Volume 213 Issue 9

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

Yada Kanjanapan · Desmond Yip

Lessons learnt from COVID-19 outreaks in residential aged care facilities could limit future impacts

Gwendolyn L Gilbert

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

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

The involvement of patient advocates should ensure that guidelines are rigorously patient‐focused The fundamental objective of clinical management guidelines for any disease entity is to ensure that the information required to provide evidence‐based management recommendations to patients is readily available to their treating clinicians. It is well established that familiarity with guidelines by clinicians and adherence to them increases the number of patients receiving best‐practice care and improves outcomes.1 However, although management guidelines are intended primarily for clinicians, they must also reflect the patient perspective.2 Patient representation on the Melanoma Guidelines Working Party After identifying the need to produce new Australian guidelines on the management of melanoma, a multidisciplinary working party — under the auspices of Cancer Council Australia and the Melanoma Institute Australia — was established in 2014 to critically assess new evidence and update the previous national guidelines. In addition to clinicians and researchers, two patient advocates (consumer representatives), representing patients with melanoma from around Australia through their affiliations with patient advocacy and support networks, were invited to join the working party. These patient advocates had personal experience of melanoma diagnosis and treatment and extensive prior involvement in melanoma advocacy. This meant that they were able to make important contributions based on their experience as well as providing feedback from the patient networks they represented. Electronic publication Whereas the two previous editions of Australian melanoma guidelines, published in 1999 and 2008 respectively, were printed documents, each taking more than 4 years to compile,3,4 the new guidelines were electronic and were made available on Cancer Council Australia's Wiki platform.5 This publication format allowed individual sections to be published as they were completed and permitted selective updating as new evidence became available. Electronic publication has also meant that the guidelines are more readily accessible to both doctors and patients. They can simply search on their computer, tablet or smartphone for “Australian melanoma guidelines” or go directly to the guidelines website (https://wiki.cancer.org.au/australia/Guidelines:Melanoma).5 The level of evidence supporting each guideline recommendation is clearly documented, informing doctors and assisting patients in their decision‐making process. Patients’ expectations from their treating clinician When patients who are concerned about the possibility of having a primary melanoma consult a general practitioner, dermatologist or surgeon, they are entitled to expect that evidence‐based guidelines will be followed and therefore that the steps below will take place: if there are any suspicious skin lesions, they will be carefully examined; if the doctor suspects that a lesion may be a melanoma, the recommended form of biopsy will be carried out (usually complete excision biopsy with a 2–3 mm margin); if melanoma is diagnosed, the recommended treatment and likely outcome will be clearly explained; the melanoma will be staged correctly, appropriately wide surgical excision will be recommended, and the option of sentinel node biopsy will be discussed for melanomas 1 mm or greater in Breslow thickness or 0.8–1.0 mm in thickness with higher risk pathological features, so that prognosis can be estimated accurately and the eligibility for adjuvant post‐operative systemic therapy can be determined;6,7 and the potential benefits and possible side effects of adjuvant therapy will be discussed. When patients are given a diagnosis of metastatic melanoma in regional lymph nodes, or at a systemic site and are referred to a surgeon, medical oncologist or radiation oncologist, again, they should be able to expect that the following will happen: appropriate surgery will be recommended, and surgery that may be unnecessary (eg, completion lymph node dissection for sentinel node positivity8,9) will not be undertaken without a full discussion of the advantages and disadvantages; and if surgery is not considered appropriate, therapeutic systemic therapy options will be discussed, again with a realistic description of the likely benefits and possible side effects.10 Use of the guidelines While different stakeholders will use guidelines in different ways, they are intended to be useful to both clinicians and patients: to GPs, particularly those who work in skin cancer clinics; to dermatologists, who see many patients when they first present with a primary melanoma but who rarely manage patients with metastatic melanoma; to surgeons who treat patients with both primary and metastatic melanoma; to medical and radiation oncologists who are involved in the care of patients with metastatic disease; and importantly, to patients by providing a reliable source of information. It is hoped that by having access to guidelines based on the best available evidence, both treating clinicians and patients will be better informed, treatment options will be better understood, and patients will receive the most appropriate care. The ongoing involvement of patient advocates in the process of developing and updating the Australian melanoma guidelines should ensure that they are useful and relevant to patients and that the health care outcomes most valued by them are considered, resulting in guidelines that are rigorously patient‐focused, as they should be.

