is combined with traditional face‐to-face teaching, is likely to capture more students’ learning styles but is also often associated with increased need for self‐directed learning, which may mainly benefit high achieving students.2,3 It is critical we equip all our students to engage effectively in adult learning to maximise the benefits of blended learning and develop engaged independent learners.4 This is an opportunity to develop these skills by ensuring that staged and increasing self‐directedness is built into new material and forms of delivery.5 Preparing educators: the attitude and preparedness of educators running or engaging in online education is crucial. As vital stakeholders, lecturers should be seen as educators and be supported and developed as such, including the training in both design and delivery of online learning.6 Preparing delivery and its content: facing the option of moving material back from online learning to face‐to-face learning, each move must be critically analysed to determine what is the most effective form of delivery. Historical modes of delivery need not be the default. Indeed, we have been given a once in a lifetime opportunity for a major, if incidental, review of each part of the curriculum and the best way it can be delivered — online, face‐to-face, or maybe a mix of both. As the mode of delivery is reviewed, the content can be refined and tailored for the students’ needs. Many of us know the deafening and discouraging silence when students are quiet in response to a question, both face‐to‐face and online. However, we are at a turning point in medical education where we must take the time to reflect and move forward with excitement regarding what has worked, and have the courage to leave behind what has not.

Lucy E Kirk · Imogen Mitchell

To the Editor: Takotsubo syndrome, also known as stress cardiomyopathy, apical ballooning syndrome, or broken heart syndrome, is a reversible cardiomyopathy frequently precipitated by a stressful event. Its clinical presentation is indistinguishable from a myocardial infarction,1 with electrocardiogram (ECG) changes and elevation in cardiac enzymes. The syndrome was first described in 1991 in Japan and named in reference to the left ventricle morphological features that resemble a pot used for trapping octopuses. Takotsubo syndrome has recently been reported in association with coronavirus disease 2019 (COVID‐19),2 but we report a case of takotsubo cardiomyopathy brought on by the stress of isolation as a result of social distancing. A 71‐year‐old woman presented to the emergency department complaining of chest pain. On arrival, an ECG demonstrated diffuse ST elevation (Box) and troponin was elevated (7800 ng/L). Coronary angiography was performed immediately which did not demonstrate any obstructive lesion and she was admitted to the intensive care unit (ICU) for ongoing haemodynamic support. Echocardiography performed in the ICU showed a dilated left ventricle with an akinetic apex and preserved contraction of the basal segments (Box) suggestive of takotsubo cardiomyopathy. On questioning regarding recent stressors, our patient, who lived alone, reported significant anxiety about not being able to visit family due to social distancing, and was particularly saddened by being unable to see her grandchildren. Public health interventions undertaken by governments around the world in an attempt to reduce the rate of transmission of COVID‐19, or to “flatten the curve”, have included measures such as social distancing.3 While being effective in the aim of lowering infections, these measures may have many unintended consequences. Social isolation is detrimental to mental health, associated with increased stress levels and anxiety, especially in older people, who may be less able to use technology to stay in contact with friends and family.4 In our patient, this stress was enough to trigger takotsubo cardiomyopathy. Box – Electrocardiogram (A) showing diffuse ST elevation. Echocardiogram (B) showing a dilated left ventricle with an akinetic apex and preserved contraction of the basal segments (arrows)

