Background Invasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort. Methods From March 2020 to March 2021, 266 mechanically ventilated adults with COVID-19 were enrolled across 5 UK hospital intensive care units (ICUs). CAPA was defined using European Confederation for Medical Mycology and the International Society for Human and Animal Mycology criteria and fungal diagnostics performed on respiratory and serum samples. Results Twenty-nine of 266 patients (10.9%) had probable CAPA, 14 (5.2%) possible CAPA and none proven CAPA. Probable CAPA was diagnosed a median of 9 (IQR 7–16) days after ICU admission. Factors associated with probable CAPA after multivariable logistic regression were cumulative steroid dose given within 28 days prior to ICU admission (adjusted OR (aOR) 1.16; 95% CI 1.01 to 1.43 per 100 mg prednisolone-equivalent), receipt of an interleukin (IL)-6 inhibitor (aOR 2.79; 95% CI 1.22 to 6.48) and chronic obstructive pulmonary disease (COPD) (aOR 4.78; 95% CI 1.13 to 18.13). Mortality in patients with probable CAPA was 55%, vs 46% in those without. After adjustment for immortal time bias, CAPA was associated with an increased risk of 90-day mortality (HR 1.85; 95% CI 1.07 to 3.19); however, this association did not remain statistically significant after further adjustment for confounders (adjusted HR 1.57; 95% CI 0.88 to 2.80). There was no difference in mortality between patients with CAPA prescribed antifungals (9 of 17; 53%) and those who were not (7 of 12; 58%) (p=0.77). Interpretation In this first prospective UK study, probable CAPA was associated with corticosteroid use, receipt of IL-6 inhibitors and pre-existing COPD. CAPA did not impact mortality following adjustment for prognostic variables.

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an "original antigenic sin" type response.

Background: Marked reductions in serum iron concentrations are commonly induced during the acute phase of infection. This phenomenon, termed hypoferremia of inflammation, leads to inflammatory anemia, but could also have broader pathophysiological implications. In patients with coronavirus disease 2019 (COVID-19), hypoferremia is associated with disease severity and poorer outcomes, although there are few reported cohorts. Methods: In this study, we leverage a well characterised prospective cohort of hospitalised COVID-19 patients and perform a set of analyses focussing on iron and related biomarkers and both acute severity of COVID-19 and longer-term symptomatology. Results: We observed no associations between acute serum iron and long-term outcomes (including fatigue, breathlessness or quality of life); however, lower haemoglobin was associated with poorer quality of life. We also quantified iron homeostasis associated parameters, demonstrating that among 50 circulating mediators of inflammation IL-6 concentrations were strongly associated with serum iron, consistent with its central role in inflammatory control of iron homeostasis. Surprisingly, we observed no association between serum hepcidin and serum iron concentrations. We also observed elevated erythroferrone concentrations in COVID-19 patients with anaemia of inflammation. Conclusions: These results enhance our understanding of the regulation and pathophysiological consequences of disturbed iron homeostasis during SARS-CoV-2 infection.

Background: Marked reductions in serum iron concentrations are commonly induced during the acute phase of infection. This phenomenon, termed hypoferremia of inflammation, leads to inflammatory anemia, but could also have broader pathophysiological implications. In patients with coronavirus disease 2019 (COVID-19), hypoferremia is associated with disease severity and poorer outcomes, although there are few reported cohorts. Methods: In this study, we leverage a well characterised prospective cohort of hospitalised COVID-19 patients and perform a set of analyses focussing on iron and related biomarkers and both acute severity of COVID-19 and longer-term symptomatology. Results: We observed no associations between acute serum iron and long-term outcomes (including fatigue, breathlessness or quality of life); however, lower haemoglobin was associated with poorer quality of life. We also quantified iron homeostasis associated parameters, demonstrating that among 50 circulating mediators of inflammation IL-6 concentrations were strongly associated with serum iron, consistent with its central role in inflammatory control of iron homeostasis. Surprisingly, we observed no association between serum hepcidin and serum iron concentrations. We also observed elevated erythroferrone concentrations in COVID-19 patients with anaemia of inflammation. Conclusions: These results enhance our understanding of the regulation and pathophysiological consequences of disturbed iron homeostasis during SARS-CoV-2 infection.