Alison E Button‐Sloan · John F Thompson

A recently developed national transport and cryopreservation service improves equity of access to fertility care for young people across Australia Loss of fertility, which is a well recognised complication of cancer treatment, has a significant impact on quality of life and is ranked as one of the top survivorship concerns.1 Improvements in survival (> 88% for adolescents and young adults) and expansion of fertility preserving options have stimulated rapid evolution of the fertility preservation landscape, aiming to decrease this devastating impact of cancer therapy.2 In addition to the gonadotoxic burden of cancer treatment, societal trends of delayed fertility mean that there are many young people who have not yet completed or even commenced trying for a family when diagnosed with a life‐threatening illness. Fertility discussion, and provision of services to preserve gametes or tissue, is no longer seen as a distraction or a luxury but is acknowledged as a mandatory part of cancer management.3 However, barriers to provision of fertility preservation care remain. These include the lack of education of health care providers about both the long term fertility consequences of cancer treatment and the clinical value of available options. There is also often a lack of clarity about whose role it is to educate patients about these options. Importantly, there can be significant logistic, geographic and economic barriers for patients, especially outside the major centres, such that only 4–50% of young people take up fertility preservation in a timely fashion.4 Established strategies to preserve fertility for the future include medical therapies to protect the primordial follicle pool, vitrification of oocytes and embryos, and ovarian tissue cryopreservation for females. Mature sperm freezing is undertaken in post‐pubertal males, and testicular tissue cryopreservation, while providing the only opportunity for pre‐pubertal boys, is still considered experimental.3 Gonadal tissue cryopreservation Ovarian tissue cryopreservation is the only option for prepubertal girls and may be the only or best option for women at high risk of infertility from cancer treatment, particularly if there are time constraints or safety concerns with other options. Ovarian tissue cryopreservation is no longer considered experimental by peak bodies,3 and there have been over 140 births worldwide following ovarian tissue grafting, including several in young women whose ovarian tissue was cryopreserved as pre‐pubertal children.5 Testicular tissue cryopreservation provides an experimental option for fertility preservation in pre‐pubertal boys at significant risk of azoospermia from gonadotoxic treatments. As boys do not produce mature sperm that can be frozen, a treatment involving testicular biopsy and cryopreservation of spermatogonial stem cells, followed by transplantation into the testis after treatment, is proposed to allow restoration of fertility.6 Recent publications of in vitro sperm maturation and live birth success using the primate animal model provide optimism, such that the joint international consensus statement of peak fertility bodies in 2015 recommended that testicular tissue cryopreservation should be offered for pre‐pubertal boys,3 despite the currently experimental nature of future use, especially as there are no other options. Testicular biopsy can be safely performed and often coordinated concomitantly with other medically necessary procedures without delaying the start of treatment.7 While cryopreservation of eggs, sperm and embryos is a routine part of assisted reproductive laboratory activity, the technique for cryopreservation of ovarian and testicular tissue is biophysically different, and very few centres nationally and internationally have established tissue cryopreservation laboratories with validated, published protocols and clinical success after thawing.8 Due to distance challenges within Australia and lack of resources to meet the needs of these patients, particularly those who reside in rural and remote areas, ovarian and testicular tissue cryopreservation is not accessible to over 70% of people who would benefit from this opportunity.4 Establishment of the National Ovarian and Testicular Transport and Cryopreservation Service To provide equity of access to fertility care, the Fertility Preservation Service at the Royal Women's Hospital in Melbourne has developed the National Ovarian and Testicular Transport and Cryopreservation Service, allowing collaboration between local units and specialised centres, with professional and patient education as part of the program. There are several successful international models for collaborative care with published protocols and data to support transportation and storage of gonadal tissue or gametes in a specialised centre with expertise, health and safety regulations.9 The live birth rates with and without overnight transportation are comparable.9 The Fertility Preservation Service, a partnership between the Royal Women's Hospital and Melbourne IVF, was established 30 years ago. It is the largest service of its kind in Australia, with clinical expertise in counselling, cryopreservation, testing, storage and transport procedures. It sees about 300 patients per year, managed by a multidisciplinary team of fertility specialists, nurses, research scientists, research managers, laboratory staff, counsellors and administrators. There have been increasing referrals each year, reflecting the increased demand. Eighty percent of these are cancer related, with serious medical conditions and gender dysphoria forming the remainder. The Fertility Preservation Service has built extremely strong relationships with cancer centres, both in Victoria and nationally, and collaborates closely with other fertility preservation units, including the Fertility and Research Centre in NSW and the Royal Children's Hospital Melbourne. It supports data collection for the Australasian Oncofertility Registry.10 Based on a recent Fertility Society of Australia survey,11 we believe that Victoria, possibly because of both the dedicated fertility preservation centre and the well developed collaborative relationships, has the highest rate of patients referred for fertility consultation. The service stores gonadal tissue from over 1000 patients. Ovarian tissue grafting has been performed in 40 patients, with five children born and a live birth rate of 20% per embryo transferred. There are also mature eggs and embryos which have been cryopreserved from ovarian tissue stimulation. Testicular tissue has been cryopreserved for 163 patients. The establishment of a centralised national tissue retrieval and transport program allows gonadal tissue harvesting to take place in a local centre with subsequent transportation to the central laboratory for processing, cryopreservation and storage. Communication with the National Ovarian and Testicular Transport and Cryopreservation Service team occurs via a paging service which is checked daily by a dedicated nurse, with treating clinician and, when appropriate, patient follow‐up by teleconference. Subsequently, ovarian tissue grafting may be performed at the Royal Women's Hospital or the tissue can be transported back to the local centres. The service also provides follow‐up and psychological support for patients, and educational resources to assist with all aspects of fertility preservation, both for patients and health practitioners. Fertility preservation is a mandatory part of cancer care; the National Ovarian and Testicular Transport and Cryopreservation Service program will improve equity of access to fertility preservation for young women and men around Australia.