Jon Rivers · Joshua F Ihle

Modelling suggests that elimination could have been achieved if Victoria had gone into stage 4 lockdown immediately from 9 July Victoria is the unlucky state in a lucky country. Australian states and territories, other than New South Wales, have achieved elimination of community transmission of the sudden acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2): 28 days of no locally acquired cases where the source is unknown; twice the maximum incubation period. The situation in NSW is mixed. On one hand, NSW had ongoing case notifications of 10–20 per day in the month to mid‐August 2020, arising largely from imported cases from Victoria. On the other hand, on 16 July there had only been three locally acquired cases of SARS‐CoV‐2 infection with no known source in the preceding 28 days, suggesting NSW was on the cusp of elimination.1 If NSW successfully contains the current outbreak, it may resume its prior trajectory towards the elimination of local transmission, leaving Victoria isolated as the only state with community transmission. As of late August, Queensland is also experiencing community transmission — possibly ending its elimination status (28 days of no locally acquired cases where the source is unknown), subject to investigation of the new cases. It seems unlikely that states and territories that have eliminated local transmission will relinquish their status by freely opening borders and engaging with Victoria (and NSW if community transmission remains). Indeed, on 17 August the Queensland Premier stated: “Let me make it very clear, we will always put Queenslanders first and … we do not have any intentions of opening any borders while there is community transmission active in Victoria and in New South Wales”.2 Australia proceeding with two separate systems (six or seven states and territories having eliminated the virus, one or two not) is a significant concern. There are three general strategic policy responses to the challenge of coronavirus disease 2019 (COVID‐19): elimination, suppression, and mitigation (or herd immunity). No response is free of economic, social and health harms; rather, it is about minimising harm. Society has largely rejected a mitigation response because of concerns about the likely high morbidity and mortality arising from such a response. On 24 July, the Australian Health Protection Principal Committee recommended “that the goal for Australia is to have no community transmission of COVID‐19”,3 and on the same day Prime Minister Scott Morrison accepted and affirmed this recommendation, stating “The goal of that is obviously, and has always been no community transmission”.4 Unfortunately, this first clear statement that Australia's goal is to eliminate community transmission was late in coming, as the Victorian outbreak was already in full swing, with case numbers peaking at a 5‐day average of about 500 per day from 29 July to 5 August, resulting in a stage 4 lockdown in metropolitan Melbourne from 6 pm on 2 August. Elimination strategy We know from New Zealand (population, 5.0 million)5 and Taiwan (23.8 million)6 that elimination of community transmission is achievable in island jurisdictions, with NZ having no community transmission for 102 days until 11 August. The advantage of elimination is that despite international border closures or strict quarantine, citizens can go about life with a near‐normal functioning of their society and economy. Elimination presents challenges. First, there is the extra effort to achieve it, and the fact that aiming to achieve elimination does not guarantee success. Second, having achieved elimination, there is the constant risk of the virus re‐entering due to quarantine breaches (eg, the current outbreak in NZ). How frequently a COVID‐19‐free jurisdiction with tight border controls will retain elimination status is unclear, although we know that NZ lasted 102 days with no community transmission and that Western Australia, Northern Territory, South Australia, Australian Capital Territory, Queensland and Tasmania achieved over 100 days without a locally acquired case with no known source (although the status of Queensland is unclear as of early September). Was elimination achievable with a 6‐week stage 3 lockdown as implemented in Victoria from 9 July, or a more stringent lockdown? Lockdowns are effective for COVID‐19 pandemic control.7,8 Our case for an explicit elimination strategy in Victoria at lockdown commencement in early July was that given Victoria was going into a lockdown for 6 weeks, there was probably only a marginal extra cost of “going hard” with a rigorous public health response that increased the probability of achieving elimination. But was elimination achievable within 6 weeks? We examined four policy scenarios using an agent‐based model, a type of microsimulation of individuals. The model accurately reflects the prior experience of both NZ and Australia ( https://github.com/JTHooker/COVIDModel), and here we adapted it to Victoria (including the case counts up to 14 July; see Supporting Information for details). The four policy approaches, all simulated from 9 July 2020, were: Standard: reflecting the first Australian stage 3 lockdown (calibrated to case numbers as described at https://github.com/JTHooker/COVIDModel), with key parameters including 85% of people observing physical distancing; those observing physical distancing doing so 85% of the time; 30% of adult workers being essential workers; 93% of people asked to isolate doing so; 20% uptake of the COVIDSafe app; but no closure of schools and no mask wearing. Standard with masks at 50%: Standard, plus 50% of people wearing masks in crowded indoor environments. Stringent with masks at 50%: Standard with masks at 50%, plus schools closed and essential workers restricted to 20% of workers. Stringent with masks at 90%: Stringent, with mask use increased to 90% (ie, close to stage 4, which was implemented in Melbourne from 6 pm on 2 August after the 5‐day moving average case numbers increased from 300 to 500 in the first 3 weeks of stage 3). Box 1 shows the percentage likelihood of elimination in Victoria, defined as the date of clearance of infection by the last case, and the date of last acquisition of infection. The model is omniscient about infectious status; in the real world, based on a definition of 28 days of no cases, elimination would occur about 2 weeks after the clearance dates shown in Box 1, A. Under the “standard” policy approach (ie, equivalent to stage 3 without masks), there was no chance that all infected people would have cleared their SARS‐CoV‐2 infection by 19 August (6 weeks after lockdown commenced; Box 1, A). The probabilities for the other three policy approaches achieving elimination 6 weeks after implementation (Box 1, A) were 0% for “standard with masks at 50%”; about 4% for “stringent with masks at 50%”; and 30% for “stringent with masks at 90%”. The probabilities of the last actual infection occurring by 19 August were more encouraging at 0%, 1%, 45% and 90%, respectively (Box 1, B). Of particular note, given that the stage 3 lockdown imposed on 9 July failed because caseloads increased to an average of 500 per day, in our simulations 48% of the 1000 iterations of the “standard” scenario (stage 3, no masks) and 22% of the 1000 