The Case for Human Challenge Trials in COVID-19.

The COVID-19 pandemic has necessitated rapid research to aid in the understanding of the disease and the development of novel therapeutics. One option is to conduct controlled human infection trials (CHITs). In this article I examine the history of deliberate human infection and CHITs and their utilization prior to the COVID-19 pandemic, key ethical considerations of CHITs in the COVID-19 setting, an analysis of the World Health Organization's (WHO) Key criteria for the ethical acceptability of COVID-19 human challenge studies, and a review of the two COVID-19 CHITs that have already commenced, their compliance with the WHO criteria and other ethical considerations.

The Case for Voluntary-Assisted Dying in Prisoners Serving Sentences of Life without Parole.

Legislation supporting voluntary-assisted dying (VAD) is becoming more common globally, where it is used to promote an individual's autonomy in settings where they choose to alleviate their suffering by ending their life. This article examines and advocates for access to VAD in a new group - prisoners serving sentences of life imprisonment without parole. It addresses several morally important issues, and offers an ethical framework based on comparison to VAD in the setting of the terminally ill.

The Reemergence of Syphilis Among Females of Reproductive Age and Congenital Syphilis in Victoria, Australia, 2010 to 2020: A Public Health Priority.

BACKGROUND: Syphilis notifications in Victoria, Australia, have been increasing over the past decade, with an increase in infectious syphilis (syphilis of less than 2 years in duration) cases in females of reproductive age and an associated reemergence of congenital syphilis (CS). Before 2017, there had been 2 CS cases in the preceding 26 years. This study describes the epidemiology of infectious syphilis among females of reproductive age and CS in Victoria. METHODS: Routine surveillance data provided by mandatory Victorian syphilis case notifications were extracted and grouped into a descriptive analysis of infectious syphilis and CS incidence data from 2010 to 2020. RESULTS: In 2020, infectious syphilis notifications in Victoria were approximately 5 times more than 2010 (n = 289 in 2010 to n = 1440 in 2020), with a more than 7-fold rise among females (n = 25 in 2010 to n = 186 in 2020). Females made up 29% (n = 60 of 209) of Aboriginal and Torres Strait Islander notifications occurring between 2010 and 2020. Between 2017 and 2020, 67% of notifications in females (n = 456 of 678) were diagnosed in low-caseload clinics, at least 13% (n = 87 of 678) of all female notifications were known to be pregnant at diagnosis, and there were 9 CS notifications. CONCLUSIONS: Cases of infectious syphilis in females of reproductive age and CS are on the rise in Victoria, necessitating sustained public health action. Increasing awareness among individuals and clinicians, and health system strengthening, particularly targeting primary care where most females are diagnosed before pregnancy, are required. Treating infections before or promptly during pregnancy and undertaking partner notification and treatment to reduce risk of reinfection are critical to reducing CS cases.

SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity.

Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.

Effect of COVID-19 restrictions and border closures on vaccine preventable diseases in Victoria, Australia, 2020-2021.

Background: In 2020, Victoria introduced multiple interventions aimed at containing the spread of coronavirus disease 2019 (COVID-19). We examine the effect of these restrictions on other vaccine preventable diseases (VPDs). Methods: We analysed the mandatory reporting data, notified to the Victorian Department of Health, for VPDs from January 2015 to December 2021. Results: Reductions in notifications were seen for most notifiable VPDs. A precipitous decline in influenza and measles notifications was recorded in April 2020, which was sustained for both diseases throughout 2020-2021. Notifications for chickenpox, invasive meningococcal disease, invasive pneumococcal disease, and pertussis were reduced by greater than 50% from the 2015-2019 average. No notified cases of diphtheria, poliomyelitis, or rubella were reported in 2020-2021. Conclusion: Restrictions placed to mitigate the effects of the COVID-19 pandemic were associated with significant reductions in other VPDs, which were sustained into 2021. Nevertheless, it is important that high levels of population vaccine coverage continue, to prevent a rebound increase in VPDs as restrictions are eased, and to maximise protection against VPDs for all Australians.

Anaphylaxis in Victoria: presentations to emergency departments, with a focus on drug- and antimicrobial-related cases.