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

Persistent Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) infection is observed among patients with haematological malignancy, conferring an increased mortality risk. Persistent SARS-CoV-2 RNA detection from clinical samples may represent redundant fragmented RNA, replication-competent virus, or reinfection. Given the role of the host immune response in viral clearance and COVID-19 immunopathogenesis, distinguishing these scenarios is important for therapeutic decision-making (antiviral versus immunomodulatory) as well as preventing onward hospital transmission. Optimal timing of subsequent chemotherapy cycles is challenging, since relapse of COVID19 can occur in individuals with impaired humoral responses. We present the investigation of relapsing SARS-CoV-2 pneumonitis, with virological persistence evidenced by SARSCoV-2 cell culture and sequencing, in the context of cellular and humoral immunodeficiency secondary to underlying lymphoma and chemo-immunotherapy. The potential clinical benefit of cell culture is discussed.

Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infectionshttps://bit.ly/3feuGsQ

A 40-year-old British man presented to St George's Hospital, St George's University Hospitals NHS Foundation Trust (London, UK), with 5 days of fever and right upper quadrant pain, with no diarrhoea. He had travelled extensively across Asia and South America 10 years previously, with travel to Germany in the past year. His partner and two children were asymptomatic. Correction to Lancet Infect Dis 2020; 20: 259Dhariwal A, Youngs J, SanFrancisco A, Bicanic T. Late presentation of amoebic liver abscess. Lancet Infect Dis 2020; 20: 259—In this Clinical Picture, the author list has been reordered so that Tihana Bicanic is the last author. This correction has been made to the online version as of Feb 20, 2020. Full-Text PDF

Triazoles remain first-line agents for antifungal prophylaxis in high-risk haemato-oncology patients, but their use is increasingly contraindicated due to drug–drug interactions and additive toxicities with novel treatments. In this retrospective, single-centre, observational study, we present our eight-year experience of antifungal prophylaxis using intermittent high-dose liposomal Amphotericin B (L-AmB). All adults identified through our Antifungal Stewardship Programme as receiving L-AmB prophylaxis at 7.5 mg/kg once-weekly between February 2012 and January 2020 were included. Adverse reactions, including infusion reactions, electrolyte loss, and nephrotoxicity, were recorded. ‘Breakthrough’ invasive fungal infection (IFI) occurring within four weeks of L-AmB was classified using European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Moreover, 114 courses of intermittent high-dose L-AmB prophylaxis administered to 92 unique patients were analysed. Hypokalaemia was the most common grade 3–4 adverse event, with 26 (23%) courses. Grade 3 nephrotoxicity occurred in 8 (7%) and reversed in all six patients surviving to 90 days. There were two (1.8%) episodes of breakthrough IFI, one ‘probable’ and one ‘possible’. In this study, the largest evaluation of intermittent high-dose L-AmB prophylaxis conducted to date, toxicity was manageable and reversible and breakthrough IFI was rare. L-AmB prophylaxis represents a viable alternative for patients with a contraindication to triazoles.

In the recent systematic review and meta-analysis by Lansbury et al. only 7% of hospitalised patients with COVID-19 were reported as having evidence of bacterial co-infection, yet >90% received empirical antibiotics1. This finding, which has been replicated elsewhere2, is hardly surprising given the challenges associated with distinguishing bacterial from viral pneumonia and that bacterial coinfection is likely to worsen an already poor prognosis in these patients3. Whilst the role of biomarkers such as procalcitonin is being explored, a desire to treat what is treatable is understandable but represents a threat to antibiotic stewardship4,5.

The cobas Liat influenza A/B and respiratory syncytial virus (RSV) assay (Liat) was used in the adult emergency department of a large London hospital from 21st January 2018 to 14th April 2018. Influenza was detected in 308 of 1027 (30%) samples tested; influenza A in 157 (15.3%), influenza B in 149 (14.5%) and RSV in 28 (2.7%). When compared against Fast Track Diagnostics Respiratory Pathogens 21 multiplex polymerase chain reaction and Cepheid Xpert Xpress Flu/RSV assay, Liat performance for the detection of influenza A or B was: sensitivity 85% [95% confidence interval (CI) 76-92)], specificity 98% (95% CI 97-99), negative predictive value 94% (95% CI 92-96) and positive predictive value 95% (95% CI 91-97). (C) 2018 Published by Elsevier Ltd on behalf of The Healthcare Infection Society.