iterations for “standard with masks at 50%” had peaks in the first 3 weeks in excess of 400 per day. This is consistent with what eventuated, and further speaks (in hindsight) to the desirability of entering a stage 4 lockdown on 9 July; the “stringent with masks at 90%” scenario had no instances of peak cases greater than 400 per day in the first 3 weeks. Undertaking simulation modelling of SARS‐CoV‐2 policy options is challenging and the uncertainties are still considerable even when using the best estimates available. Nevertheless, our results lend weight to the proposition that elimination was achievable if Victoria had gone into stage 4 lockdown with mandatory wearing of masks immediately from 9 July. A ten‐point plan to maximise the chance of elimination in Victoria Box 2 lists enhancements to the stay‐at‐home orders of the 9 July lockdown. The first and critical point was leadership. As above, we did get a clear statement of an elimination goal from the Chief Health Officers (who comprise the Australian Health Protection Principal Committee membership) and Prime Minister Scott Morrison on 24 July, but with the benefit of hindsight it was perhaps too late. Target‐setting is still not occurring (eg, a target number of cases per day could be set for when we step out of stage 4 under both elimination and suppression strategy options). Moreover, an expert advisory group on elimination was not convened, limiting the capacity for an optimal evidence‐informed policy response. Nevertheless, since the 9 July lockdown, progress with other aspects of the ten‐point plan has been made with the closure of schools, mandatory mask wearing, and commitments to improve contact tracing capacity. Conclusion We argued in the preprint version of this article on 17 July that Melbourne and Victoria should not waste the opportunity that the (then) 6‐week lockdown presented and go hard and early. By learning from the lessons on social and preventive measures to lower SARS‐CoV‐2 transmissibility,7,8,12,14 and specifically the lessons from NZ,3 Taiwan and the six Australian jurisdictions that have achieved elimination, Victoria could have increased its chances of also eliminating community transmission. Our work and that of others who have independently considered the alternatives consistently demonstrates that elimination was possible, and if achieved would have been optimal for health and for the economy in the long term.15,16,17 In this article, we modelled the situation as at mid‐July — we are now updating modelling under the current situation. Authors’ note: This Perspective was submitted to the MJA on 16 July 2020 and published as a preprint on 17 July.9 The revised version, submitted on 23 August, retains the simulation modelling of the original but the uncertainty of inputs was updated to include uncertainty other than stochastic uncertainty. Our aim was rapid modelling to estimate the probability of virus elimination during the planned 6‐week stage 3 lockdown that Victoria had just commenced. The revised version was also published as a preprint on mja.com.au on 4 September, following full peer review and prior to typesetting, pagination and proofreading. Box 1 – Percentage likelihood of elimination of community transmission of SARS‐CoV‐2 infection in Victoria, by date of clearance of last active infection (A) and date of acquisition of last infection (B)* * Across 1000 Monte Carlo simulations in an agent‐based SEIR (susceptible, exposed, infectious, recovered) model. The vertical dashed line is the date 6 weeks after implementation of the lockdown policies. Compared with modelling published in the preprint version of this article,9 the only change here is the inclusion of additional parameter uncertainty in addition to stochastic uncertainty (see Supporting Information), resulting in increased sloping in the curves due to a wider range of potential parameter values (ie, the time distribution to elimination is wider). Box 2 – A ten‐point plan to maximise the chance of successful elimination of community transmission of SARS‐CoV‐2 in Victoria, based on the planned 6‐week lockdown from 9 July 2020 (as published on 17 July 2020)9 Strong and decisive leadership with strategic clarity. An explicit goal of elimination should be articulated, learning from the New Zealand experience (Prime Minister Jacinda Ardern, government ministers and senior officials).10 A clear set of targets for loosening of policies needs to be articulated, so citizens know what is likely to happen and when. Convene an advisory group of experts in the elimination strategy and SARS‐CoV‐2 public health response, reporting weekly to the Victorian Chief Health Officer, with the agenda, papers and minutes made publicly available. Close all schools. Although children do not usually suffer severe illness from SARS‐CoV‐2 infection, the virus still transmits between children and staff in schools.11 Accordingly, schools need to close until such time as the daily rate of SARS‐CoV‐2 infection without a known source falls beneath a target set by the Chief Health Officer. Tighten the definition of essential shops to remain open. Supermarkets and chemists need to remain open. However, department stores and hardware stores should be closed. A staged re‐opening based on set target levels of daily numbers of SARS‐CoV‐2 infection without a known source should then be implemented, so long as mask wearing by both staff and patrons is mandatory, along with hand sanitiser use on entry and exit from stores. Require mask wearing by Melbourne residents in indoor environments where 1.5 m physical distancing cannot be ensured, such as supermarkets and (especially) public transport. While no panacea, the wearing of masks reduces the chance of infected people spreading the virus.12 Tighten the definition of essential workers and work. There is currently a loose definition of who is an essential worker and what is essential work. This needs urgent tightening; for example, as per the NZ definitions used in their level 4 lockdown.13 Require mask wearing by essential workers whenever they are in close contact with people other than those in their immediate household. Ensure financial and other supports to businesses, community and other groups most affected by more stringent stay‐at-home and lockdown requirements, and provide enhancements, targeted where warranted, to programs such as JobKeeper and JobSeeker. Further strengthen contact tracing to ensure the majority of notifications (and their close contacts) are interviewed within 24 hours of the index case notification and placed in isolation if necessary. The use of smart phone and digital adjuncts needs to be improved, be that for initial contact tracing (eg, the COVIDSafe app, or a South Korean‐style use of telecommunications data) or monitoring of adequacy of isolation (eg, text message follow‐up, GPS monitoring, or electronic bracelets). Extend suspension of international arrivals into Victorian quarantine and divert resources. To allow a stronger focus on elimination within Victoria, extend the suspension of international arrivals to Victoria. Quarantine capacity can be redeployed for isolation of Melbourne residents infected with SARS‐CoV‐2 (and potentially high risk close contacts) if they do not have satisfactory home environments for self‐isolation.

