Infectious diseases

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

The coronavirus disease 2019 (COVID‐19) pandemic is pushing health systems to, and possibly beyond, their limits.1 In Italy, the exponential rise in case numbers has caused a corresponding rise in demand for intensive care unit (ICU) beds.2 To determine how many ICU beds will be required in Australia, we propose a simple model of an uninterrupted pandemic process based on the local situation in late March 2020, and compare this model with recent data from the Lombardy.3 The uninterrupted exponential growth scenario In queueing theory, Little's law4 describes the relationship between the number of patients in a system (L) and the mean arrival rate (λ) and length of time the patient remains in the system (W) as: L = λW If a tertiary hospital has a steady state rate of 20 new admissions of patients with confirmed COVID‐19 per day, of whom one requires ICU admission5 (λ) for a mean 10 days (W), the hospital ICU will need at least 10 beds to accommodate these patients. If, however, the number of new confirmed cases increases by 20% each day (in late March 2020, the number was increasing in Australia by 23% each day6), and 100 cases are confirmed on one day, about 120 will be confirmed on the next. This increase in the daily rate of 20 new cases will mean one extra ICU admission per day, and the need for at least 10 further ICU beds. That is, the total number of ICU beds needed will be about 10% of the number of confirmed cases, or 50% of the number of new cases during the exponential growth phase of the epidemic. Approximately 2300 ICU beds are available in Australia;7 if public health measures fail to curb the rate of growth in case numbers, the national ICU capacity would be exceeded when the number of COVID‐19 cases reaches 23 000. Other sources8 have estimated that Australia could cope with as many as 44 580 COVID‐19 cases, but this would grant only a 3‐day extension before ICU capacity was exceeded. In our exponential growth scenario, commencing with 100 confirmed cases on day 1, 31 ICU beds would be required by day 7 and 119 by day 14 (Box 1). In sensitivity analyses, ICU bed capacity is sufficient even after 30 days if the ICU admission rate is reduced to 2.5%, but would be exceeded by day 26 were the ICU admission rate as high as 10%. It is important to note that our model describes a particularly serious scenario, and that actual outcomes will be modified by parameters not included in the model, including potential lags between diagnosis, hospital admission, and transfer to intensive care, and the proportion of true positive results among people tested for infecton. Is the modelled scenario plausible? To evaluate how realistic the uninterrupted exponential growth scenario is, we compared exponential and linear growth models with recent data for the Lombardy in Italy.9 Using piecewise regression models, the increase in the number of ICU patients during days 1–14 was exponential (R2 = 0.96); from day 15, ICU admissions continued to rise steeply, but the increase was linear (R2 = 0.99) (Box 2). To determine the reason for the change in growth rate at day 15, we compared the ICU admission and mortality rates for patients hospitalised with COVID‐19. The mortality rate during days 1–14 was fairly constant at about 8.8%, but rose dramatically from day 15 to a mean 23%. Most deaths during the first 14 days were probably of patients in intensive care, but we suspect that from day 15 patients died partly because of the lack of access to ICU beds as demand exceeded the capacity of the system to provide them, as indicated by the fall in ICU admission rate (Box 3). Conclusion While the assumptions of our model can be debated, the exponential increase in Australian cases until late March suggested that it described a realistic clinical scenario consistent with overseas data available at that time. The exponential increase in case numbers and subsequent demand for ICU beds could have overwhelmed the capacity of even the largest Australian hospitals if SARS‐CoV‐2 transmission had not been as drastically reduced as it appears to have been by the successful public health measures enacted by the federal and state governments and the adherence to these measures by the Australian public. The rate of ICU admissions per positive case may be lower in Australia than reported for Italy and China — because of healthier underlying demographic conditions, a greater number of detected milder cases, or both — but this would not change the overall implications of the model. Australia must maintain measures to strictly control the rate of new cases and continue to improve our ICU surge capacity, lest we squander the chance to avoid an Italian fate. Box 1 – Intensive care unit (ICU) bed demand, by time and proportion of patients with confirmed COVID‐19 who require intensive care Box 2 – Intensive care unit (ICU) admission rate in the Lombardy: actual and modelled Box 3 – Intensive care unit (ICU) admission rate and mortality for all patients with COVID‐19 admitted to hospitals in the Lombardy

Hamish DD Meares · Michael P Jones

To the Editor: Thiopurines are used in oncology, immunology and inflammatory bowel disease (IBD). In the coronavirus disease 2019 (COVID‐19) pandemic, patients taking thiopurines face uncertainty as to the risk of serious complications or death if infected. Traditionally, thiopurine use has been associated with an increased risk of opportunistic viral infections.1,2,3 A large IBD registry study found that using thiopurines and having active disease were associated with a higher risk of serious viral infection.3 However, all identified causative agents were species of the Herpesviridae genus.1,2,3 The risk associated with thiopurine use can therefore not yet be generalised to other virus genera, and indeed only corticosteroid use is associated with risk of contracting influenza in patients with IBD.4 COVID‐19 is caused by a novel coronavirus — the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) — and there are no available data from previous coronavirus strains such as SARS‐CoV or Middle East respiratory syndrome coronavirus (MERS‐CoV) to allow for estimation of risk in patients taking thiopurines.3,5 Although, intuitively, immunosuppression with thiopurines may increase the risk from COVID‐19, there are in vitro and in silico data to suggest that thiopurines constrain maturation of MERS‐CoV via inhibition of a viral protease.5 Although this study has not been replicated for COVID‐19 or progressed into animal models, it does raise the possibility that thiopurines use may not necessarily increase the risk of contracting COVID‐19. Thiopurine withdrawal is associated with a 12‐month relapse rate of 17–53% in patients with Crohn's disease and 11–77% in patients with ulcerative colitis.6 This is an important consideration in COVID‐19, as disease relapse requiring steroid use has previously been associated with increased risk of viral complications.3,4 The consequences of thiopurine withdrawal due to COVID‐19 are not yet clear and this information is eagerly awaited as many centres collect prospective data. Preliminary data from SECURE‐IBD — a COVID‐19 database for IBD — report 87 COVID‐19 cases to date in patients taking thiopurines, of whom 52 were managed as outpatients and 35 were admitted to hospital, with two reported deaths.7 These evolving data provide cautious support for the relative safety of thiopurines but cannot be interpreted conclusively in the setting of the rapidly evolving situation. Perhaps the best advice we can currently offer patients is that effective control of disease may carry less risk than poorly considered withdrawal of therapy. The Gastroenterological Society of Australia has issued recommendations that the minimum level of immunosuppression should be continued to control disease although a drug holiday may be considered in some patients with long term stable disease.8 This dilemma highlights the importance of online registries to gather vital data as we work together as a profession to provide evidence‐based advice for our patients during this pandemic.