BackgroundThe need for antifungal stewardship is gaining recognition with increasing incidence of invasive fungal infection (IFI) and antifungal resistance alongside the high cost of antifungal drugs. Following an audit showing suboptimal practice we initiated an antifungal stewardship programme and prospectively evaluated its impact on clinical and financial outcomes.Patients and methodsFrom October 2010 to September 2016, adult inpatients receiving amphotericin B, echinocandins, intravenous fluconazole, flucytosine or voriconazole were reviewed weekly by an infectious diseases consultant and antimicrobial pharmacist. Demographics, diagnosis by European Organization for Research and Treatment of Cancer (EORTC) criteria, drug, indication, advice, acceptance and in-hospital mortality were recorded. Antifungal consumption and expenditure, and candidaemia species and susceptibility data were extracted from pharmacy and microbiology databases.ResultsA total of 432 patients were reviewed, most commonly receiving AmBisome® (35%) or intravenous fluconazole (29%). Empirical treatment was often unnecessary, with 82% having no evidence of IFI. Advice was given in 64% of reviews (most commonly de-escalating or stopping treatment) and was followed in 84%. Annual antifungal expenditure initially reduced by 30% (£0.98 million to £0.73 million), then increased to 20% above baseline over a 5 year period; this was a significantly lower rise compared with national figures, which showed a doubling of expenditure over the same period. Inpatient mortality, Candida species distribution and rates of resistance were not adversely affected by the intervention.ConclusionsProvision of specialist input to optimize antifungal prescribing resulted in significant cost savings without compromising on microbiological or clinical outcomes. Our model is readily implementable by hospitals with high numbers of at-risk patients and antifungal expenditure.

BACKGROUND:During high-incidence influenza seasons, a robust infection prevention and control policy is imperative to reduce nosocomial transmission of influenza. AIM:To assess the impact of influenza point-of-care testing (POCT) in an emergency department (ED) and patient cohorting on an influenza ward on infection prevention and control and clinical outcomes. METHODS:Influenza POCT was operational in the study ED from 21st January 2018 and patient cohorting was operational on an influenza ward from 25th January 2018. A retrospective 'before-after' analysis was performed with pre-intervention defined as 1st November 2017 to 20th January 2018 and post-intervention defined as 21st January 2018 to 30th April 2018. The primary outcome was the rate of hospital-acquired influenza. Secondary outcomes included antiviral prescription and length of stay. The length of time that inpatients remained influenza-positive was estimated by polymerase chain reaction (PCR). FINDINGS:There were 654 inpatients with confirmed influenza during the 2017/18 influenza season: 223 pre- and 431 post-intervention. Post-intervention, there were fewer cases of hospital-acquired influenza per day (0.66 vs 0.95, P < 0.0001), median length of stay was shorter (5.5 vs 7.5 days, P = 0.005) and antiviral prescription was more frequent (80% vs 64.1%, P < 0.0001). Cohorting released 779 single rooms for use elsewhere in the trust. The fixed probability of being PCR-negative by the next day (P) was 0.14 [95% confidence interval (CI) 0.12-0.16] for immunocompetent patients. This implies that half of immunocompetent patients are PCR-negative by five days post-diagnosis (95% CI 5-6). CONCLUSION:Influenza POCT in an ED and patient cohorting on an influenza ward were associated with reduced nosocomial transmission of influenza and improved patient flow. A policy of retesting immunocompetent patients five days post-diagnosis could allow half of these patients to come out of respiratory isolation earlier.

A 40-year-old man who had refractory, very severe, aplastic anaemia 6 months after an unsuccessful allogenic stem-cell transplant, presented with neutropenic (0·1 × 109/L) septic shock. Examination showed a tender papule on his thigh. Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli grew from the skin biopsy. Blood, urine, and stool cultures were all negative (no oganisms grew). CT showed many liver abscesses. The patient recovered after 6 weeks of ertapenem (1 g once a day) with teicoplanin (initially 200 mg once a day), remaining neutropenic throughout, but 12 days after finishing therapy he re-presented with pyrexia and additional skin lesions (figure A). Blood cultures grew the same ESBL-E coli as was isolated from the skin biopsy. CT showed pulmonary nodules suggestive of septic emboli with a healthy colon and biliary tract. PET showed uptake in the terminal ileum and wall-thickened caecum, consistent with neutropenic enterocolitis (figure B).