Genia Rozen · Stephanie Sii · Franca Agresta · Debra Gook · Catharyn Stern

The advent of CAR T‐cell therapy has seen significant improvements in survival and is a potential cure for patients with advanced haematological malignancies Cancer immunotherapy is a burgeoning field which, in the last decade, has produced unprecedented improvements in outcomes across a variety of advanced malignancies. The eventual translation of decades of research into clinically available immunotherapies stems from the expanded knowledge of the role that the immune system plays in preventing tumour initiation and progression as well as the mechanisms by which tumours learn to evade this immune surveillance.1 Immunotherapies that have reached the clinic include monoclonal antibodies and, more recently, their augmented counterparts including antibody–drug conjugates and bi‐specific T‐cell engagers. Other treatments are immunomodulatory, meaning that they augment endogenous anti‐tumour immune activity. These include immune checkpoint inhibitors such as pembrolizumab, which are prolonging survival in melanoma and several solid organ malignancies as well as relapsed or refractory Hodgkin lymphoma. Cellular immunotherapies offer the potential to overcome immune tolerance and generate immune memory.1 Allogeneic stem cell transplantation (ASCT), a largely unmanipulated form of cellular immunotherapy, acts by completely replacing the recipient’s entire haematopoeitic and immune systems, leveraging differences between the recipient and donor to produce a graft‐versus‐tumour effect, with the potential negative consequence of immune attack on recipient’s normal tissues, known as graft‐versus‐host disease, as well as other serious toxicities. ASCT has been the only curative option for many patients with haematological malignancies. However, it is generally considered a consolidative therapy; that is, the patient’s malignancy must be in or near complete remission in order to be effective. This is not always possible in refractory cases. For others, ASCT may be contraindicated because of age or comorbidities. With advances in genetic manipulation technology, the notion of combining the specificity of a monoclonal antibody with the cytotoxicity and memory of a T‐cell came to fruition in the chimeric antigen receptor (CAR) T‐cell. “Chimeric” here means that the DNA comes from two or more sources; the antigen‐binding domain of the CAR construct is an antibody fragment, tethered to the intracellular signalling domain of the T‐cell receptor, with an additional co‐stimulatory domain acting to improve their expansion and persistence in vivo. The fundamental steps in generating and delivering CAR T‐cell therapy are summarised in Box 1.2 Specific toxicities are characteristic of CAR T‐cell therapy, the two most important being cytokine release syndrome and neurotoxicity. Cytokine release syndrome is an inflammatory state induced by the rapid proliferation of CAR T‐cells and tumour cell death, releasing an array of inflammatory cytokines. The hallmark is a fever, with the potential for hypotension, hypoxia and organ dysfunction. As one of the key cytokines driving the syndrome is interleukin‐6, its blockade using the interleukin‐6 receptor antagonist tocilizumab is now routinely used for more severe grades of cytokine release syndrome. The pathogenesis of neurotoxicity has not been fully elucidated; however, it most often manifests with speech disturbance or aphasia, dysgraphia and attention deficits, with more severe manifestations including altered level of consciousness, seizures and, rarely, cerebral oedema. Fortunately, even patients with severe neurotoxicity who are adequately supported in intensive care settings most often have complete neurological recovery. By far the most successful antigen target of all CAR T‐cell therapies developed to date is the pan‐B‐cell antigen CD19, as it arguably comes closest to the characteristics of an ideal target. CD19 is widely expressed across the full maturation spectrum of B‐cell malignancies, from B‐cell lymphoblastic leukaemia cells to mature B‐cell lymphomas, giving broad applicability. Second, CD19 is only expressed on B‐cells (normal and malignant) and not other tissues. Third, the toxicity resulting from the on‐target, off‐tumour effects, in this case normal B‐cell aplasia, is manageable by immunoglobulin replacement