Thomas M Goodsall · Samuel P Costello · Robert V Bryant

The maintenance of sustainable low cost physical distancing and enhanced hygiene may decrease the number and severity of cases It is estimated that about two‐thirds of cases of coronavirus disease 2019 (COVID‐19) exported from China between 1 and 13 January 2020 were undetected globally.1 Most of these exported cases were mild and were only detected after several hundred cases had accumulated and severe or fatal cases were recognised 5–8 weeks later, as likely occurred in the COVID‐19 outbreaks in Iran, South Korea, Italy and Seattle, United States.2 The spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) transmission globally has been very rapid. The basic reproduction number (R0) is estimated at between 2 and 3.3,4 The mode of transmission is thought to be droplet and contact infection, although opportunistic or close range airborne infection may be involved.4 The transmission dynamics of the early cases of COVID‐19 were significantly different to those during the severe acute respiratory syndrome (SARS) epidemic in 2003. In particular, the proportion of COVID‐19 cases from health care settings was low and the proportion with no known risk exposures was high.4 Another significant factor is that viral loads in nasopharyngeal and respiratory secretions are highest soon after symptom onset in patients with COVID‐195 compared with a peak of around 10 days in patients with SARS,6 making transmission before entering health care facilities and in the pre‐symptomatic phase more likely.7 Even though the understanding of transmission dynamics is at an early stage, they do suggest that the stepwise introduction of stringent measures will be necessary to control this epidemic and highlight the importance of early community control. Australia and other countries have experienced a first wave of disease and managed to effect a decline in cases.8 Quarantine; city lockdowns; complete childcare, school, university and workplace closures; and cancellation of mass gatherings and events have a significant social and economic impact and were not often implemented until significant transmission was confirmed — when they may be less effective. Countries are now challenged with identifying which of these various controls can be relaxed to allow some routine societal and economic activities to return. However, there are low cost, sustainable interventions that may be maintained over what may be many years of continued mitigation9 (Box 1). These low cost enhanced hygiene and physical distancing measures are applicable pre‐emptively before confirmation of local community transmission or where transmission of SARS‐CoV‐2 appears to be under control. The purpose of these interventions is to slow the transmission of disease and limit the impact on health services, particularly on hospitals and intensive care units, to ensure access to high level care when needed. The interventions are based on the following assumptions, which require further exploration: community‐wide SARS‐CoV‐2 transmission may be occurring undetected or may only be recognised after containment is no longer feasible; interventions implemented after community‐wide transmission is detected will be less effective; reduction of the force of infection, particularly early, will delay the epidemic peak, blunt the epidemic peak, spread cases over a longer time, and help limit the potential for critical care services to be overwhelmed, which may be lifesaving;12,13 low cost sustainable interventions will assist in the relaxation of more economically costly interventions, and enhanced hygiene and physical distancing interventions should: ▸decrease the total number of cases per week; and ▸decrease the severity of cases through reducing viral inocula. Box 2 illustrates the concept of limiting the peak in cases so that health services are less likely to be overwhelmed and there is less unmet health service need. Unmet need may include inability to admit patients to a hospital or to provide hospitalised patients in critical condition access to intensive care. Interventions to reduce infection lead to longer but less peaked epidemics. A slower evolution in the epidemic also allows time for health care staff to provide better care, for recovery of infected health care workers, for learning and adapting to the evolving situation by administrators, and for vaccines and treatments to be developed. This principle is validated in simulations for influenza14 and appears to be validated with the reduction in COVID‐19 cases in Australia and the relative lack of overburden on clinical services.8 Measures to decrease the number and severity of cases Pre‐emptive and ongoing maintenance of low cost interventions (such as enhanced hygiene and physical distancing measures) (Box 1) may not only decrease the total number of cases but may also decrease the severity of cases. The R0 is the average number of secondary cases of an infectious disease that arise from cases in a totally susceptible population and reflects the epidemic potential of a pathogen.15R0 is a function of the number of contacts an infectious person has, the risk of transmission per contact, and the duration of infectiousness. Physical distancing mostly acts on the first factor by reducing the number of contacts each person makes. Hygiene measures mostly act on the second factor, as they reduce the risk of transmission if a contact occurs. It is difficult to disentangle the effectiveness of the multiple control measures implemented in pandemic‐affected areas. The World Health Organization–China Joint Mission on COVID‐19 determined that widespread community transmission and outbreaks occurred in Wuhan before the implementation of comprehensive control measures.4 However, in other parts of China, community transmission has been limited and after public gatherings were cancelled and people were restricted to their homes, most transmission occurred in families. For example, among 344 clusters involving 1308 cases (out of a total 1836 cases reported) in Guangdong Province and Sichuan Province, 78–85% have occurred in families.4 Community‐wide interventions may decrease the average viral exposure dose encountered in the community. People exposed to a higher viral dose (inoculum) are more likely to become infected and have more severe disease. Animal models for other coronavirus infections demonstrate that increased viral inocula lead to more severe disease and higher viral loads in the lungs and other organs and fluids.16 The SARS outbreak in Amoy Gardens, Hong Kong, in 2003 provided evidence that patients with presumed higher exposure to the index case had higher nasopharyngeal viral loads and more severe illness.17 SARS‐CoV‐2 cases with more severe disease have been found to have around 60 times higher viral load than those with mild disease.18 Modelling of the 2009 influenza pandemic also supported a hypothesis that severe illness was due to a higher infectious dose of the virus mediated by the number of simultaneous infectious contacts.19 Viral loads in severe patients with Middle East respiratory syndrome (MERS) were higher than those in a mild group, and the patients in the severe group had more prolonged viral shedding in respiratory secretions, beyond 21 days after the onset of symptoms, whereas viral RNA was no longer detected by 21 days in the mild group.20 Therefore, it is proposed that early measures that lower the number of contacts, the likelihood of transmission, and average viral infective dose in an area of transmission may have a multiplier effect leading to fewer cases and fewer severe cases that are less infectious. Maintaining the early reduction of the R0 would result in fewer cases overall and have a significant negative multiplier effect on the overall impact of the epidemic, including the number of deaths (Box 3). The higher case fatality rate in Wuhan, compared with other provinces in China, may partially relate to health care resource availability and shortages in the face of overwhelming community transmission as well as greater severity of disease due to higher infection doses.12,17 These interventions will be particularly important for people over 60 years of age and those with underlying medical conditions. The costs of intervention The suite of low cost interventions, other than a working from home policy, is unlikely to affect work productivity and may provide the community with some reassurance that all is being done to prevent the epidemic and that maintenance of the low cost measures may allow earlier opening of some workplaces. WHO is supportive of pre‐emptive interventions to prevent COVID‐19 in workplaces.21 Some may see it as being overreaching, but thus far, communities seem to voluntarily adopt low cost interventions, and acceptance may be enhanced through consultation and trust building.22,23 Influenza co‐benefits For regions approaching their influenza season, optimal prevention and control of seasonal influenza, such as vaccination, in the face of potential COVID‐19 cocirculation is also crucial to minimise the double burden on health services. The measures discussed here (enhanced hygiene and physical distancing) are also effective against influenza, resulting in potential co‐benefits for both pathogens. Early indications from Flutracking.net (https://info.flutracking.net/reports-2/australia-reports) indicate that physical distancing and hygiene enhancements have markedly decreased influenza‐like illness in Australia. Limitations While physical distancing and enhanced hygiene interventions in Australia appear to be working, the evidence on the effectiveness of individual interventions in preventing COVID‐19 is not yet available. However, there is evidence from observational and simulation studies for the effectiveness of physical distancing measures in controlling seasonal influenza.13 Other measures, such as hand hygiene and cleaning surfaces, have a long history of use in infection prevention and control.24 Despite the lack of robust evidence of effectiveness for these measures, their relative low cost means that there is little harm and much potential benefit in maintaining and optimising them. We have made no recommendations in regard to masks. The use of masks outside of health settings is controversial and it is important that medical grade masks not be diverted from health care supplies. Nevertheless, surgical masks are protective of large droplet spread, have about half the effectiveness of N95 masks for small droplet transmission, and are suggested to be cost‐saving in some modelled pandemic influenza scenarios.25 The use of masks may have a role in the community setting if there are adequate supplies.10 There is evidence suggesting that community use of masks may have reduced the risk of contracting SARS.26 It is clear that masks should be used in households caring for patients with COVID‐19 at home. Policy development and scientific review of the literature on community use of masks is very dynamic at this time. The US Centers for Disease Control and Prevention has made a recent recommendation that cloth masks be used at the community level and many recent reviews have come to divergent conclusions about the usefulness and risks of community mask use.27,28,29,30 Coherent policy development in this space will rely on transparently articulating the scientific evidence on community mask use with a public conversation on the potential risks in implementation. The interventions discussed here should be tailored to individual settings and communities, in partnership with members of those communities. In particular, these interventions should be adapted to the unique circumstances of groups, such as Indigenous communities; vulnerable groups, including homeless populations; and culturally and linguistic diverse communities. Conclusion SARS‐CoV‐2 continues to disseminate globally and there are likely to be recurrent waves of infection into the foreseeable future. We would argue that these low cost interventions, although formulated at an earlier stage of the epidemic, have increasing relevance. They will protect against the emerging concern for pre‐symptomatic transmission and their optimisation will better enable the more restrictive and economically damaging constraints to be relaxed.7 Box 1 – Low cost hygiene and physical distancing interventions Settings Interventions Workplace No handshaking policy Promote cough and sneeze etiquette, but focus is on excluding ill staff Videoconferencing as default for meetings Defer large meetings Signage for all offices/meeting rooms advising of maximum occupancy based on 4 m2 per person and 2 m distancing Enforced sanitisation of hands at entrance Regular hand sanitation schedule reminders via email Avoid gathering in lunch and break rooms Gamifying hygiene rules, for example, to discourage touching face Ill* people should stay at home and ill workers immediately isolated Hold necessary meetings outside in open air if possible Staff with ill household contacts should stay at home† Disinfect high touch surfaces regularly and between users Work from home where possible and consider staggering of staff Consider opening windows and adjusting air conditioning to increase air flow and maintain warmer more humid environments‡ Limit food handling and sharing of food in the workplace Assess staff business travel risks§ Enhance hygiene and screening for illness among food preparation (canteen) staff and their close contacts Analyse the root cause of crowding events on site and prevent through rescheduling, staggering or cancelling Mark floor areas to indicate 2 m distancing points in areas where staff spontaneously gather to prompt distancing Minimise the number of employees in a work vehicle at any one time School Supervised sanitisation of hands at entrance and at regular intervals Defer activities that lead to mixing between classes and years Promote cough and sneeze etiquette, but focus on excluding ill persons Strict stay at home policy if ill Gamifying hygiene rules, for example, to discourage touching face Regular handwashing schedule Disinfect high touch surfaces regularly and between users Outdoor lessons where possible Consider opening windows and adjusting air conditioning Enhance hygiene and screening for illness among food preparation (canteen) staff and their close contacts Review after‐school care arrangements that lead to mixing of children from multiple classes and ages Commercial, entertainment and transport Sanitisation of hands at building entrance encouraged Tap and pay preferred to limit handling of money Disinfect high touch surfaces regularly Avoid crowding through booking and scheduling, online pre‐purchasing, limiting attendance numbers Enhance hygiene and screening for illness among food preparation staff and their close contacts Enhance airflow and adjust air conditioning to increase air flow and maintain warmer more humid environments Public transport workers, taxi and ride share drivers — vehicle windows opened where possible, increased air flow, high touch surfaces disinfected Household All households Enhanced hand sanitisation Gamifying hygiene rules, for example, to discourage touching face Disinfect high touch surfaces regularly “Welcome if you are well” signs on front door Increase ventilation rates in the home by opening windows or adjusting air conditioning Promote cough and sneeze etiquette Households with ill members Measures listed above Confirmed cases of COVID‐19 should be isolated away from susceptible household members if there are not completely separate bedroom, bathroom and kitchen facilities If care must be provided at home, ill household members are given their own room and only one person cares for them The door to the ill person's room is kept closed10 Wearing simple surgical or dust masks by both infected persons and other family members caring for the patient if needing to be in the same room Consider extra protection or alternative accommodation for household members aged over 65 years or with underlying illness COVID‐19 = coronavirus disease 2019. *Ill person refers to someone with symptoms of respiratory illness or fever, who is not yet under investigation for COVID‐19 but could be an unrecognised case. †This could be costly unless used judiciously while awaiting exclusion of COVID‐19 in the suspected case and should be introduced based on likelihood of local transmission. ‡Evidence that low temperature and low humidity in air‐conditioned environments may enhance the survival of coronaviruses such as severe acute respiratory syndrome (SARS).11 §When international travel restrictions are lifted, sites such as the Centers for Disease Control and Prevention travel risk assessment site may be useful (https://www.cdc.gov/coronavirus/2019-ncov/travelers/map-and-travel-notices.html). Box 2 – Intended impact of enhanced hygiene and physical distancing measures on the coronavirus disease 2019 (COVID‐19) pandemic* *Figure adapted from Fong et al.13 Box 3 – Conceptual model of how pre‐emptive interventions with a negative multiplier effect could affect an impending epidemic