Tony Blakely · Jason Thompson · Natalie Carvalho · Laxman Bablani · Nick Wilson · Mark Stevenson

The coronavirus disease 2019 (COVID‑19) pandemic has forced many countries to take extraordinary measures to prevent spread of disease. In New South Wales, public health orders introduced during 18–26 March 2020 required the closure of major industries and prohibited non‐essential gatherings of more than 100 people or allowing less than 4 m2 space per person. On 29 March, further public health orders prohibited people leaving home other than for work, study, shopping, medical care, or exercise.1,2 Changes in patterns of presentations to emergency departments (EDs) have been reported during COVID‐19 lockdowns overseas, including reduced numbers of patients with certain high acuity conditions, such as acute coronary syndrome (ACS) and stroke.3,4,5 Understanding the situation in Australia is important for public health policy during this and future pandemics. The Western Sydney Local Health District is a metropolitan health network in NSW of four hospitals (each with EDs) with a total capacity of 1925 beds, serving a catchment of 950 000 people. We analysed triage, International Classification of Diseases, tenth revision, Australian modification (ICD‐10‐AM) coding, and separations data for ED presentations during 29 March – 31 May in each of 2019 and 2020. Differences in mean daily presentation numbers for each triage category and selected presentation types were assessed in non‐paired Student t test with Bonferroni correction. All data analysis was performed in Excel (Microsoft). As a quality assurance project, the study was exempted from formal ethics approval. The number of ED presentations during 29 March – 31 May was almost 25% lower in 2020 than in 2019 (26 617 v 35 268). Presentation numbers in all triage categories were lower in 2020 (P < 0.001), except for category 1 (resuscitation) (506 v 445, 14% increase; P = 0.40). The proportion of patients discharged from the ED was greater in 2020 (60% v 53%) and that of patients who did not wait for treatment smaller (1% v 5%). The number of patients admitted to hospital was lower in 2020 than 2019 (8047 v 11 838), as were the proportions admitted to hospital (30% v 34%) (Box 1). ED presentations with fourteen selected diagnoses were further examined: common infectious diseases (infectious enteric disease, pneumonia), conditions frequently seen in EDs (wrist or hand fractures, femur fractures, appendicitis, renal calculi), conditions for which fewer ED presentations have been reported during COVID‐19 restrictions overseas (stroke or cerebral haemorrhage, ACS, chest pain, transient ischaemic attacks), and conditions that may be exacerbated or for which follow‐up in routine medical services may be reduced by COVID‐19 and its associated restrictions (mental health problems, substance misuse, malignancy). The numbers of presentations with infectious enteric disease, pneumonia, wrist or hand fractures, stroke or intracerebral haemorrhage, and chest pain not resulting in another diagnosis were lower in 2020 than in 2019. The numbers of presentations with ACS were similar. The number of presentations with mental health problems was higher in 2020 (daily mean, 8.4; standard deviation [SD], 3.1) than in 2019 (daily mean, 6.9; SD, 2.6; difference, +1.5 presentations per day; 95% confidence interval, +0.1–2.9) (Box 2; online Supporting Information). Social distancing may have reduced the spread of infectious enteric diseases and community‐acquired pneumonia, and home isolation may have led to fewer fractures. However, lower numbers of presentations with chest pain or stroke (also reported overseas4) may reflect factors other than lower incidence, such as suspension of outpatient clinics and elective procedures, social distancing measures, and public anxiety. COVID‐19 has profoundly affected health care delivery. We found concerning reductions in ED presentation numbers that may indicate delayed seeking of appropriate medical attention. Public health messages should encourage timely presentation of people with time‐sensitive, potentially life‐threatening conditions, even during pandemics. Equally concerning is the higher number mental health‐related presentations, which may reflect anxiety about COVID‐19, loss of job security, or prolonged isolation. Studies of patients presenting to health care services as they re‐open are required to fully appreciate the health implications of the COVID‐19 epidemic. Box 1 – Emergency department presentations to Western Sydney Local Health District hospitals during corresponding two‐month periods in 2019 and 2020 Triage category Resuscitation Emergency Urgent Semi‐urgent Non‐urgent Total 29 March – 31 May 2019 Total number of presentations 445 8910 12 464 10 726 2723 35 268 Daily presentations, mean (standard deviation) 7.0 (3.2) 139 (15.9) 195 (19.3) 168 (22.3) 42.5 (10.7) 551 (41.8) Admitted to hospital 350 (79%) 4550 (51%) 4524 (36%) 2156 (20%) 258 (9%) 11 838 (34%) Discharged: treatment complete 38 (9%) 3350 (38%) 6155 (49%) 7093 (66%) 2039 (75%) 18 675 (53%) Transferred to another hospital or service 26 (6%) 521 (6%) 577 (5%) 299 (3%) 68 (2%) 1491 (4%) Did not wait 0 65 (1%) 560 (4%) 735 (7%) 239 (9%) 1599 (5%) Discharged against medical advice 7 (2%) 413 (5%) 646 (5%) 442 (4%) 81 (3%) 1589 (5%) Died in emergency department/dead on arrival 24 (5%) 11 (< 1%) 2 (< 1%) 1 (< 1%) 38 (1%) 76 (< 1%) 29 March – 31 May 2020 Total number of presentations 506 7609 9095 7346 2061 26 617 Daily presentations, mean (standard deviation) 7.9 (2.6) 119 (18.4) 142 (17.5) 115 (17.9) 32.2 (8.4) 416 (40.6) Admitted to hospital 370 (73%) 3112 (41%) 3072 (34%) 1279 (17%) 214 (10%) 8047 (30%) Discharged: treatment complete 62 (12%) 3836 (50%) 5146 (57%) 5324 (72%) 1525 (74%) 15 893 (60%) Transferred to another hospital or service 26 (5%) 424 (6%) 461 (5%) 304 (4%) 136 (7%) 1351 (5%) Did not wait 0 22 (< 1%) 84 (1%) 170 (2%) 107 (5%) 383 (1%) Discharged against medical advice 9 (2%) 210 (3%) 328 (4%) 267 (4%) 64 (3%) 878 (3%) Died in emergency department/dead on arrival 39 (8%) 5 (< 1%) 3 (< 1%) 0 15 (1%) 62 (< 1%) Change in presentation numbers, 2020 v 2019 +14% –15% –17% –32% –25% –25% table#t1 tbody td:nth-child(n+2) P. Pleft { text-align: center; } Box 2 – Mean changes (with 95% confidence intervals) for numbers of emergency department presentations with selected diagnoses (ICD‐10‐AM codes), 29 March – 31 May 2020 v 29 March – 31 May 2019 ICD-10-AM = International Classification of Diseases, tenth revision, Australian modification. * Not resulting in another diagnosis. † Excluding cases without mention of obstruction.