in patients who experience recurrent or severe infections. The decision for health authorities to fund a personalised, genetically engineered treatment is a complex one, taking into account considerations such as cost, efficacy, safety, the level of evidence and the maturity of outcome data, alternative therapies, equity of access, and resource utilisation. The cost of a single product is measured in hundreds of thousands of dollars and the mechanism by which such therapies will be funded is certainly not self‐evident. In the Australian context, the new therapy is evaluated by the Medical Services Advisory Committee, an independent committee that appraises new medical services proposed for public funding, taking into account all the above‐mentioned considerations, and providing advice to government. Moreover, given the high cost and limited, immature data, regulatory bodies worldwide have come to unprecedented outcomes‐based reimbursement agreements with pharmaceutical companies — such as rebates and staged payments according to defined response criteria — in order to mitigate risk. Two CAR T‐cell products targeting CD19 were approved by the United States Food and Drug Administration in 2017 and 2018: tisagenlecleucel and axicabtagene ciloleucel. The landmark studies which led to their approval, and a summary of their key outcomes, are shown in Box 2.3,4,5,6 In Australia, tisagenlecleucel is approved by the Therapeutic Goods Administration for paediatric and young adult patients up to 25 years of age with B‐cell lymphoblastic leukaemia that is refractory, in relapse after transplant or in second or later relapse, as well as adult patients with relapsed or refractory diffuse large B‐cell lymphoma after two or more lines of systemic therapy. In April 2019, a joint state and federal government funding initiative commenced for tisagenlecleucel for the B‐cell lymphoblastic leukaemia indication, and in January 2020, the government announced its funding for diffuse large B‐cell lymphoma. Soon after, the Therapeutic Goods Administration approved axicabtagene ciloleucel in February 2020 and the Medical Services Advisory Committee made a positive recommendation for its public funding for the lymphoma indication. Further, Novartis announced an agreement with an Australian cell and gene therapy manufacturing company for manufacture of tisagenlecleucel for the region to commence in late 2020 (https://www.celltherapies.com.au/kymriah-to-be-manufactured-at-cell-therapies-pty-ltd-marking-australias-first-on-shore-commercial-production-of-car-t-therapy/). In the case of tisagenlecleucel for relapsed or refractory B‐cell lymphoblastic leukaemia, evaluation began with a comparison with best available therapy. In the ELIANA trial4 outcomes compared very favourably with other chemo‐ or immunotherapeutic salvage options such as clofarabine7 and blinatumumab,8 respectively. For example, blinatumomab, a bispecific T‐cell engager, in the paediatric relapsed or refractory setting produced a complete remission rate of 39% within the first two cycles, with a relapse‐free survival at 6 months of 42%, and this therapy is considered to be a bridging therapy to ASCT. Tisagenlecleucel on the other hand can be used as a stand‐alone therapy; however, it is notable that a substantial proportion of responders do relapse, particularly between 6 and 12 months, which raises the question of whether this treatment should also serve as a bridge to ASCT. The available evidence is currently insufficient to confidently provide an answer, and practice therefore varies among treating centres worldwide. However, a major concern is the financial implications of CAR T‐cell therapy as a bridge to ASCT, which itself is a highly resource‐intensive therapy, with some suggestion that the cost‐effectiveness may be unbalanced if this practice were routine. In the case of high grade B‐cell lymphomas, patient outcomes also appear to be superior to other available treatments in the third line setting. In the ZUMA‐1 trial, the recently updated 3‐year overall survival rate of 47% does likely reflect a significant cure fraction.6 In comparison, the SCHOLAR‐1 retrospective study of the outcomes of patients with refractory diffuse large B‐cell lymphoma showed that this pooled patient population only achieved complete remission rates of 7% with conventional therapies and had a median overall