Craig B Dalton · Stephen J Corbett · Anthea L Katelaris

Introduction: This statement was planned on 11 March 2020 to provide clinical guidance and aid staff preparation for the coronavirus disease 2019 (COVID‐19) pandemic in Australia and New Zealand. It has been widely endorsed by relevant specialty colleges and societies. Main recommendations: Generic guidelines exist for the intubation of different patient groups, as do resources to facilitate airway rescue and transition to the “can't intubate, can't oxygenate” scenario. They should be followed where they do not contradict our specific recommendations for the COVID‐19 patient group. Consideration should be given to using a checklist that has been specifically modified for the COVID‐19 patient group. Early intubation should be considered to prevent the additional risk to staff of emergency intubation and to avoid prolonged use of high flow nasal oxygen or non‐invasive ventilation. Significant institutional preparation is required to optimise staff and patient safety in preparing for the airway management of the COVID‐19 patient group. The principles for airway management should be the same for all patients with COVID‐19 (asymptomatic, mild or critically unwell). Safe, simple, familiar, reliable and robust practices should be adopted for all episodes of airway management for patients with COVID‐19. Changes in management as a result of this statement: Airway clinicians in Australia and New Zealand should now already be involved in regular intensive training for the airway management of the COVID‐19 patient group. This training should focus on the principles of early intervention, meticulous planning, vigilant infection control, efficient processes, clear communication and standardised practice.

David J Brewster · Nicholas Chrimes · Thy BT Do · Kirstin Fraser · Christopher J Groombridge · Andy Higgs · Matthew J Humar · Timothy J Leeuwenburg · Steven McGloughlin · Fiona G Newman · Chris P Nickson · Adam Rehak · David Vokes · Jonathan J Gatward

It is time for health professionals to step up and lead to ensure a sustainable environment and health

Nicholas J Talley

A lockdown can substantially reduce epidemic size and flatten the curve, ensuring that health system capacity is not exceeded and economic recovery occurs sooner than with a phased approach Exponential epidemic growth has been clearly demonstrated for coronavirus disease 2019 (COVID‐19) in every country it has touched, with ascertained cases growing from 25 at the start of March in Australia to over 6000 cases 6 weeks later. For every ascertained case, there may be anywhere up to nine infections that are not detected.1 This silent component of spread is likely driven by asymptomatic2 or mild infection, especially in younger people. In countries which restrict testing to symptomatic high risk people only, there will be silent growth of undetected infection until the epidemic is large enough to be felt in the health system.3 The epidemic in China was largely localised through January 2020, with small numbers of imported cases in other countries. Following a lockdown on 23 January, it peaked on 5 February4 and has declined since. However, as the cases decreased in China, COVID‐19 began surging in other countries by late February. Asian countries such as South Korea took an aggressive approach to testing and achieved control.5 In contrast, a more relaxed approach saw Europe becoming the new epicentre, followed by the United States,6 which had epidemic growth because of major testing failures. In Italy, Spain and parts of the US, health systems capacity has been exceeded, with resulting shortages of intensive care beds and ventilators. Case fatality rates (CFRs) have varied globally, from 0.85% in South Korea to over 10% in Italy.7 Whether the CFR is 0.85% or 10%, this is orders of magnitude higher than seasonal influenza8 or even the 2009 influenza pandemic.9 Two factors influence CFR — testing and capacity to ventilate. More widespread testing will result in identification of mild and asymptomatic cases, as in South Korea, and a lower apparent CFR. Given respiratory failure is the leading cause of death from COVID‐19, the inability to ventilate patients will drive the CFR up. In Germany, the number of intensive care unit (ICU) beds per head of population is 29.2 per 100 000 compared with 12.5 per 100 000 in Italy,10 so despite having a high number of cases, capacity has not been exceeded. In Italy and Spain, however, ICU capacity was exhausted. In contrast, in China, large hospitals were built in a matter of days to ensure that capacity to ventilate patients was not lost, keeping the CFR lower than in Italy. From this perspective, it is key that Australia flattens the curve to keep health system capacity available to ventilate every patient who needs it. We have 9.4 ICU beds per 100 000 population — less than Italy — although Australian capacity has been expanded as part of COVID‐19 preparedness.11 R0 and flattening the curve Central to flattening the epidemic curve is R0, the basic reproductive number. R0 is the number of secondary cases arising from one index case in a completely susceptible population. The epidemic threshold is defined mathematically as when R0 exceeds 1, which creates conditions for an epidemic, although an epidemic may not always occur. If R0 is less than 1, an epidemic cannot be sustained because one infectious case infects less than one other person on average, and infection will die out. The best estimates of R0 for COVID‐19 lie between 2 and 3.12 Public health disease control strategies such as vaccination, social distancing and travel bans aim to reduce the R value to below 1, thereby stopping the epidemic. The R modified by such measures is manifested as flattening of the curve, which is dampening of the natural trajectory of the epidemic that would otherwise occur. Herd immunity strategy — risks and no benefits Closely related to R0 is the concept of herd immunity. Herd immunity is a concept related largely to vaccination programs. It is the observation that when enough people are immune to an infection, even people who are non‐immune are protected because the number of non‐immune individuals is too small for infection to spread. Immunity can be gained by infection or by vaccination. Unless we can eradicate an infection, vaccination is the only way to control it long term. However, a range of non‐pharmaceutical measures will also control epidemics, and can be used in the short to medium term to reduce the size of the epidemic, manage demand in the health system, and save as many lives as possible. The required proportion of people in a population who need to be immune to induce herd immunity (H) is related to R0 and calculated by the formula H = 1 − (1/R0).13 If we assume R0 is 2.6, we need 61% of the Australian population to be immune to gain herd immunity for the remaining 39% of people. Therefore, any desire to “allow” some transmission (an idea floated by some experts in the United Kingdom and Australia) will only cause more disease and death without any benefit at infection rates < 60%.14 If > 60% of Australians were infected, we would have a worst‐case scenario, endanger our health workers, and rapidly exhaust our health system capacity. Further, allowing transmission of COVID‐19 would not get rid of the disease — it would cause recurrent, cycling epidemics of a mass scale, as seen with measles, mumps, rubella, smallpox and all other epidemic infectious diseases before vaccination. We would also see resulting high morbidity and mortality in older people, as 50% of the population is aged over 40 years. Younger people would also be affected. In the US, 36% of patients admitted to the ICU were aged 45–64 years and 12% were aged 20–44 years. Deaths in the US have been seen in all age groups above 18 years.6 Large studies also show that children can have severe disease or die — 50% had mild disease, 30% moderate disease and 6% critical illness.15 In one study, a child aged 10 months died.16 Young people and children tend to transmit respiratory infections most intensely in society because they have the highest contact rates.17 This means that mild or asymptomatic infection in young people could be a driver of epidemic growth. Many people live in multigenerational arrangements, so young people becoming infected could result in older people or people with chronic diseases becoming ill. The Australian response The Deputy Chief Medical Officer suggested, based on modelling, a worst case scenario of 15 million Australians infected and 150 000 deaths.18 We are a high income country of 26 million people, and it should be noted that in China, with nearly 1.4 billion people, even if true case numbers were 100 times greater than reported, less than 1% of their population was infected and 3298 people had died as of 23 March 2020.7 We may not be able to achieve China‐style lockdowns, but surely we can control the disease enough to spare our health system and minimise morbidity and mortality. Modelling for Australia suggests we could run out of ICU beds if the epidemic trajectory remains unaltered.19 The protection of the health workforce is also key to our response. The other impact of health system overload is the infection of health workers, who are already vulnerable because of the failure to stockpile adequate personal protective equipment (PPE), thus further compromising the ability to respond. Studies have shown that viable severe acute respiratory syndrome coronavirus 2 can be found widely on surfaces and in the air 3 hours after aerosolisation, highlighting the risk of airborne transmission.20 This is supported by the finding of the virus in air outlet fans in the hospital room of an infected patient.21 It is therefore likely that transmission is multimodal, including respiratory and contact. In the US, critical PPE shortages forced health workers to use plastic garbage bags as gowns, with some workers dying. The US Centers for Disease Control and Prevention initially recommended respirators for health workers treating COVID‐19, but as shortages worsened, downgraded this to surgical masks and even bandanas.22 We must flatten the curve to ensure that Australian health workers are not placed at risk by PPE shortages. Further, if hospital beds are full with COVID‐19 patients and a large proportion of health workers are infected, the ability to treat other serious conditions like cardiovascular disease will be reduced. Mass community palliative care Another consequence of health system overload will be the need for community palliative care for patients with COVID‐19 who are unable to access hospital care. While the potential for mass mortality is sometimes considered in major disaster plans, the issue of mass palliation is often neglected. In severe COVID‐19 pneumonia, where respiratory support is not available there is a progressive decline of the patient until ultimate demise associated with severe hypoxaemia, cardiac failure, acute respiratory failure and sepsis. In the days and hours before death, however, the patient will usually suffer from progressive dyspnoea, chest pain and delirium, and will become progressively moribund and immobile.23 Provision of equitable, compassionate, safe and dignified end‐of‐life care to people with COVID‐19 who are unable to be offered life‐saving critical care is fundamental to ensuring the integrity of the Australian social fabric, and the moral and mental welfare of potentially large swathes of the population. Up to 40% of older women and 22% of older men aged 80 years and over live alone (https://aifs.gov.au/publications/nature-living-alone-australia), complicating how to achieve what is necessary and right. Planning around the country for this worst case outcome is currently underway, but requires significant resources, personnel, government support and a national approach. Short, sharp lockdown versus phased approach The impact of interventions is generally seen one to two incubation periods from implementation. The flattening of the curve seen in Australia from 24 March probably reflects the impacts of rolling travel bans implemented from 5–10 March. However, New South Wales is the epicentre of infection in Australia, and the lapses in border control with the Ruby Princess and other cruise ships may have led to an increase in cases by mid‐April. In light of this, a comprehensive lockdown including school closure buys time to scale up testing for when restrictions are lifted. A slow trickle of phased interventions and a “wait and see” strategy will leave us dealing with COVID‐19 in the health system for longer. For doctors, it is no consolation to hear that “we are not like Italy, Spain or the US”. All are high income countries that used a restricted testing strategy, unlike our Asian neighbours. The UK is probably the country whose approach has been most similar to ours. They are facing a strain on the National Health Service and shortages of PPE, despite confident assertions by authorities only weeks ago. The UK, like Australia, used restricted testing and did not test asymptomatic close contacts and other high risk groups.24 To ensure that Australia continues to flatten the curve, social distancing is especially important because of asymptomatic transmitters of infection. Being unable to identify infectious cases makes disease control much harder. Until we have a vaccine, all we have available in the toolkit is social distancing and travel restrictions, along with isolation of sick people and quarantine of contacts and return travellers. The World Health Organization recommends school closure during a serious pandemic, and outlines the evidence showing that comprehensive, simultaneous social distancing measures and early school closure work better than phased or gradual measures.25 China has demonstrated the feasibility of a short lockdown followed by phased lifting of restrictions. The Chinese epidemic curve4 shows the success of the lockdown, implemented in Wuhan on 3 January, while the epidemic was in the exponential growth phase with thousands of new cases a day. Within one incubation period, cases started to fall. China began lifting restrictions on 9 February, just over one incubation period from the lockdown. They have continued to gradually lift restrictions, from a more manageable baseline position of far fewer cases to track and contain, all within 8 weeks. A lockdown is a temporary measure which can result in substantial reduction of epidemic size, more manageable case numbers and a flattening of the curve so that health system capacity is not exceeded and economic recovery can occur sooner. Lockdown can be relaxed safely in a phased manner, but must be accompanied by extensive testing, including of asymptomatic high risk people such as close contacts, evacuees and people in institutional outbreak settings. To ensure all community cases are detected, any doctor should be able to exercise clinical judgement and order a test for COVID‐19. Failure to test asymptomatic at‐risk people and allow wider community testing will result in undetected transmission in the community and a bounce‐back of the epidemic as lockdown restrictions are lifted. The only two countries to achieve sustained flattening of the curve to date are South Korea and China. South Korea has achieved this with more targeted, short lockdowns along with extensive testing.5 The risk of a phased and gradual approach is continued epidemic growth, potential failure of the health system, and a far longer road to recovery. We have examples of countries that have failed and succeeded, which can guide such a response. Epidemic control is time critical, because epidemics rise exponentially. There is no real choice available between jobs and lives — failing to save lives now will result in more net job losses and a longer recession. In addition to expanded testing, key strategies to accompany a lockdown must be a financial aid package that is accessible and leaves no person in need; a mental health and domestic violence package with outreach capability; aged care and disability support; and support for Aboriginal and Torres Strait Islander communities. Much of this is already being addressed by the government. Other needs may also become apparent, such as a communications and social engagement package; a physical fitness package; and identification of other vulnerable groups and required support to ensure the wellbeing of all Australians. The unedited version of this article was published as a preprint on mja.com.au on 1 April 2020.