Andrew W Kam · Sarah G Chaudhry · Nathan Gunasekaran · Andrew JR White · Matthew Vukasovic · Adrian T Fung

Serological assays for SARS‐CoV‐2 present challenges and opportunities Timely, scalable and accurate diagnostic testing is crucial in the prevention and control of the coronavirus disease 2019 (COVID‐19) pandemic.1 With limited treatment options and no available vaccine, the accurate and timely identification of infectious patients with COVID‐19 is instrumental to the public health outbreak response. Isolation of patients with COVID‐19, contact tracing and quarantine measures, in addition to physical distancing within the community, have proven effective in reducing case numbers.2 Due to the high sensitivity and specificity in symptomatic individuals, detection of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection by reverse transcriptase polymerase chain reaction (RT‐PCR) is the gold standard method for confirming cases of COVID‐19.3 In contrast, serological assays have lower utility in the initial investigation of suspected cases, but are essential in the development and evaluation of therapeutic agents and to inform modelling and public health policy as this pandemic progresses. As part of initial laboratory responses, Chinese investigators released the viral whole genome sequence in early January 2020, which enabled the rapid development of RT‐PCR workflows for the detection of SARS‐CoV‐2.4 However, the unprecedented scale of RT‐PCR diagnostic testing has placed extraordinary demands on health care and laboratory systems, with both challenges relating to supply chains of reagents and to the workforce resource required to support population‐level testing. Since the start of the pandemic, a range of commercially available diagnostic tests has been released, including RT‐PCR assays, point‐of‐care and laboratory‐based serological tests. These tests vary both in analytical performance and in their particular utility in the overall public health response to COVID‐19. Performance aspects of serological tests Following SARS‐CoV‐2 infection, specific antibodies to different components of this virus are generated. Depending on the antigen target used by the assay, detection of these antibodies (IgM, IgA, IgG or total antibody) may indicate exposure (non‐neutralising antibodies) or potential immunity (neutralising antibodies). To date, a range of serological tests for COVID‐19 have been developed, each with particular test characteristics (Box 1). Broadly, these serological tests can be divided into tests that (i) can be performed at the point‐of‐care; (ii) can be performed in routine diagnostic laboratories, and (iii) can only be performed in specialised reference laboratories (Box 1). The majority of point‐of‐care and laboratory‐based assays have incorporated either the nucleocapsid antigen (N) or part of the spike protein (S), often the S1 region or the receptor binding domain (RBD). The RBD has been shown to correlate well with the production of neutralising antibodies,5 while some studies have shown N to be immunodominant, producing an earlier or stronger immune response.6 Most patients with COVID‐19 seroconvert by day 10–14 (~ 80%) following the onset of symptoms, with almost 100% seroconversion by day 20.7 However, comparisons across published studies are challenging due to the different antigens used in assays, differences in the complexity of patient populations, variations in the RT‐PCR assays used as the gold standard for determining the sensitivity of serological assays, and often limited data on the timing of sample collection post‐COVID‐19 symptom onset. Further, it is not clear whether the type and amount of antibody correlate with severity of disease or, more importantly, with immune protection from re‐infection. As noted by the World Health Organization, the Australian Public Health Laboratory Network (PHLN) and the Royal College of Pathologists of Australasia (RCPA), a negative result using a serological test does not rule out SARS‐CoV‐2 infection, particularly in individuals with strong epidemiological risk factors, and both the PHLN and the RCPA note that there is no role for serological point‐of‐care tests (PoCT) in the acute diagnosis of COVID‐19.8,9 Point‐of‐care testing As some of the first COVID‐19 serological assays available, significant publicity accompanied the release of PoCT. PoCT involve detection of anti‐SARS‐CoV‐2 antibodies through binding to immobilised antigens, generally bound to colloidal gold on a test strip (Box 2). The relatively cheap and simple nature of lateral flow assays means that production is suited to scale‐up for increased testing capacity. Post‐market validation studies have demonstrated variable performance characteristics, often inferior to that reported by manufacturers, with sensitivities for IgG reported in the range of 53–100% for samples collected more than 14 days after symptom onset, and specificities of 91.7–100%.10,11 Careful test selection and consideration of the clinical utility before application are therefore critical. The National Pathology Accreditation Advisory Council has existing guidelines on the use of PoCT in Australia.12 These guidelines cover issues such as clinical supervision for performing PoCT, ensuring test quality, staff training and competency for performing PoCT, and appropriate reporting of test results. More recently, this advice has been extended to serological PoCT for COVID‐19, with an emphasis on a robust quality framework to support the implementation and deployment of such tests. Of note, in Australia, the supply of self‐testing kits (eg, testing at home) for many infectious diseases, including COVID‐19, is prohibited under another Therapeutic Goods Administration regulation, the Therapeutic Goods (Excluded Purposes) Specification 2010.13 Laboratory‐based assays A wide variety of laboratory‐based serological assays are now available, most commonly enzyme immunosorbent assays (ELISA) or chemiluminescent immunoassay (CLIA/CMIA) format. Assays may be semi‐automatic or completely automated, lending themselves to large scale testing and reporting. In general, performance characteristics have been more consistent and closer to that reported by manufacturer's compared with PoCT, with IgG sensitivities in the range of 80–100% for samples collected more than 14 days after symptom onset, and specificity commonly falling between 95% and 100%.10,11,14 Use of serological assays Given the time lag from symptom onset to detectable antibody, serological PoCT have no role in the detection of acute COVID‐19. However, there are some settings where serological assays, including PoCT, may have potential utility, including defining antibody prevalence in key populations such as frontline workers and determining the