survival of 6.3 months.9 One concern is that the outcomes of the CAR T‐cell trials may not be generalisable to the real‐world population where patient selection may not be as strict as in clinical trials. Interestingly, the real‐world data seems to be conflicted on this, with the US experience from the Center for International Blood and Marrow Transplant Research registry being comparable to trial data for both tisagenlecleucel and axicabtagene ciloleucel, while preliminary United Kingdom experience appears to be considerably worse.10,11,12 The cause of this discrepancy is unclear. In terms of future directions, many clinical trials are assessing CAR T‐cells in earlier lines of therapy. For example, two trials are randomising patients in first relapse of large B‐cell lymphoma to receive either CAR T‐cell therapy or standard salvage plus autologous stem cell transplant: ZUMA‐7 (NCT03391466) and BELINDA (NCT03570892). The results of these trials, if favourable, could greatly alter treatment paradigms. Other trials are assessing CAR T‐cells in other B‐cell lymphomas, such as follicular non‐Hodgkin lymphoma (ELARA [NCT03568461]) and mantle cell lymphoma.13 The response to KTE‐X19, an anti‐CD19 CAR T‐cell therapy with a manufacturing process that removes circulating tumour cells, seen in the ZUMA‐2 trial in relapsed or refractory mantle cell lymphoma (overall response rate of 93%) is the highest reported response rate in patients with mantle cell lymphoma who failed previous BTK inhibitor treatment, with a high proportion of durable responses in this very challenging malignancy.13 Strategies to improve the availability and timeliness of CAR T‐cell therapy include the development of third party allogeneic CAR T‐cells, which could produce off‐the‐shelf treatments for many patients. Other alterations to the CAR construct aim to improve characteristics such as persistence and safety, as well as addressing the problem of antigen escape, where the malignancy loses the targeted antigen, potentially through multi‐antigen targeting. Others are combining CAR T‐cells with immunomodulatory therapies such as immune checkpoint inhibition to improve efficacy. Finally, there is great interest in CAR T‐cell therapies for malignancies such as multiple myeloma, acute myeloid leukaemia and T‐cell lymphomas and leukaemias, many of which are at various phases of clinical trials. The furthest advanced are CAR T‐cell therapies targeting B‐cell maturation antigen in multiple myeloma. JNJ‐4528, an investigational B‐cell maturation antigen CAR T‐cell therapy, has recently demonstrated very high response rates in the phase 1b/2 CARTITUDE‐1 study in relapsed or refractory myeloma.14 In the 29‐patient cohort, the overall response rate was 100%, with 69% complete remission, the median time to complete remission being 1 month, and measurable residual disease negativity in all 17 evaluable patients. These are very promising times in cancer immunotherapy and the task ahead for regulatory authorities will be immense as evidence rapidly accumulates for these high cost therapies. In the meantime, we are pleased to add CD19 CAR T‐cell therapy to our armamentarium and await the results of trials across a wide range of haematological and solid organ malignancies. Box 1 – Overview of the processes for manufacture and delivery of a chimeric antigen receptor (CAR) T‐cell product Procurement of T-cells, usually via leukapheresis (1); transduction of the CAR genes via viral vector or non-viral methods (2); ex vivo expansion of the CAR T-cells (3); preconditioning with lymphodepleting chemotherapy (4); and infusion into a patient (5). ◆ Box 2 – Summary of data from pivotal CD19 chimeric antigen receptor (CAR) T‐cell trials Trial name CAR T‐cell product Disease Complete response rate Other response parameters Safety ELIANA4 Tisagenlecleucel Relapsed or refractory paediatric B‐ALL 81% 12‐month OS, 76%; 12‐month EFS, 50% Grade ≥ 3 CRS, 47% Grade ≥ 3 NT, 13% JULIET5 Tisagenlecleucel Relapsed or refractory DLBCL 38% Median OS, 12 months Grade ≥ 3 CRS, 23% Grade ≥ 3 NT, 11% ZUMA‐13,6 Axicabtagene ciloleucel Relapsed or refractory DLBCL 58% 3‐year OS, 47% Grade ≥ 3 CRS, 13% Grade ≥ 3 NT, 28% B‐ALL = B‐cell acute lymphoblastic leukaemia; CRS = cytokine release syndrome; DLBCL = diffuse large B‐cell lymphoma; EFS = event‐free survival; NT = neurotoxicity; OS = overall survival.