C Raina MacIntyre · David J Heslop

Clinical record A 42‐year‐old woman presented to the Sunshine Coast University Hospital, Queensland, with a 5‐day history of odynophagia, orthopnoea and rapid onset of neck swelling over 12 hours. She had returned one week prior from a year‐long trip to Central America, Sri Lanka and Indonesia. Relevant past medical history included nephrotic syndrome due to minimal change disease, use of prednisolone 2.5 mg daily and previous treatment with rituximab. Childhood vaccinations were reported, but she had no booster travel vaccinations. On examination, she had right‐sided neck swelling, consistent with “bull neck” (Box, A), and an exudative right tonsil with a haemorrhagic component (Box, B). The patient had several healed skin lesions and a 2 cm non‐healing ulcer on her buttock. Flexible nasendoscopy showed supraglottic oedema with a patent airway. The diagnosis of diphtheria was strongly considered, with differentials including peritonsillar abscess and tonsillitis. Computed tomography scan of the neck demonstrated peritonsillar phlegmon and oedema in the parapharyngeal space, pre‐vertebral fat and subcutaneous neck tissues. She was commenced on intravenous benzylpenicillin, lincomycin and dexamethasone, was placed on contact and droplet precautions, and was admitted to the intensive care unit. Multiple tissue and swab samples were taken from the pharyngeal membrane and the buttock wound and urgently sent to the laboratory for culture into selective media. She underwent elective intubation 24 hours later due to worsening laryngeal oedema. Tissue and swabs from the pharyngeal membrane and sacral wound grew Corynebacterium diphtheriae. Diphtheria antitoxin (DAT) 100 000 IU was administered 36 hours into her admission. The isolates were confirmed to be toxigenic by polymerase chain reaction.1,2 The patient was discharged from the intensive care unit on Day 6. On Day 7, she developed anterior T wave inversions on her electrocardiogram, with an elevated troponin value (0.39 μg/L; reference range, < 0.040 μg/L). Her cardiac enzymes showed serial improvement. She developed a moderate glossopharyngeal and vagal palsy, which resolved after 3 weeks, and peripheral neuropathy, which resolved after 4 months. The cardiac and neurological sequelae were thought to be complications of pharyngeal diphtheria. The local Public Health Unit and the infection management service identified 12 staff and seven close community contacts. All contacts had nasal and throat swabs taken, were treated with oral erythromycin and were vaccinated where appropriate.3 Staff were excluded from work until returning negative throat and nasal cultures at 48–72 hours. Discussion Diphtheria is an acute pharyngeal or cutaneous infection caused by toxigenic strains of C. diphtheriae — a gram‐positive, non‐motile, non‐encapsulated bacillus.4 The infection spreads by respiratory droplets or direct contact with nasopharyngeal secretions or skin lesions. The incubation period of diphtheria is commonly 2–5 days. Data from the World Health Organization show that diphtheria is endemic to South‐East Asia, including Indonesia, Malaysia and the Philippines.5 Our case illustrates the need for a thorough travel history and administration of timely antitoxin therapy in suspected diphtheria cases to limit diphtheria‐related neurological and cardiovascular consequences. Diphtheria is rare in Australia after the widespread use of the effective vaccine following World War II, with most cases associated with sporadic importations. There have been seven cases of diphtheria reported since 2001, including one that was fatal in 2011.6 Diphtheria affects the upper respiratory tract, presenting with sore throat and cervical lymphadenopathy; a coating membrane forms in about a third of cases. Simultaneous infection of the skin and respiratory tract is uncommon. Accumulation of the C. diphtheriae organism within the membrane along with fibrin debris result in the appearance of a white pseudomembrane.4 The pathognomonic bull neck is caused by superficial oedema of neck tissues and is associated with a more severe course and higher mortality. The diphtheria toxin is produced by toxigenic strains of the bacterium and affects the cardiovascular, renal and nervous systems via haematogenous spread. The toxin is bound on cell surface receptors and acts to arrest protein synthesis.7 Toxin‐producing infections have a mortality rate between 5% and 10%.8 Diphtheritic myocarditis occurs in 10–20% of patients with pharyngeal diphtheria manifesting as ST disturbance, corrected QT interval (QTc) prolongation, or heart block.9 Cardiac abnormalities are associated with extensive respiratory tract involvement and bull neck appearance as well as neurological sequelae, which occur in 75% of patients with severe respiratory disease.4 Cranial nerve neuropathy develops first; often presenting as swallowing difficulties and resulting in aspiration. DAT and antibiotics should be administered promptly upon clinical suspicion. Early administration of DAT reduces circulating toxin load and reduces clinical sequelae.3 Our patient received DAT at 36 hours, yet significant neurological sequelae were observed up to 4 months later. Penicillin and/or erythromycin are the antimicrobials of choice; however, resistance has been described.10 Lessons from practice Diphtheria should be suspected in patients presenting with pseudomembranous tonsillitis, significant neck swelling and relevant travel history. It is important for clinicians to liaise with their local laboratory and Public Health Unit in suspicious cases so appropriate investigations and follow‐up can be established. Timely administration of diphtheria antitoxin is imperative and should not be delayed awaiting laboratory confirmation. Booster vaccinations should be considered before travel, particularly in patients who may have waning immunity. Box – “Bull neck” characteristic of diffuse cervical lymphadenopathy with tracheal deviation (A). Pseudomembrane coating right tonsil, soft palate and uvula on presentation (B)