OBJECTIVE: To investigate the causes, characteristics, and outcomes of anaphylaxis, particularly drug-related anaphylaxis, in Victoria during the first two years of mandatory notification. DESIGN: Review of all anaphylaxis cases reported by emergency departments to the Victorian Department of Health and Human Services. SETTING, PARTICIPANTS: People presenting to all public and private hospital emergency departments in Victoria, 1 November 2018 - 31 December 2020. MAIN OUTCOME MEASURES: Rates of drug- and food-related anaphylaxis, by age group; characteristics of cases of drug-related anaphylaxis. RESULTS: A total of 4273 anaphylaxis episodes were reported (females: 2292 cases, 54%); the overall anaphylaxis rate was 31.9 episodes per 100 000 person-years. The most frequently reported causes were foods (2659 cases, 62%); drugs were implicated in 533 cases (12%), insect venoms in 342 (8%), and other causes in 144 (4%). No deaths were recorded. The median age in cases of food-related anaphylaxis was 17 years (IQR, 6-29 years), and 45 years (IQR, 30-60 years) in cases of drug-related anaphylaxis. Hospitalisation was required by 1538 patients (36%) and intensive care by 111 (2.6%; 7% of people admitted to hospital). Antimicrobial drugs were implicated in 258 cases of drug-related anaphylaxis (48%) and non-steroidal anti-inflammatory drugs in 85 cases (16%). Penicillin-class agents were implicated in 143 cases of antimicrobial-related anaphylaxis (56%), cephalosporins in 80 cases (31%). CONCLUSION: Our review of notified cases of anaphylaxis in Victoria over two years provides insights into drug- and antimicrobial-related anaphylaxis in non-hospitalised people presenting to emergency departments.

COVID-Care - a safe and successful digital self-assessment tool for outpatients with proven and suspected coronavirus-2019.

INTRODUCTION: The coronavirus-2019 (COVID-19) pandemic and restrictions placed on movement to prevent its transmission have led to a surge in demand for remote medical care. We investigated whether COVID-Care, a patient-reported, telehealth, symptom monitoring system, was successful at delivering safe monitoring and care for these patients leading to decreased hospital presentations. METHODS: We performed a single centre, prospective, interventional cohort study with symptomatic outpatients who presented for COVID-19 screening at Austin Health, Australia. Participants were invited to take part in the COVID-Care programme, entering common COVID-19 symptoms on a purpose-built, online survey monitored by infectious diseases physicians, and matched with clinical data including date of symptom onset, hospital admission, and screening clinic presentations. RESULTS: 42,158 COVID-19 swabs were performed in 31,626 patients from March to October 2020, with 414 positive cases. 20,768 people used the COVID-Care survey at least once. COVID-Care users were significantly younger than non-users. Of the 414 positive cases, 254 (61.3%) used COVID-Care, with 160 (38.6%) non-users. Excluding presentations on the same day or prior to the COVID-19 swab, of the positive cases there were 56 hospital presentations. 4.3% (11) of COVID-Care users and 28.1% (45) non-users were admitted to hospital or the emergency department (p < 0.001), with 3.9% (10) versus 22.5% (36) requiring inpatient admission (p < 0.001). There were no deaths in COVID-Care users versus 2 deaths in non-users. CONCLUSION: COVID-Care, a digitally integrated, outpatient, symptom tracking and telemedical service for patients with COVID-19, was safe and successful at reducing hospital and emergency department admissions, suggesting a strong role for telemedicine for future healthcare delivery in this logistically challenging setting.

Defective Severe Acute Respiratory Syndrome Coronavirus 2 Immune Responses in an Immunocompromised Individual With Prolonged Viral Replication.

We describe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immune responses in a patient with lymphoma and recent programmed death 1 (PD-1) inhibitor therapy with late onset of severe coronavirus disease 2019 disease and prolonged SARS-CoV-2 replication, in comparison to age-matched and immunocompromised controls. High levels of HLA-DR+/CD38+ activation, interleukin 6, and interleukin 18 in the absence of B cells and PD-1 expression was observed. SARS-CoV-2-specific antibody responses were absent and SARS-CoV-2-specific T cells were minimally detected. This case highlights challenges in managing immunocompromised hosts who may fail to mount effective virus-specific immune responses.

Practical ethical challenges and moral distress among staff in a hospital COVID-19 screening service.

The COVID-19 pandemic has led to unprecedented disruptions to established models of healthcare and healthcare delivery, creating a host of new ethical challenges for healthcare institutions, their leadership and their staff. Hospitals and other large organisations have an obligation to understand and recognise the downstream effects that highly unusual situations and professionally demanding policy may have on workers tasked with its implementation, in order to institute risk-mitigation strategies and provide additional support where required. In our experience, targeted ethics-based forums that provide a non-confrontational platform to discuss and explore the ethical dilemmas that may have arisen have been well received, and can also serve as useful and immediate feedback mechanisms to managers and leadership. Using two case illustrations, this article examines some of the ethical challenges and dilemmas faced by these staff, based on discussions of shared experience during a clinical ethics forum for the Screening Clinic staff at Austin Health, Melbourne, Victoria.