Adrian G Selim · Constantine S Tam

An 83-year-old male non- smoker presented with chronic purulent cough

Adrián López Alba · Agustín Blanco Echevarría

More evidence is required to explain the differences in cancer treatment reported by data linkage studies

Ian N Olver

The associated risks, particularly that of long term use, are underestimated, and appropriate measures are needed

Stephan A Schug

Objective: To compare treatments for localised prostate cancer for men diagnosed in private and public health services in Victoria. Design: Retrospective analysis of Victorian Cancer Registry data linked to population‐based administrative health datasets. Setting, participants: 29 325 Victorian men diagnosed with prostate cancer during 2011–2017. Main outcome measures: Proportions of men in private and public health services receiving radical prostatectomy (with or without curative radiation therapy) or curative external beam radiation therapy alone within 12 months of diagnosis. Results: After adjusting for age, tumour classification and comorbidity, men diagnosed in private health services received radical treatment more frequently than men diagnosed in public health services (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.31–1.49). The proportion of private patients who underwent radical prostatectomy was larger than that for public patients (44% v 28%; OR, 2.28; 95% CI, 2.13–2.44) and the proportion of private patients who received curative external beam radiation therapy alone (excluding brachytherapy) was smaller (9% v 19%; OR, 0.45; 95% CI, 0.42–0.49). These differences were apparent for all International Society of Urological Pathology (ISUP) tumour grades. The magnitude of the difference for prostatectomy was greater for men aged 70 years or more; for radiation therapy alone, it was larger for those diagnosed before age 70. The differences between private and public services narrowed during 2011–2017 for men with ISUP grade 1 disease, but not ISUP grade 2–5 tumours. Conclusion: Prostate cancer treatment choices differ substantially between men diagnosed in private and public health services in Victoria. These differences are not explained by disease severity or comorbidity.