Sarah Grigg · David Hogan · F Shaun Hosein · Dean Johns · Amy Jennison · Shradha Subedi

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

Early empirical evidence provides grounds for optimism about eliminating HCV by 2030

Marianne Martinello · Behzad Hajarizadeh · Gregory J Dore

Clinical record A 40‐year‐old woman of Karen ethnicity presented with 5 days of generalised abdominal pain. The pain was worsening and associated with vomiting in the 12 hours preceding presentation. She had been constipated for 5 weeks. There was no diarrhoea, no blood or mucous in the stool and no haematemesis. There were no sick family, friends or colleagues and no recent travel. She had an omnivorous diet, which had not changed recently, and worked casually at a vegetable farm. In the emergency department, vital signs were normal and the abdomen was mildly distended and tender. Initial blood tests showed a neutrophil count of 9.6 × 109/L (reference range [RR], 2.0–8.0 × 109/L), serum bicarbonate 22 mmol/L (RR, 22–32 mmol/L), normal renal function, and C‐reactive protein below 2.9 mg/L (RR, < 3.0 mg/L). Computed tomography of the abdomen and pelvis was consistent with colitis of the descending colon and ileus (Box 1). She was admitted for observation under the general surgical team. Five hours after admission, her condition rapidly deteriorated. Blood pressure was 80/40 mmHg, heart rate 129 beats per minute in sinus rhythm, and there was severe abdominal tenderness with generalised guarding. Repeat tests showed serum creatinine 175 μmol/L (RR, 60–110 μmol/L), bicarbonate below 10 mmol/L (RR, 22–32 mmol/L), blood pH 6.97 (RR, 7.35–7.45), and lactate 14.8 mmol/L (RR, < 1.5 mmol/L). At emergency surgery, colonoscopy and ileoscopy revealed mucosal inflammation affecting the distal 20 cm of terminal ileum, caecum, transverse and sigmoid colon, with patches of frank mucosal necrosis (Box 2). The bowel was grossly dilated, with small patches of full thickness caecal necrosis but no perforation. Subtotal colectomy, terminal ileectomy, and formation of an end ileostomy were performed, with resultant resolution of circulatory shock. Pathological examination demonstrated severe acute pancolitis and extensive mucosal necrosis (Box 3). Clostridium perfringens infection was suspected, due to a striking similarity to published cases.1,2C. perfringens was isolated from biopsy specimens of the necrotic colonic mucosa using selective culture media. The isolate expressed C. perfringens enterotoxin and α‐toxin, defined as toxinotype F.3 Postoperative management included vancomycin both orally and per rectum. Three months after the operation, she was pain‐free, with a normal appetite and functional state. Reversal of ileostomy is planned in coming months. Discussion C. perfringens is a gram‐positive bacillus that forms hardy spores, is ubiquitous in environmental soil and water, and can be part of normal bowel flora. Toxigenic strains commonly cause both foodborne and sporadic cases of acute, self‐limiting diarrhoea. The typical foodborne strain F produces C. perfringens enterotoxin and α‐toxin and was found in our patient.3 The organism exhibits the shortest known doubling time of any cell when grown at 42°C in cooked minced beef.4 Exposure to large inocula of toxigenic organisms may arise when meat is kept lukewarm before consumption. Enteric infections are characterised by adherence of organisms to small bowel mucosa before concurrent sporulation and release of toxin. This typically induces self‐limiting diarrhoea 10–12 hours after eating. Necrotising enterocolitis is a manifestation of C. perfringens enteric infection that is rare in high income countries. Some reported cases associate the condition with constipation, either pre‐existing due to medication side effects or induced by the high protein content of ingested contaminated meat. Constipation has been proposed to impair the usual expulsion of C. perfringens bacteria and spores, leading to mucosal necrosis and shock as opposed to the usual syndrome of transient diarrhoea. Mortality in case series is greater than 50%.1,2 Despite thorough assessment, the cause of our patient's constipation and means of exposure remain unclear. She most likely contracted the infection hours before the onset of her pain, 5 days before presentation. Exposure could have occurred during food preparation at home, meals with social groups, or via soil at her workplace. While rare in Australia, a type of C. perfringens necrotising enteritis was endemic throughout the 20th century in the Papua New Guinea highlands, caused by β‐toxin‐producing strains. Called “pigbel” in Tok Pisin, the disease is closely associated with traditional pig feasts. In the 1960s and 1970s, pigbel accounted for almost a quarter of paediatric deaths in highlands hospitals. Implementation of a β‐toxoid vaccine in 1979 resulted in an eightfold reduction in incidence and an even greater reduction in disease‐specific mortality.5 C. perfringens infection is an important differential diagnosis in cases of acute severe enteritis or colitis, particularly if accompanied by circulatory shock. Prompt operative intervention is necessary in such situations. In Papua New Guinea, toxoid vaccination has proven very successful. In Australia, food safety practices likely play the greatest role in controlling disease burden. Lessons from practice Toxigenic Clostridium perfringens type F commonly causes acute diarrhoea, with illness typically commencing hours after meat consumption. Cases are usually self‐limiting, and require symptomatic management only. Very rarely, toxigenic C. perfringens strains can cause fulminant bowel necrosis requiring emergency bowel resection, which may be associated with pre‐existing constipation. In the highlands of Papua New Guinea, necrotising enteritis has been a common cause of paediatric morbidity and mortality, where it is caused by a locally endemic strain of toxigenic C. perfringens. Box 1 – Coronal computed tomography image of the abdomen and pelvis with portal venous phase contrast, demonstrating mural thickening of the descending colon in the left lower quadrant and fluid‐filled distension of the transverse colon, ascending colon, and ileum Box 2 – Endoscopy images obtained immediately before laparotomy, showing mucosal necrosis of the ascending colon Box 3 – Macroscopic appearance of resected colon, demonstrating extensive mucosal necrosis and oedema

Harry N Walker · Kwee‐Chin Liew · Vicki Adams · Sarah Larcombe · Sonal S Nagra · Glenn Guest · Eugene Athan

An 80- year- old man presented with 2 days of fever and a widespread, itchy, nonblanching, erythematous rash involving more than 50% of body

David WJ Griffin · Genevieve E Martin · Catriona McLean · Allen C Cheng · Michelle L Giles

Herpes zoster ophthalmicus (HZO), a condition that affects the ophthalmic division of the trigeminal nerve, is caused by reactivation of latent varicella zoster virus;1,2 about 10% of people with varicella zoster infections experience HZO.1 Over the past decade, the number of emergency department presentations by people with herpes zoster in Australia has increased by 2–6% per year, and the number of people with herpes zoster managed in general practice has almost doubled.3 The purpose of our study was to develop a contemporary perspective of the clinical presentation, incidence of complications, and treatment practice for patients with HZO referred to an Australian tertiary eye hospital. We performed a retrospective audit of digital health records of the first 100 consecutive patients who presented to the Royal Victorian Eye and Ear Hospital (RVEEH) emergency department with HZO during July 2017 – July 2018. The investigation was approved by the Human Research Ethics Committee of the Hospital as a quality control project (reference, 18/1416HL). The clinical features at the time of presentation of the 100 patients are summarised in the Box. Sixty‐five patients initially presented to their general practitioner, 20 to a hospital emergency department, and 15 directly to the RVEEH. The mean time between rash onset and presentation to a GP or emergency department was 3.3 days (range, 0–14 days). For 51 patients, treatment commenced before presentation to the RVEEH (famciclovir, 27; valaciclovir, 16; acyclovir, 6; two patients had received no topical treatment); treatment had commenced within 72 hours of the rash developing for 36 of these patients (71%). The recommended dose and frequency were prescribed for 16 of the 51 patients: famciclovir (500 mg three times a day), two patients; valaciclovir (1 g three times a day), 12 patients; acyclovir (800 mg five times a day), two patients. For 29 patients, antiviral therapy was prescribed at lower than the recommended dose (famciclovir, 21 patients; valaciclovir, two patients; acyclovir, two patients) or prescribed as a topical treatment (acyclovir, two patients); the prescribing information was not documented for five patients. Nineteen of the 68 patients who attended follow‐up 7–14 days after their initial presentation to the RVEEH presented with ocular symptoms regarded as late complications, including four with more than one complication. Eight of 29 patients (29%) who had not commenced systemic antiviral therapy within 72 hours of rash onset developed late complications, as did 13 of 71 patients (18%) who were treated within 72 hours (Fisher exact test: P = 0.78). We found concerning variations in timing and practice of treating HZO, despite recognised clinical guidelines.4,5 This may be partly explained by diagnostic uncertainty caused by the variability of clinical signs during the early stages of HZO,6 and by an earlier discrepancy between the famciclovir dosing recommended by therapeutic guidelines (250 mg three times a day) and recommendations based upon the results of a clinical trial4 (500 mg three times a day). This discrepancy has since been resolved in the therapeutic guidelines.4 Our findings suggest that education of all health care professionals involved in the care of patients with HZO needs to be improved. Clinical practice guidelines must provide clear and consistent information about managing HZO. Box – Demographic characteristics and clinical features of 100 consecutive people presenting with herpes zoster ophthalmicus to the Royal Victorian Eye and Ear Hospital, July 2017 – July 2018 Characteristic Sex (men) 52 Age at presentation (years), median (IQR) 59 (39–76) Age at presentation (years), range 16–93 Clinical features at presentation Best‐corrected visual acuity ≥ 6/12 62 Intra‐ocular pressure (mmHg), mean (SD) 15.4 (5.9) Rash 92 Pain 63 Conjunctivitis 62 Lid swelling 53 Skin erythema 41 Anterior uveitis 26 Keratitis 20 Other* 6 Late complications 19 Uveitis 11 Keratitis 5 Other† 3 IQR = interquartile range; SD = standard deviation. * Raised intra‐ocular pressure, retinitis/choroiditis, optic neuritis, cranial nerve palsy. † Neuralgia, elevated intra‐ocular pressure.