extent of COVID‐19 transmission within the community. For other applications, such as identifying individuals for further evaluation of therapeutic immunoglobulin donation and vaccine development and evaluation, assays that assess neutralising antibody response are likely to be required. Regardless of the type of serological assay used, in order to appropriately deploy serological testing, it is critical to understand the limitations of test performance in the epidemiological context in which tests are used. This is particularly important in a setting such as Australia, where, based on the number of reported cases of COVID‐19 (24 236 cases as of 20 August 2020), there is an estimated COVID‐19 period prevalence of 0.095% (January to August 2020). As such, even with serological tests that are highly sensitive and specific, the majority of positive tests are likely to represent false positive results. When considering the use of serology to inform policies relating to relaxing of physical distancing interventions, the specificity of the assay becomes critical. If most individuals considered immune actually represent false positive results, then the threshold to maintain immunity (if this indeed correlates with antibody detection) within the community will not be achieved. Consideration should therefore be given for confirmation of initial positive results by either retesting on an assay with an alternative target, or retesting with serological gold standard assays, such as microneutralisation or western blot assays.15 Application of serological assays and future research needs Understanding local transmission dynamics and/or exposure risk through serological surveys can inform local health policy at an institutional, state or national level. For example, a recent large serological survey in Spain, including more than 50 000 residents, used both PoCT and a laboratory‐based CLIA to estimate a seroprevalence across the country of 5.0%, following an initial COVID‐19 outbreak in February to April.16 It was estimated that approximately a third of cases were asymptomatic, while health care workers had a higher seropositivity than the community (10.2% v 5.0%). This is in contrast to health care workers in Belgium, where direct contact with patients with COVID‐19 did not increase the odds of being seropositive.17 The degree and duration of immunity following SARS‐CoV‐2 infection is unknown, but if in keeping with other coronaviruses (approximately 40 weeks), immunity is unlikely to be lifelong and may be shorter lived in milder infections.7 Duration of immunity is a critical area for future research, as it is the key component in models estimating the frequency of SARS‐CoV‐2 infection incidence in the coming years (eg, second or third waves, or annual seasonal COVID‐19 activity similar to influenza), and to determine the utility of policies such as “immunity passports”.18 Conclusion The unprecedented demands on laboratories to rapidly upscale testing for COVID‐19 has necessarily led to fast‐tracking of normally stringent regulatory requirements for test approval, both globally and in Australia. Following the recent publication of peer‐reviewed high quality validation data, serological testing is now available in many Australian laboratories. Serological testing will complement the current clinical utility of RT‐PCR for SARS‐CoV‐2 infection diagnosis, highlight local transmission dynamics, and further our understanding of what the future brings for the COVID‐19 pandemic. Box 1 – Main serological assays used to date for the detection of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Serological assay Detection method Advantages Disadvantages Implications Neutralisation Determines ability of test sera to inhibit live virus replication Gold standard Highly specific Requires PC3 facilities Technically demanding Slow turnaround time Low throughput Only undertaken in specialist laboratories Gold standard for initial validation of other assays and challenging cases Not suited to routine testing Indirect fluorescent antibody (IFA) Whole virus inactivated and fixed to a slide Addition of test sera with fluorescent detection of antibody binding Can be undertaken at PC2 facilities once slides prepared Less technically demanding than neutralisation assays Preparation of slides requires PC3 facilities Less specific than neutralisation Technically demanding Subjective end point Low throughput Not available in routine laboratories Not suited to large‐scale testing Enzyme immunoassay (EIA) Recombinant antigen fixed to solid surface (often 96 well plate), test sera applied and antigen–antibody binding detected by enzyme‐mediated colour change Good sensitivity Less technically demanding than IFA or neutralisation Semi‐automated High throughput Objective end point with machine‐based optical density reading Less specific than neutralisation Initial expertise and time required to determine, test and manufacture suitable recombinant antigen Generally relies on commercial companies to manufacture and distribute test kits Suitable for routine testing Good for screening Lateral flow EIA A particular type of EIA Recombinant antigen present on immunochromatographic paper, test sera applied to test pad, antigen‐antibody binding detected visually by colour change on a membrane Variable sensitivity Least technically demanding Fast turnaround time for individual tests Test on demand May be less sensitive and specific than laboratory‐based assays Limited scalability Subjective end point Data capture less robust Suited to point‐of‐care testing Can be undertaken by non‐laboratory staff Systems for data capture of results need to be implemented PC2 = physical containment level 2; PC3 = physical containment level 3. Box 2 – Schematic of a lateral flow immunoassay for detection of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) IgM and IgG antibodies* *The sample is added to the sample pad, and then travels by capillary motion to the conjugation pad. Anti‐SARS‐CoV‐2 IgM and/or IgG antibodies in the patient sample then bind to the specific SARS‐CoV‐2 antigen. This antigen is bound to colloidal gold, which acts as a colorimetric indicator. The bound antigen‐antibody‐gold complex then travels to the nitrocellulose membrane and bind to specific anti‐human IgM or IgG antibodies, with a resultant colorimetric change. To monitor test validity, excess conjugated colloidal gold binds to antibody on the control line, which allows assessment of whether the fluid has successfully migrated across the test strip. Source: Adapted from Li Z, Yi Y, Luo X, et al. Development and clinical application of a rapid IgM–IgG combined antibody test for SARS‐CoV‐2 infection diagnosis. J Med Virol 2020; https://doi.org/10.1002/jmv.25727. [Epub ahead of print]

