Prospective study of policies and use of therapies for COVID-19 among Australian health services during 2020.

BACKGROUND: The COVID-19 pandemic has generated significant debate about how emerging infections can be treated in the absence of evidence-based therapies to combat disease. In particular, the use of off-label therapies outside of a clinical trial setting has been controversial. AIM: To longitudinally study policies and prescribing practices pertaining to therapies for COVID-19 in Australian health services during 2020. METHODS: Prospective data were collected from participating Australian health services who may care for patients with COVID-19 via an electronic portal. A single informant from each health service was emailed a survey link at regular intervals. Information was sought regarding changes to COVID-19 policy at their service and use of therapies for COVID-19. RESULTS: Overall, 78 hospitals were represented from 39 respondents with longitudinal data collection from May to December 2020. All Australian states/territories were represented with the majority (34/39; 87%) of respondents located in a major city. Just over half (20/39) of respondents had a written policy for COVID-19 therapy use at their health service at survey enrolment and policies changed frequently throughout the pandemic. Therapy use outside of a clinical trial was reported in 54% of health services, most frequently in Victoria, correlating with higher numbers of COVID-19 cases. At study commencement, hydroxychloroquine was most frequently used, with corticosteroids and remdesivir use increasingly throughout the study period. CONCLUSION: Our results reflect the reactive nature of prescribing of therapies for COVID-19 and highlight the importance of evidence-based guidelines to assist prescribers.

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses.

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3+cTFH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.

CRyptOcoccosis in Newcastle and the hUnTer (CRONUT) - An epidemiological study.

BACKGROUND: Cryptococcus neoformans and Cryptococcus gattii are yeasts responsible for invasive infection, primarily pulmonary and neurological. Their clinical epidemiology has been previously described in an Australian national study, but this included no data from the Hunter region, where we anecdotally noted a high incidence of infection. We aimed to describe the epidemiology, management and outcomes of cryptococcal disease in the Hunter region and to compare this with previous Australian data. METHODS: We searched our laboratory database for positive cryptococcal antigen and culture results from January 2003-December 2016. We extracted demographic factors, risk factors, clinical presentation, treatment and outcomes from medical records. We used the 2010 census-derived estimated resident population to calculate population-based incidences. RESULTS: Over a 13-year period, 107 patients had either a positive culture or a positive cryptococcal antigen with a compatible clinical syndrome. Of these, 46 (42.2%) were C. neoformans, 28 (25.7%) C. gattii, and 33 (30.3%) antigen only. The crude incidence (per million with 95% CI) for all disease was 9.5, and for culture proven disease was 2.5 for C. gattii and 4.1 for C. neoformans. Geospatial mapping by species revealed no evident cluster. Of the 63 patients where detailed information was available, around half were immunocompromised (3 [15%] for C. gattii and 25 [81%] for C. neoformans, p < 0.001). Complications were common, including visual loss (11 cases, 17.7%) and hearing loss (5 cases, 8%). Adverse outcomes at one year (death or neurological sequelae) occurred in 42%, and was significantly more likely (OR = 5.2, 95% CI 1.4-18.8) in those with raised intracranial pressure at baseline. Adverse outcomes were no more common in those treated with lower doses of liposomal amphotericin (≤150 mg/day, 5/10) than those treated with the recommended dose of 3-5 mg/kg (≥150 mg; 13/27). CONCLUSION: Although a rare disease, cryptococcosis is more common in the Hunter region than in other parts of Australia, and long-term sequelae are serious and common.

Incidental mucocutaneous cytomegalovirus detection and its predictive value for systemic disease.

Multiplex polymerase chain reaction (PCR) testing has revolutionised microbiological practice but also increased the number of positive results of uncertain significance. This phenomenon has been seen in the increasing detection of cytomegalovirus (CMV) in mucocutaneous swabs for herpesviruses, the microbiological significance of which is a priori unclear. The aim of our study was to determine if an incidental finding of a positive CMV result represented CMV disease, if it facilitated a timely diagnosis of CMV disease or whether there were any deleterious outcomes. We performed a retrospective review of patients with an incidentally positive PCR result for CMV on external and mucosal swabs, including medical comorbidities and presence of immunosuppression, subsequent investigations, whether a diagnosis of CMV disease was made, and treatment. CMV detection was infrequent, detected in 158 (3.4%) of 4626 herpes multiplex PCR tests performed. The majority (60.4%) of patients were immunocompromised, and amongst these patients a positive swab represented a new diagnosis or already known CMV disease in 14%. In seven patients (5%), all of whom were immunocompromised, the positive CMV PCR on a swab led to further investigation and subsequent diagnosis and treatment of CMV disease. Whilst not recommended for diagnosis of CMV disease, if CMV is detected on a mucocutaneous swab in an immunocompromised patient, further assessment and investigation for CMV disease should be undertaken.

Risk factors for relapse or persistence of bacteraemia caused by Enterobacter spp.: a case-control study.

BACKGROUND: Enterobacter spp. possess chromosomal AmpC beta-lactamases that may be expressed at high levels. Previous studies have demonstrated a risk of relapsed bacteraemia following therapy with third generation cephalosporins (3GCs). What additional factors predict microbiological failure in Enterobacter bacteraemia is unclear. We aimed to determine factors associated with microbiological failure in Enterobacter bacteraemia. METHODS: We retrospectively identified cases of bacteraemia caused by Enterobacter spp. occurring in four hospitals. Using a case-control design, we determined clinical risk factors for persistence or relapse defined as repeated positive blood cultures collected between 72 hours and up to 28 days post initial positive blood culture. RESULTS: During the study period a total of 922 bacteraemia events caused by Enterobacter spp. in adults were identified. The overall risk of relapsed or persisting bacteraemia at 28 days was low (31 of 922, 3.4%), with only 2 patients experiencing emergent resistance to 3GCs. A total of 159 patients were included in the case-control study. Using multivariate logistic regression, independent predictors for relapse were a line-associated source of infection (OR 3.87; 95% CI 1.56-9.60, p = 0.004) and the presence of immunosuppression (OR 2.70; 95% CI 1.14-6.44, p = 0.02). On univariate analysis definitive therapy with a broad-spectrum beta-lactam-beta-lactamase inhibitor (BLBLI, e.g. piperacillin-tazobactam) was not associated with relapse (OR 1.83; 95% CI 0.64-5.21, p = 0.26) although the proportion of patients receiving a BLBLI as definitive therapy was relatively small (21/159, 13.2%). CONCLUSIONS: The risk of relapsed or persistent Enterobacter bacteraemia appears to be low in Australia. A line-associated source of infection and immunocompromise were significant independent predictors for relapse. Larger, preferably randomized, studies are needed to address whether BLBLIs represent an effective carbapenem-sparing option for Enterobacter bacteraemia.