Rahul Chakrabarti · Grace George · Kristen Wells · Carmel Crock

Gaps in availability of both meningococcal ACWY and B vaccines exist for high risk groups Invasive meningococcal disease (IMD) is a serious disease and an emotive public health issue in Australia. In the early 2000s, IMD case numbers declined nationally by about 80%, from 688 in 2002 to 149 in 2013,1 due to a drop in serogroup C and B disease. The decline in serogroup C disease followed the comprehensive childhood meningococcal C vaccination program — free vaccination was available up to age 19 years — introduced in 2003.2 Simultaneously, but without clear cause in the absence of vaccination, meningococcal B (MenB) disease declined slowly from 1.49 cases per 100 000 population in 2003 to 0.47 in 2015 (293 and 112 cases respectively).3 Overall, the IMD incidence rose again after 2014, driven mainly by the emergence of serogroup W and, to a lesser extent, serogroup Y.1,4 Most serogroup W strains are close variants of the virulent ST‐11 clone initially identified in the United Kingdom and South America in 2009, which was associated with more frequent atypical clinical presentations, greater severity and increased mortality.1 Although the emergence of serogroups W and Y was a game changer, serogroup B still accounted for about half of all IMD cases in Australia between 2016 and 2018.4 Compared with some other vaccine‐preventable diseases, IMD is relatively rare, affecting about one in every 100 000 Australians, equating to an average of 250 cases per year between 2014 and 2018.1,4 However, the case fatality rate is high, and around 10–30% of survivors experience long term sequelae.3,5 Although IMD can occur at any age, it is more common in children aged less than 2 years (especially those aged < 12 months) and older adolescents (Box 1). Aboriginal and Torres Strait Islander (hereafter respectfully referred to as Indigenous) children aged up to 14 years are also disproportionately affected compared with non‐Indigenous children (Box 2). For example, rates of serogroup W IMD in Indigenous children were more than 30‐fold higher compared with non‐Indigenous children of the same age during 2016–2018 (Box 2). People with certain medical conditions also have a high risk of IMD.6 These conditions include asplenia; complement deficiency, which in some types the risk is up to 10 000 times greater than in the general population;7 and use of eculizumab, which is a monoclonal antibody directed against complement and is used for treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Increased use of quadrivalent meningococcal conjugate vaccines Three brands of quadrivalent meningococcal conjugate (MenACWY) vaccines are available in Australia: Menactra (Sanofi), Menveo (GlaxoSmithKline) and Nimenrix (Pfizer). These quadrivalent vaccines include a capsular polysaccharide from each ACWY serogroup conjugated to a carrier protein, superseding the less immunogenic polysaccharide‐only vaccines previously used. The rapid rise of serogroups W and Y disease prompted all states and territories to fund MenACWY vaccination programs in 2017 and 2018 as an outbreak response.8 These programs varied but predominantly targeted adolescents aged 15–19 years, aiming to both directly prevent disease and to interrupt community transmission of meningococci through reduced acquisition of nasopharyngeal carriage, which is most prevalent in this age group.9,10 Some jurisdictions also implemented time‐limited vaccination programs covering select age groups, from infancy up to older adolescence, to control serogroup W outbreaks. The most notable of these outbreaks began in September 2017 in the Northern Territory and spread to nearby communities in central Australia, including regions in Western Australia, Queensland and South Australia. Indigenous children aged less than 10 years living in remote communities were primarily affected, with 19 cases within a few months.11 Meningococcal B vaccine use in Australia The modes of transmission, pathogenesis and treatment of serogroup B IMD are the same as for IMD caused by other serogroups, although the case fatality rate appears lower for serogroup B (6.9%) than for serogroups W, C and Y (12.8%, 12.0% and 10.8% respectively).12 However, the development of a vaccine against serogroup B disease was problematic for decades because serogroup B capsular polysaccharide is cross‐reactive with human tissues (an autoantigen) and thus poorly immunogenic.13 Two MenB vaccines, developed using novel recombinantly derived protein antigens common to many serogroup B strains, are now available in Australia: Bexsero (GlaxoSmithKline), since 2013, and Trumenba (Pfizer), since 2017. Trumenba is only registered for use from 10 years of age, whereas Bexsero can be used from 6 weeks of age. Both MenB vaccines have a high cost (around $100 per dose) and require multiple doses. Bexsero also causes higher rates of fever in young children than other vaccines included in the National Immunisation Program (NIP), necessitating the use of prophylactic paracetamol around the time of immunisation.6 Data on the benefits of MenB vaccine use are gradually accumulating, predominantly from the UK, which is the only country to have formally evaluated an ongoing funded population‐based program. Infants in the UK have been offered a three‐dose course of Bexsero (scheduled at ages 2, 4 and 12 months) since 2015. New data from the UK over 3 years estimate vaccine effectiveness against serogroup B IMD to be 52.7% (95% CI, −33.5 to 83.2) for a two‐dose primary schedule for infants, and 59.1% (95% CI, −31.1 to 87.2) for a two‐dose primary schedule followed by a booster dose at one year.14 However, Bexsero does not appear to have an impact on nasopharyngeal carriage of serogroup B,9 which implies that herd immunity (indirect protection in unvaccinated individuals) would be limited or absent despite population‐based vaccination.9 In addition, for both vaccines, protection against only around three‐quarters of all circulating MenB strains is predicted, based on in vitro assays.15 To date, the use of MenB vaccines in Australia has been limited in the absence of NIP funding. In October 2018, in the context of higher serogroup B IMD incidence rates compared with other parts of Australia, the South Australian government introduced the only state‐funded MenB vaccination program for young children, expanding to adolescents in February 2019.8 In 2020, a population‐level study of adolescent MenB vaccination in the Northern Territory will commence to explore its impact on gonorrhoea — a high incidence sexually transmitted disease caused by the related organism Neisseria gonorrhoea — as well as on serogroup B IMD (Helen Marshall, Professor in Vaccinology and National Health and Medical Research Council Practitioner Fellow, Robinson Research Institute, University of Adelaide, Australia, personal communication, January 2020). Assessment and introduction of meningococcal vaccines to Australia's National Immunisation Program Both equity and cost‐effectiveness are important considerations when approaching decision making regarding vaccine incorporation into immunisation programs. To be added to the Australian NIP, vaccines require a comprehensive assessment and must be recommended as cost‐effective by the Pharmaceutical Benefits Advisory Committee (PBAC); this is based on economic modelling, typically undertaken by the vaccine manufacturer.16 With a low IMD incidence (one per 100 000), relatively small numbers of deaths, and trends in serogroup incidence being difficult to predict, the accurate assessment of the cost‐effectiveness of both types of meningococcal vaccines (MenACWY and MenB) has been challenging. Low incidence rates have meant reliance on immunologic correlates of protection to predict vaccine impact (randomised placebo‐controlled efficacy studies are not feasible for such rare outcomes) and a limited number of post‐market vaccine effectiveness estimates. Other key uncertainties include the duration of protection and the magnitude of any herd protection effect, particularly for MenB vaccines, for which evidence is showing that there is no effect on nasopharyngeal meningococcal carriage.9 These uncertainties, together with the high cost of the MenB vaccines in particular, provide challenges for the value for money assessment necessary to underpin vaccine introduction into long term programs. In 2018, the MenACWY vaccine Nimenrix replaced the meningococcal serogroup C vaccine on the NIP at 12 months of age, and was also added to the NIP for use in a single birth cohort of adolescents aged 14–16 years from early 2019, replacing jurisdictionally funded programs.8 This is expected to provide direct protection to vaccinated individuals as well as some indirect protection to unvaccinated people over time.17 The potential to fund the MenACWY vaccine for certain high risk groups with underlying medical conditions through the NIP has also been flagged in a recent positive PBAC recommendation,18 which is under active consideration by the Australian Government. The Bexsero MenB vaccine was assessed by the PBAC on three occasions between 2013 and 2015, but was deemed as not being cost‐effective at the manufacturer's proposed price.19 In November 2019, following another manufacturer application, the PBAC recommended the NIP inclusion of Bexsero for Indigenous infants (with a catch‐up to 2 years of age) and for anyone with certain medical conditions (asplenia, complement deficiency, and eculizumab treatment). However, once again, the use of the vaccine in a broader population‐based program for infants and adolescents was not considered cost‐effective.20 The implementation of these recommendations is under active consideration by the Australian Government. Gaps in the prevention of meningococcal disease in Australia The Australian immunisation handbook recommends that any person who wants to protect themselves against invasive meningococcal disease can receive MenACWY and MenB vaccines from as early as 6 weeks of age.6 Box 3 shows groups particularly recommended for vaccination based on their higher risk of disease, compared with current and anticipated funded meningococcal vaccine programs. New proposed and existing funded programs are a substantial achievement and will provide protection to many individuals most at risk from vaccine‐preventable meningococcal strains. However, some equity gaps remain. It will take time to accrue the benefits of reduced MenACWY disease incidence and disease transmission across the population when vaccinating only at ages one and 15 years, especially without including all infants in the NIP‐funded program. It is possible that the disparity in IMD rates between Indigenous and non‐Indigenous children may persist for years, particularly for serogroup B disease, in the absence of herd immunity and of an adolescent program funded by the NIP. Assessing program impact on disease, particularly in jurisdictions where wider populations did, or continue to, receive state‐funded vaccines (against MenACWY or MenB disease), such as Western Australia, Tasmania and South Australia,8 is essential to evaluate evidence of benefit. The remaining access gaps are very challenging to address for high cost vaccines that are not offered at cost‐effective prices by the manufacturer. Other initiatives, such as ensuring that health services fund vaccination of persons living with human immunodeficiency virus and of at‐risk laboratory workers (two groups not included in the NIP), and addressing the social determinants of health that underpin high rates of meningococcal disease (and other vaccine‐preventable diseases), are also important.21 Conclusion Australia has progressively implemented funded vaccination programs for various high risk groups using MenACWY and MenB vaccines over the past 5 years. The anticipated expansion of NIP funding to include medical at‐risk groups for both vaccines and to include young Indigenous children for MenB vaccine, in addition to established MenACWY programs, should be effective over time to protect those most at risk of disease. Close monitoring of emerging data on the duration of vaccine protection from Australia and internationally is needed, particularly for individuals with underlying medical conditions whose risk is enduring. It remains challenging that for one disease, IMD, we must use two vaccines; while at least one pentavalent vaccine (MenABCWY) is under development, it is years away from use, and the assessment of cost‐effectiveness is equally uncertain. This rare but deadly disease will continue to challenge; clinicians should remain aware and discuss vaccination options against both MenB and MenACWY disease with their patients. Box 1 – Invasive meningococcal disease (IMD) notification rates by serogroup and age group (Australia, 2016–2018) The graph shows the rate of cases of IMD notified to the National Notifiable Diseases Surveillance System between 1 January 2016 and 31 December 2018. The total cases include all notified cases of IMD, including serogroups B, C, E, W, Y and unknown serogroup. There were no cases of serogroup A in this period. Box 2 – Average annual notification rates of invasive meningococcal disease (IMD) for Aboriginal and Torres Strait Islander people compared with non‐Indigenous people, by age group and serogroup (Australia, 2016–2018) RR = rate ratio. The graph shows the rate of cases of serogroup B and W IMD notified to the National Notifiable Diseases Surveillance System between 1 January 2016 and 31 December 2018. Box 3 – Australian recommendations for meningococcal vaccination and funded programs*† Recommendations Funded programs for MenB vaccines‡ Funded programs for MenACWY vaccines‡ Overall AIH recommendation Any person who wants to protect themselves against invasive meningococcal disease can receive MenACWY and MenB vaccines from as early as 6 weeks of age No funded programs that cover all age groups No funded programs that cover all age groups Specific AIH recommendations for high risk groups§ All individuals in particular age groups (6 weeks to 4 years and 15–19 years) State/territory: South Australia: 6 weeks to 12 months of age, with catch‐up to 4 years of age8 Northern Territory: to be provided for adolescents from early 2020 as part of an NHMRC‐funded research study¶ NIP: One dose at age 12 months One school‐based cohort (age ~ 15–16 years)8 State/territory: Various current and previous programs — for further detail refer to summary document8 or individual health department websites Aboriginal and Torres Strait Islander people (6 weeks to 19 years of age) NIP: Nil, but anticipated it will likely be included for infants, with catch‐up to 2 years of age20 NIP: One dose at age 12 months One school‐based cohort (age ~ 15–16 years)8 State/territory: South Australia: 6 weeks to 12 months of age, with catch‐up to 4 years of age8 Northern Territory: to be provided for adolescents from early 2020 as part of an NHMRC‐funded research study¶ State/territory: Various current and previous programs — for further detail refer to summary document8 and individual health department websites High risk due to medical condition (asplenia/hyposplenia, complement deficiency, eculizumab use, HIV, post‐HSCT; all people aged ≥ 6 weeks) NIP: Nil, but anticipated it will be included for individuals with asplenia/hyposplenia, complement deficiency, eculizumab use20 NIP: Nil, but anticipated it will be included for individuals with asplenia/hyposplenia, complement deficiency, eculizumab use20 Other: Some individual hospitals or local health services may fund the vaccine for patients with HIV or HSCT Other: Some individual hospitals or local health services may fund the vaccine for patients with HIV or HSCT Other risk factors (young adults aged 20–24 years who smoke or live in close quarters; eg, military barracks or university residential accommodation) Nil (self‐funded) Nil (self‐funded) Laboratory workers at risk Nil (may be employer‐funded) Nil (may be employer‐funded) Travellers to endemic areas Nil (self‐funded) Nil (self‐funded) AIH = Australian immunisation handbook; HIV = human immunodeficiency virus; HSCT = haematopoietic stem cell transplant; NHMRC = National Health and Medical Research Council; MenACWY = serogroups A, C, W and Y meningococci; MenB = serogroup B meningococcus; NIP = National Immunisation Program. * Adapted from the AIH6 and other referenced sources. † Note that the number of doses recommended varies by specific group — refer to the AIH for details. ‡ As of 17 January 2020. § Recommendations are for both MenACWY and MenB vaccines. ¶ Helen Marshall, Professor in Vaccinology and NHMRC Practitioner Fellow, Robinson Research Institute, University of Adelaide, Australia, personal communication, January 2020.