Katherine Bond · Eloise Williams · Benjamin P Howden · Deborah A Williamson

Guidelines need to reflect the mounting evidence for airborne transmission of SARS-CoV-2

C Raina MacIntyre · Michelle Ananda‐Rajah · Mark Nicholls · Ashley L Quigley

Patience and well designed studies are important for balancing opportunity and risk in uncertain times

Michael Wagels · Dietmar W Hutmacher

Collecting nasal samples with 3D-printed swabs is feasible, acceptable to patients and health carers, and convenient

Eloise Williams · Katherine Bond · Nicole Isles · Brian Chong · Douglas Johnson · Julian Druce · Tuyet Hoang · Susan A Ballard · Victoria Hall · Stephen Muhi · Kirsty L Buising · Seok Lim · Dick Strugnell · Mike Catton · Louis B Irving · Benjamin P Howden · Eric Bert · Deborah A Williamson

To the Editor: We thank Davidson and colleagues1 for their comprehensive narrative review on skin infections in Australian Aboriginal children. A significant factor in both individual and mass drug administration therapy of scabies is the uncertainty regarding the safety of oral ivermectin in small children and during pregnancy. Australian guidelines state ivermectin should not be used in children aged under 5 years or who weigh less than 15 kg or in pregnant women.2 A retrospective cohort study of 170 children aged 1–64 months (median age, 15 months) or weighing under 15 kg treated with ivermectin (mean dose, 223 μg/kg) found only minor self‐limiting adverse effects in seven patients (4%).3 A review of previous literature found 60 children aged under 5 years or weighing less than 15 kg who had been treated with ivermectin at a dose range of 150–200 μg/kg for whom safety data were available.4 Only four of 60 children (7%) developed an adverse reaction, all of which were benign and transient, with no long term sequelae. A recent study of oral ivermectin (dose 400 μg/kg) in the treatment of head lice revealed no adverse effects in 54 children aged under 5 years.5 The Ivermectin Exposure in Small Children Study Group expected to commence the analysis in late 2019 of data collected from 2017 to 2019.6 Three studies totalling 363 women with inadvertent maternal exposure to ivermectin 150 μg/kg (76–85% in first trimester) for filariasis and onchocerciasis found no increased risk of congenital malformations, miscarriage or stillbirth.7 A study of 199 pregnancies with maternal treatment in the second trimester with ivermectin and albendazole, and 198 with ivermectin alone in the management of helminth infections, found no increased risk of adverse pregnancy outcomes.8 In France, the use of oral ivermectin is permitted during pregnancy and in children weighing less than 15 kg when topical therapy has failed.9 Further published data regarding the safety of ivermectin in these populations would be useful, particularly with respect to mass drug administration programs.