In his response to our paper, Andorno, like us, defends Claim-A and denies Claim-B , but for different reasons than ours. This is in contrast to Tak Kwong Chan, who defends both claims, and Charles Foster, who appears to deny both. We are grateful to be able to reply to these divergent positions below. Andorno continues to defend a general ‘right not to know’ (at least in the context of genetic information), grounded in autonomy, which may only be overridden in the interests of others. We stated this position as Claim-BA , it is always morally wrong to override a competent adult's desire not to know unless disclosure might prevent serious harm to others . In our article, we suggested that Andorno would probably deny that people have a right not to know their HIV result ( Claim-B, which we also deny) because disclosure of HIV might prevent serious harm to others. In his response to our paper, Andorno makes clear that this is, in fact, his view. His reason is that while people have an interest not to know, grounded in autonomy, this is outweighed by the interest that other people have in not being harmed:[T]he value of autonomy in this context is not strong enough to justify the recognition of a right not to know. Andorno makes clear that this does not negate the fact that people retain a right to refuse an HIV test ( Claim-A , which we also defend). He argues that while autonomy grounds are insufficient to defend a right not to know an HIV result , they are sufficient to defend a right to refuse an HIV test . We find this distinction problematic. If the harm posed to others overrides an individual's interest in not knowing their HIV result, why does it …

In the recent case of Re P1, Newton J ordered and directed that renal replacement therapy (RRT) continue for a patient who lacked capacity. This was notwithstanding that the trust had sought a declaration permitting them to withdraw RRT and so appears to be an instance of the Court of Protection (COP) forcing doctors to provide a treatment. The ruling sits in tension with the principle laid down in Re J (1993),2 namely that the court cannot compel medical professionals to provide treatment contrary to their professional judgement. In that case, Lord Donaldson declared that a doctor's fundamental duty is ‘to treat the patient in accordance with his own best clinical judgment’ and it would amount to an ‘abuse of power’ were the court to require that he do otherwise.3 The question then is whether the Re J principle continues to be binding and, if so, whether Newton J breached it.

In April 2015, the first legally approved HIV self-testing kit went on sale in the UK-except Northern Ireland where they remain illegal. These tests allow individuals to test their HIV status and read the result in the privacy of their own home, much like a home pregnancy test. This paper explores the ethical implications of HIV self-testing. We conclude that there are no strong ethical objections to self-testing being made widely available in the UK. Pretest counselling for an HIV test is not an ethical necessity, and self-testing has the potential to increase early diagnosis of HIV infection and thus improve prognosis and reduce ongoing transmission. Self-testing kits might also empower people and promote autonomy by allowing people to dictate the terms on which they test their HIV status. We accept that there are some potential areas of concern. These include the possibility of user error with the tests, and the concern that individuals may not present to health services following a reactive result. False negatives have the potential to cause harm if the 'window period' is not understood, and false positives might produce psychological distress. There is, however, little evidence to suggest that self-testing kits will cause widespread harm, and we argue that the only way to properly evaluate whether they do cause significant harm is to carefully evaluate their use, now that they are available on the market.

It is a tenet of the prevailing ethic in medicine that competent adults have the 'right to know' information necessary to make informed decisions about their healthcare. Whether there is a 'right not to know' unwanted information is more hotly debated. When deciding whether or not to override a competent adult's desire not to know his/her HIV result, a desire to respect patient autonomy can be seen to pull in both directions. We thus conclude that there is not a very strong presumption on the side of non-disclosure but rather the adult's interest in not knowing must be weighed against the potential harms and benefits of disclosure for both the individual and others. This does not, however, negate the fact that patients retain a right to refuse an HIV test and this is so even where issues of bodily integrity are not at stake. This implies that explicit consent should still be sought for HIV testing, at least where there is some possibility that the patient may refuse, or want more information, if given the chance.