Cyra Patel · Clayton K Chiu · Frank H Beard · Nigel W Crawford · Kristine Macartney

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

A 33-year-old male tour guide presented at our clinic with rash and swelling on the anterior upper arms

Minh Cuong Duong · Phuc VD Le · Oanh NK Pham · Hong Quang Huynh

Chronic fatigue syndrome (CFS) is a prevalent condition affecting about one in 100 patients attending primary care. There is no diagnostic test, validated biomarker, clear pathophysiology or curative treatment. The core symptom of fatigue affects both physical and cognitive activities, and features a prolonged post‐activity exacerbation triggered by tasks previously achieved without difficulty. Although several different diagnostic criteria are proposed, for clinical purposes only three elements are required: recognition of the typical fatigue; history and physical examination to exclude other medical or psychiatric conditions which may explain the symptoms; and a restricted set of laboratory investigations. Studies of the underlying pathophysiology clearly implicate a range of different acute infections as a trigger for onset in a significant minority of cases, but no other medical or psychological factor has been reproducibly implicated. There have been numerous small case–control studies seeking to identify the biological basis of the condition. These studies have largely resolved what the condition is not: ongoing infection, immunological disorder, endocrine disorder, primary sleep disorder, or simply attributable to a psychiatric condition. A growing body of evidence suggests CFS arises from functional (non‐structural) changes in the brain, but of uncertain character and location. Further functional neuroimaging studies are needed. There is clear evidence for a genetic contribution to CFS from family and twin studies, suggesting that a large scale genome‐wide association study is warranted. Despite the many unknowns in relation to CFS, there is significant room for improvement in provision of the diagnosis and supportive care. This may be facilitated via clinician education.

Carolina X Sandler · Andrew R Lloyd

Objectives: To assess progress in Australia toward the 2030 WHO hepatitis C elimination targets two years after the introduction of highly effective direct‐acting antiviral (DAA) treatments. Design: Analysis of quarterly data on government‐subsidised hepatitis C RNA testing and hepatitis C treatment in Australia, January 2013 – June 2018. Changes in testing and treatment levels associated with DAA availability were assessed in an autoregressive integrated moving average (ARIMA) statistical model, and the impact by 2030 of different levels of testing and treatment were estimated using a mathematical model. Major outcome measures: Hepatitis C prevalence among people who inject drugs; annual hepatitis C incidence relative to 2015 levels; projections for the hepatitis C care cascade in 2030. Results: The mean annual number of treatments initiated for people with hepatitis C increased from 6747 during 2013–2015 (before the introduction of DAAs) to 28 022 during 2016–18; the mean annual number of diagnostic RNA tests increased from 17 385 to 23 819. If current trends in testing and treatment continue (ie, 2018 testing numbers are maintained but treatment numbers decline by 50%), it is projected that by 2030 only 72% of infected people would be treated (by 2025 all people diagnosed with hepatitis C would be treated). The incidence of hepatitis C in 2030 would be 59% lower than in 2015, well short of the WHO target of an 80% reduction. The identification and testing of people exposed to hepatitis C must be increased by at least 50% for Australia to reach the WHO elimination targets. Conclusion: Hepatitis C elimination programs in Australia should focus on increasing testing rates and linkage with care to maintain adequate levels of treatment.