Sarah K Morton · Adam Morton

A live‐streamed teaching strategy that can be applied to all areas of medicine and many clinical scenarios The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has resulted in unprecedented challenges to hospitals, the community and society. Although the necessary focus has been to care for patients and communities, the profound effects of coronavirus disease 2019 (COVID‐19) have disrupted medical education and required intense and prompt attention from medical educators. COVID‐19 poses unique challenges to the clinical clerkship model that is fundamental to medical students’ education and has the potential to change forever how future physicians are educated.1 For more than a decade, medical schools have been working to transform pedagogy by reducing live face‐to‐face didactic lectures; using technology and simulation; implementing team‐facilitated, active and self‐directed learning; and promoting individualised and interprofessional education.2,3 However, as described by Sir William Osler, clinical teaching of medical students at the bedside remains vitally important: “to study the phenomena of disease without books is to sail an uncharted sea, while to study without patients is not to go to sea at all”.4 Medical graduates must function in a team‐based, collaborative work environment, have sound knowledge and clinical skills, and have a capacity for lifelong learning.5 In response to COVID‐19, there has been rapid development of the “boot camp” model of accelerated learning for final year medical students to support their swift transition to assistants in medicine. However, it is unclear how medical schools will manage students from the middle years of medical school, where clinical exposure is a vital part of clinical education. Typically, during years 3 and 4 of the Doctor of Medicine degree at the University of Newcastle, students spend about 50% of their time attached to wards, clinics, operating theatres and other clinical exposure opportunities. How can this clinical education continue while medical students are omitted from the clinical environment due to the COVID‐19 pandemic? Further, given that social distancing is anticipated to last many months, clinical teaching rounds with multiple medical students are unlikely to be able to recommence soon. The clinical teaching team from the University of Newcastle at John Hunter Hospital have developed the concept of “live‐streamed ward rounds”. The initiative addresses the challenge of maintaining the clinical clerkship model of education while students are excluded from the hospital for several months during the vital early years of clerkship training. This model of education has three phases (Box 1), which broadly align to advanced cognitive levels of learning expected of medical students. The Hunter New England Local Health District Ethics Committee confirmed that ethics approval was not required for this project. Phase 1: student remote observation (assess and analyse) Clinicians undertake routine ward rounds with medical students in attendance as part of routine inpatient care. During live‐streamed ward rounds, a medical student is engaged securely (password‐protected) via mobile phone to participate in the ward round, including discussion before and after a patient visit. In addition to participating in discussions, similar to face‐to‐face teaching, the student can be shown clinical records (eg, pathology results, observation charts, medical imaging, intraoperative photographs) on video via platform‐agnostic streaming software (eg, Skype for Business, Pexip, Zoom) to broaden engagement with the clinical interaction. When the patient is visited, the patient provides verbal consent for student involvement in the live‐streamed round before the consultation. This is documented in the clinical record of each patient. After obtaining verbal consent, student introduction occurs by turning the phone around so the patient can see the student and vice versa. After the introduction, the phone is turned back to the clinician so the student can see the clinician holding the phone to observe non‐verbal cues. No streaming of the clinical examination occurs during the patient encounter. When the consultation is complete, the phone is turned briefly to the patient to facilitate eye contact when the student thanks them for permission to participate in the encounter. This process is repeated with each patient on the ward round, after which the student is involved in the post‐round clinical discussion that occurs routinely as part of multidisciplinary patient care. The phone is muted or disconnected during the patient encounter if the patient declines student involvement. Phase 2: student preparation (evaluate and synthesise) During the live‐streamed ward round, the student is directed to take detailed notes so they can formulate a series of case presentations for the subsequent student case‐based ward round. The medical student obtains any missing medical information from the junior medical officer at the completion of Phase 1. Clinical records are not available electronically for the students. The aim is to prepare the student for the role of a junior medical officer in the ward environment. Phase 3: student remote case‐based ward round presentation (construct and justify) This element of the learning cycle is typically held later in the week of the live‐streamed clinical round at a time when three to 40 students can be engaged simultaneously for 60–90 minutes through videoconferencing software. The student who attended the live‐streamed clinical round presents each patient to the group as if they were a junior medical officer performing clinical handover. A clinician educator is present to facilitate case‐based discussion. After each patient is discussed, the student presents what actually occurred on the clinical round and presents the plan for ongoing care with justification. This element of the interaction is designed to emphasise patient‐centred care. We have conducted live‐streamed rounds at John Hunter Hospital in obstetrics, gynaecology and birth suite handover rounds. Approval was provided by the hospital executive after review by the local health district privacy team — student involvement by phone using a secure application (Skype for Business) was thought to be similar to student involvement with telehealth consultations in outpatient clinics. The benefits and challenges experienced with live‐streamed ward rounds are summarised in Box 2. After completion of 50 live‐streamed rounds, an informal evaluation was conducted via an anonymous voluntary Qualtrics online survey. Most of the 25 student respondents and clinicians provided positive feedback. Key findings from this survey are presented in the Supporting information. Clinical teaching is a fundamental component of medical education, particularly for developing tangible and intangible skills of medical students.6 Bedside teaching is a key opportunity for medical students, with the presence of the medical teacher, to develop medical knowledge, history taking and physical examination skills, clinical data gathering and clinical decision making.7 While students cannot participate in the clinical examination component of the patient interaction during live‐streamed ward rounds, they can hear the relevant history taking. Evidence indicates that physicians can collect 60–80% of the information relevant for a diagnosis just by taking a medical history, leading to a final diagnosis in more than 70% of cases.8 Previous studies investigating factors that are most important in creating an effective learning environment for medical students found that the level of participation students are afforded in the workplace is vital in clinical practice learning.9 Greater participation in the workplace facilitates greater confidence and competency, especially in clinical practice.9,10 A recent Australian study11 of final year medical students found the top six responses as to why students found clinical venues the most educationally useful include: the amount of patient contact; various patient presentations; being part of the clinical team; the opportunity to ask questions and receive useful information; the high level of supervision in training; and the amount of formal bedside teaching. Tutorials in a clinical setting also allow for professional development to be taught, such as communication, teamwork and ethics.12 Students require teaching in real clinical settings to develop skills for success in the real clinical environment. The structured live‐streamed ward round stimulates student participation and effectively develops clinical knowledge, enhances depth and permanency of learning, and enriches the stability and dependability of the knowledge attained. Being able to follow up patients to discharge is the ideal ending to these scenarios, where the student can see how effective the management plan was, as well as its implementation and results.11 We identified quality supervision as a key factor for maximising the educational value of clinical learning in live‐streamed ward rounds. Supervisors who are experienced and engaging make students more motivated to critically analyse patients’ clinical conditions, encourage their learning about these presentations, and formulate management plans.13,14 Live‐streamed clinical encounters should inspire us to revisit and prioritise the development of virtual clinical encounters, involving detailed scenarios that can be delivered flexibly, are always accessible and adaptive, and prioritise individualised learning. There are many advantages to live‐streamed clinical encounters, including their cost‐effectiveness in both set‐up and maintenance, the possibility of increasing access and usability of streaming technology, and allowing for the nuance of expertise and immediate feedback. As demonstrated by the COVID‐19 pandemic, they can be rapidly implemented and use principles of adult learning. The live‐streamed teaching strategy can be applied to all areas of medicine and many clinical scenarios, including ward rounds and clinical handover rounds. Recommendations on how to introduce this innovative teaching method are summarised in Box 3. This strategy is one of the many that the University of Newcastle plans to use to provide ongoing clinical teaching during the COVID‐19 pandemic. Being adaptable and flexible, cognisant of costs and driven by evidence are critical features of delivering medical education and contemporary medical practice.15 Box 1 – The three phases of the live‐streamed ward round Box 2 – Benefits and challenges of live‐streamed ward rounds Benefits The program is able to continue while students are not allowed in hospital The program is able to run while social distancing rules severely limit the number of students physically able to attend face‐to-face ward rounds The program facilitated discussions in Phase 3 which can go into greater depth than is possible in a ward environment The program provided the ability to engage larger number of students than possible in physical ward rounds The program creates more opportunity to simulate the role of a junior medical officer The program moderates clinical team variability for capacity to provide equivalent learning focus each week Challenges The program may potentially slow down ward round There is risk of technological limitations (eg, dependent on mobile phone signal and teleconferencing software) There are timetabling challenges in an unpredictable clinical environment There is inability to observe or participate in physical examination There is a loss of some of the valuable elements of the informal curriculum on ward round (eg, exemplary professional values, behaviour and collegiality via positive role modelling) Box 3 – Recommendations for introducing live‐streamed ward rounds into teaching Step 1 Design a live‐streamed round and a follow‐up reflective simulation round. This should include addressing the process for privacy, consent and technology (ie, preferred mobile videoconference platform) Step 2 Include discipline and departmental consultants running the live‐streamed round and follow‐up round in reviewing the design Step 3 Include technology support officers in reviewing the design Step 4 Seek written approval from relevant senior local health district and hospital staff (eg, medical and clinical directors) Step 5 Pilot, refine, implement

Craig E Pennell · Hannah Kluckow · Shirley Q Chen · Kerrie M Wisely · Ben LD Walker