Immune responses in COVID-19 respiratory tract and blood reveal mechanisms of disease severity.

Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.

Asystolic cardiac arrest following liposomal amphotericin B infusion: anaphylaxis or compliment activation-related pseudoallergy?

Allergic reaction to liposomal amphotericin B is rare. We report a case of cardiac arrest in a 64-year-old woman following liposomal amphotericin B infusion, requiring resuscitation. We also present the results of subsequent skin prick and intradermal testing to liposomal amphotericin on the patient and three healthy controls, highlighting the need for further research into the immunopathogenesis of this reaction.

Multi-site assessment of rapid, point-of-care antigen testing for the diagnosis of SARS-CoV-2 infection in a low-prevalence setting: A validation and implementation study.

BACKGROUND: In Australia, COVID-19 diagnosis relies on RT-PCR testing which is relatively costly and time-consuming. To date, few studies have assessed the performance and implementation of rapid antigen-based SARS-CoV-2 testing in a setting with a low prevalence of COVID-19 infections, such as Australia. METHODS: This study recruited participants presenting for COVID-19 testing at three Melbourne metropolitan hospitals during a period of low COVID-19 prevalence. The Abbott PanBioTM COVID-19 Ag point-of-care test was performed alongside RT-PCR. In addition, participants with COVID-19 notified to the Victorian Government were invited to provide additional swabs to aid validation. Implementation challenges were also documented. FINDINGS: The specificity of the Abbott PanBioTM COVID-19 Ag test was 99.96% (95% CI 99.73 - 100%). Sensitivity amongst participants with RT-PCR-confirmed infection was dependent upon the duration of symptoms reported, ranging from 77.3% (duration 1 to 33 days) to 100% in those within seven days of symptom onset. A range of implementation challenges were identified which may inform future COVID-19 testing strategies in a low prevalence setting. INTERPRETATION: Given the high specificity, antigen-based tests may be most useful in rapidly triaging public health and hospital resources while expediting confirmatory RT-PCR testing. Considering the limitations in test sensitivity and the potential for rapid transmission in susceptible populations, particularly in hospital settings, careful consideration is required for implementation of antigen testing in a low prevalence setting. FUNDING: This work was funded by the Victorian Department of Health and Human Services. The funder was not involved in data analysis or manuscript preparation.

The Role of Immunological and Clinical Biomarkers to Predict Clinical COVID-19 Severity and Response to Therapy-A Prospective Longitudinal Study.

Background: The association of pro-inflammatory markers such as interleukin-6 (IL-6) and other biomarkers with severe coronavirus disease 2019 (COVID-19) is of increasing interest, however their kinetics, response to current COVID-related treatments, association with disease severity and comparison with other disease states associated with potential cytokine storm (CS) such as Staphylococcus aureus bacteraemia (SAB) are ill-defined. Methods: A cohort of 55 hospitalized SARS-CoV-2 positive patients was prospectively recruited - blood sampling was performed at baseline, post-treatment and hospital discharge. Serum IL-6, C-reactive protein (CRP) and other laboratory investigations were compared between treatment groups and across timepoints. Acute serum IL-6 and CRP levels were then compared to those with suspected COVID-19 (SCOVID) and age and sex matched patients with SAB and patients hospitalized for any non-infectious condition (NIC). Results: IL-6 was elevated at admission in the SARS-CoV-2 cohort but at lower levels compared to matched SAB patients. Median (IQR) IL-6 at admission was 73.89 pg/mL (30.9, 126.39) in SARS-CoV-2 compared to 92.76 pg/mL (21.75, 246.55) in SAB (p=0.017); 12.50 pg/mL (3.06, 35.77) in patients with NIC; and 95.51 pg/mL (52.17, 756.67) in SCOVID. Median IL-6 and CRP levels decreased between admission and discharge timepoints. This reduction was amplified in patients treated with remdesivir and/or dexamethasone. CRP and bedside vital signs were the strongest predictors of COVID-19 severity. Conclusions: Knowledge of the kinetics of IL-6 did not offer enhanced predictive value for disease severity in COVID-19 over common investigations such as CRP and vital signs.