Nick Scott · Rachel Sacks‐Davis · Amanda J Wade · Mark Stoove · Alisa Pedrana · Joseph S Doyle · Alexander J Thompson · David P Wilson · Margaret E Hellard

Information on COVID‐19 and its impact is being updated constantly and Australia must continue to be prepared at all levels of the health care system An outbreak of a novel coronavirus, formally named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and causing coronavirus disease 2019 (COVID‐19), emerged in the city of Wuhan in Hubei province in central China in December 2019. The first cases were noted as a cluster of patients with pneumonia who were all linked to a live animal market, and testing found the presence of a previously unknown coronavirus. Coronaviruses are a group of viruses that affect both animals and humans, and several (OC43, 229E, HKU1 and NL63) are a cause of the common cold.1,2 However, two coronaviruses previously caused significant outbreaks associated with more severe disease: the SARS coronavirus in 2002–2003 and the Middle East respiratory syndrome coronavirus that emerged in 2012.1,2 In contrast to previous outbreaks, the rapid sharing of viral sequences enabled laboratories worldwide to develop diagnostic tests within weeks of discovery of the pathogen.3 An Australian laboratory subsequently isolated the virus from a clinical sample (the first to do so outside of China), and rapidly shared this virus with relevant global agencies, further aiding diagnostic, therapeutic and vaccine development efforts. Information on the new virus and its impact is being updated constantly. While ascertainment of the milder end of the disease spectrum varies between countries,4 the age‐specific severity profile appears to be relatively consistent.5 Age is clearly an important risk factor — there have been few severe cases reported in children, and a high case fatality risk in the elderly. However, it is not clear whether comorbidities reflect the age group affected or whether they are risk factors for severe disease.6,7 Early studies using data before the institution of public health interventions in China suggest that SARS‐CoV‐2 is as transmissible as SARS coronavirus and probably more transmissible than influenza viruses.8,9 Emerging data suggest that viral load is highest around the onset of illness in milder cases, and transmission may occur during this pre‐symptomatic period.10,11,12 Careful analysis of early data suggests that the mean incubation period is 6 days, with a range of up to 14 days.13 There have been a considerable number of large clusters associated with large events, including religious communities, weddings, business meetings, closed communities, dormitories and cruise ships.14,15,16,17 The importance of infection control is also reinforced by a report that 41% of cases in Wuhan were acquired nosocomially (including 40 health care workers and 17 patients).6 Since the World Health Organization was first notified of this new pathogen, more than 2 million cases and over 130 000 deaths have been reported globally. On 16 April 2020, there were 6462 confirmed cases of COVID‐19 in Australia, including 63 deaths. After early outbreaks in Asia, the hardest hit countries currently are the United States and in Europe. There is great concern about low and middle income countries with limited diagnostic and public health capacity. The public health, political and societal ramifications have been considerable, with disruptive interventions that would have been unthinkable even a few months ago. Ultimately, a vaccine will be required; at the time of writing, 60 vaccine candidates have been developed, including three entering human trials (https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/). For clinicians, the main considerations are the clinical management of patients with suspected COVID‐19 but also systems to facilitate the identification of potential cases and to permit safe assessment and referral as appropriate. The experience with SARS and Middle East respiratory syndrome also reinforces the need for health services (both internationally and within Australia) to promptly identify patients with suspected infection and implement effective infection control measures, including adequate protection of health care workers. Based on clinical features, it can be difficult to distinguish patients with COVID‐19 from those with other respiratory viral infections, including influenza. Although the original case series described fever in almost all patients,7 further experience has noted cases with only respiratory symptoms, and even a small proportion with gastrointestinal symptoms.6 This has resulted in constant changes to case definitions, initially limited to febrile respiratory infections in travellers, but now including the full spectrum of illness in patients with broader epidemiological risk factors. Clinicians should refer to current information to guide testing and management (Box 1). Nucleic acid assays for SARS‐CoV‐2 are available at all Australian reference laboratories and commercial tests are now available in diagnostic laboratories. Compared with other countries, Australia has now performed a proportionately large amount of testing per capita.18 However, the sheer scale of testing has placed extraordinary pressure on supply chains for essential components required for laboratory testing, both in Australia and globally. Current World Health Organization advice is to test patients who meet the case definition for COVID‐19, regardless of whether another respiratory virus is detected, as co‐infections may occur.19 In recent weeks, surveillance for COVID‐19 has expanded to include a much broader range of risk factors to ensure capture of community transmissions. The role of serological assays (particularly point‐of‐care testing) in the overall public health response to COVID‐19 has yet to be defined, although peak bodies such as the Royal College of Pathologists note that there is no role for point‐of‐care assays in the diagnosis of acute COVID‐19.20 Lessons of the past are instructive for Australia, particularly the experience in Canada with its similar federated government and comparable health care system. In 2003, an outbreak of SARS coronavirus in Toronto infected 438 people and caused 44 deaths, including many health care workers. Following this public health disaster, two important reviews were conducted: the National Advisory Committee on SARS and Public Health,21 and Ontario's SARS Commission.22 The former reinforced the need for a strong and adequately funded nationally coordinated public health and laboratory system and led to the establishment of the Public Health Agency of Canada. The SARS Commission made detailed recommendations, including endorsing the “importance of the precautionary principle that reasonable efforts to reduce risk need not await scientific proof [which] was demonstrated over and over during SARS”.22 It made recommendations regarding clear governance, preparing for the need for unexpected interventions (including the closure of three hospitals to control the outbreak), effective distribution of outbreak alerts and directives, the need for effective crisis communication, and the value of robust and timely surveillance. With the involvement of health care workers as cases, the Commission highlighted the need to listen to frontline workers and unions and ensure a robust safety culture and effective infection control. We have many more information (and misinformation) sharing tools than were available in 2003. It has been breathtaking to watch the scientific process unfold in almost real time. Rapid genomic sequencing and online databases are being used to generate and analyse primary data. Preprint servers and rapid review in traditional journals are quickly publishing research findings. Research centres and platforms are responding to rapidly collect data and evaluate interventions. Social media and traditional media platforms are disseminating public health messages and findings. However, the fundamental structure of our public health care system remains unchanged, with the same channels of formal communication and direction through jurisdictions and national networks. A future review should consider whether surveillance and response for all infectious disease threats could be better coordinated by a centralised national agency. There are still many major unresolved clinical and public health issues (Box 2). Clear communication to the public and to clinicians has been difficult, particularly with constantly changing epidemiology and evidence. Australia was not significantly challenged by the two previous zoonotic coronavirus outbreaks, but this global crisis has now significantly disrupted the lives of all Australians. With thousands of cases reported in Australia, public health authorities, governments at all levels, researchers and clinicians, laboratories and the community need to continue to work together in a timely and transparent manner to ensure an effective response. Box 1 – Useful sources of official information* Australian information Australian Government Department of Health: https://www.health.gov.au/health-topics/novel-coronavirus Smart Traveller: https://www.smartraveller.gov.au/ Jurisdictional health department sites: New South Wales: https://www.health.nsw.gov.au/Infectious/diseases/Pages/coronavirus.aspx; Victoria: https://www.dhhs.vic.gov.au/coronavirus; Australian Capital Territory: https://www.health.act.gov.au/health-professionals/chief-health-officer-alerts; Tasmania: https://www.coronavirus.tas.gov.au/; South Australia: https://www.sahealth.sa.gov.au/wps/wcm/connect/public+content/sa+health+internet/clinical+resources/clinical+topics/infectious+disease+control/novel+coronavirus+%282019-ncov%29+infection+for+health+professionals/novel+coronavirus+%282019-ncov%29+infection+information+for+health+professionals; Western Australia: https://ww2.health.wa.gov.au/Articles/A_E/Coronavirus; Northern Territory: https://coronavirus.nt.gov.au/; Queensland: https://www.qld.gov.au/health/conditions/health-alerts/coronavirus-covid-19 International situation reports and resources World Health Organization: https://www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en/ United States Centers for Disease Control and Prevention: https://www.cdc.gov/coronavirus/2019-ncov/index.html European Centre for Disease Prevention and Control: https://www.ecdc.europa.eu/en/coronavirus * Websites viewed April 2020. Box 2 – Major unresolved clinical and public health issues Clinical Optimal samples for diagnostic testing (upper versus lower respiratory tract samples) Utility of existing and investigational antiviral agents and other treatments Host risk factors associated with poor clinical outcomes Public health and control The long term public health strategy for control to minimise morbidity and mortality, but taking into account broader impacts of health, the economy and society The optimal mix of case finding and isolation, contact tracing and quarantine, social distancing and personal hygiene Optimal, yet pragmatic, infection control measures to prevent infections in health care facilities and residential aged care facilities

Allen C Cheng · Deborah A Williamson

CYD-TDV (Dengvaxia) use in travellers should be considered on a case-by-case basis, with a detailed discussion of risks and benefits in light of its safety and efficacy profile

Irani Thevarajan · Joseph Torresi · Cameron Simmons

A 79-year-old Indian man who immigrated to Australia in 1976 presented with a 15- year history of left wrist swelling and forearm sinus tracts

Lakshana Kalatharan · Peter Kelley

The automatic assumption that sexually transmissible infections in young people means sexual abuse further stigmatises them and discourages them from presenting to health services

James S Ward · Belinda Hengel · Donna Ah Chee · Olga Havnen · John D Boffa