Luc te Marvelde · Roger L Milne · Colin J Hornby · Adam B Chapman · Graham G Giles · Ian E Haines

Objectives: To evaluate whether educating junior doctors and hospital pharmacists about analgesic prescribing improved discharge prescribing of opioids for opioid‐naïve patients after surgical admissions. Design: Cluster randomised controlled trial, undertaken during the first half of 2019. Setting: The Alfred Hospital, a major Melbourne teaching hospital with 13 surgical units. Participants: Opioid‐naïve patients discharged from surgical units after a stay of at least 24 hours. Intervention: Surgical units were randomised to the intervention or control arms. Interns, residents, and clinical pharmacists assigned to intervention arm units attended education sessions, presented by the hospital analgesic stewardship pharmacist, about appropriate analgesic prescribing for patients in hospital surgical units. Main outcome measures: The patients prescribed slow release opioids on discharge from hospital during the baseline (1 February – 30 April 2018) and post‐intervention periods (17 February – 30 April 2019). Results: During the baseline period, 1369 intervention unit and 1014 control unit admissions were included in our analysis; during the evaluation period, 973 intervention unit and 706 control unit episodes were included. After adjusting for age, length of stay, pain score, acute pain service involvement, and use of immediate release opioids prior to admission, patients in the intervention group were prescribed slow release opioids at discharge less frequently than patients in the control group (adjusted odds ratio [aOR], 0.52; 95% CI, 0.35–0.77) and were more frequently discharged without any prescribed opioids following the intervention (aOR, 1.69; 95% CI, 1.24–2.30). Providing de‐escalation plans was more frequent for intervention than control group patients prescribed slow release opioids on discharge post‐intervention (OR, 2.36; 95% CI, 1.25–4.45). Conclusions: Specific education for clinicians and pharmacists about appropriate analgesic prescribing for surgical patients is effective in reducing prescribing of opioids at discharge. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000876291 (prospective).

Ria E Hopkins · Thuy Bui · Alex H Konstantatos · Carolyn Arnold · Dianna J Magliano · Danny Liew · Michael J Dooley

Prostate cancer continues to be the most commonly diagnosed cancer, and the second leading cause of cancer death among Australian men

Xuan Rui S Ong · Dominic Bagguley · John W Yaxley · Arun A Azad · Declan G Murphy · Nathan Lawrentschuk

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

Kyra YL Chua · Natasha E Holmes · Jason Kwong

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

Jessica Stanhope · Philip Weinstein

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

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

To the Editor: The recent discussion on chronic liver disease and ultrasonographic surveillance is welcome.1 Over two decades ago, investigators at Westmead Hospital in Sydney showed that ultrasonographic surveillance of 232 Australian patients with chronic liver disease (most of whom had cirrhosis) was superior to α‐fetoprotein in the detection of hepatocellular carcinoma (HCC).2 In this research, we detected six HCCs with ultrasound for an annual cohort incidence of 1.4%; we calculated that each HCC detected cost $US8472 (in 1998 dollar terms). Further, the superior detection of HCCs with ultrasonography did not translate into improved survival either because of tumour multicentricity, metastases at diagnosis, or patient comorbidity factors precluding surgery. Since that time, our technical expertise in liver screening with ultrasound has grown. Nevertheless, we remain concerned by the relatively poor sensitivity compared with computed tomography or magnetic resonance imaging. In addition, specialists in diagnostic imaging understand that the distorted liver architecture from cirrhosis and the presence of regenerating nodules pose significant challenges in distinguishing HCC from benign lesions. While published meta‐analyses3,4 offer some promise, they are by their very nature highly selective in the data evaluated and seldom consider the downstream costs of false positive tests. It is perhaps unsurprising that recent appropriateness criteria guidelines from the American College of Radiology sound a note of caution on the role of ultrasound in this context.5 Despite the above, there remains a need to perform a contemporary analysis of the potential benefits and costs of screening in patients with cirrhosis in Australian settings. However, as a recent Australian HCC surveillance study6 has concluded, it is difficult to interpret survival outcomes from selective retrospective studies, and conducting a randomised controlled trial may be nigh on impossible.

George Larcos

In reply

Gary P Jeffrey