BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial

Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19.The trial is supported by the Bill & Melinda Gates Foundation [ INV-017302 ], the Minderoo Foundation [ COV-001 ], Sarah and Lachlan Murdoch, the Royal Children’s Hospital Foundation [ 2020-1263 BRACE Trial], Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare and individual donors. The funders had no role in the collection, analysis and interpretation of data or in the preparation, review or approval of the manuscript. The Murdoch Children’s Research Institute (MCRI) leads the BRACE trial across 36 sites in five countries. It is supported by the Victorian Government’s Operational Infrastructure Support Programme. NC, AG and KPP are supported by a National Health and Medical Research Council (NHMRC) Investigator Grants [ GNT1197117, GNT1194694, GNT2008911 ]. DJL is supported by an EMBL Australia Group Leader award. HSM is supported by a NHMRC Practitioner Fellowship. LFP is supported by the Swiss National Science Foundation (Early Postdoc Mobility Grant, P2GEP3_178155 ). KPP is supported by a Melbourne Children’s Clinician-Scientist Fellowship. AW is supported by the UK Medical Research Council ( MR/N006364/2 ).Peer reviewe

Antecedent and persistent symptoms in COVID-19 and other respiratory illnesses: insights from prospectively collected data in the BRACE trial

Background: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospectively collected data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illness, to identify factors associated with the risk of PACS, and to explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses. Methods: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms. Findings: Compared to those with a non-COVID-19 illness, participants with COVID-19 had significantly more severe illness (OR 7·4, 95%CI 5·6–9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4–18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4–4·3). When considering only participants with COVID-19, age 40-59 years (aOR 2·8, 95%CI 1·3–6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3–23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4–6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath). Interpretation: Healthcare workers with COVID-19 were more likely to have severe and longer-lasting symptoms than those with a non-COVID-19 respiratory illness, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

EXPH (EXpert Panel on effective ways of investing in Health). Opinion on Vaccination Programmes and Health Systems in the European Union.

Vaccination is one of the most cost-effective public health interventions available and the main tool for primary prevention of communicable diseases. However, the EU is facing increasing outbreaks of vaccine preventable diseases, while some fatal cases of measles and diphtheria have been reported. This opinion identifies the main factors (enablers and obstacles) influencing vaccination uptake, and assesses measures that can be expected to improve vaccination coverage. After providing a systems approach to national vaccination programmes (including an appropriate legislative framework, governance arrangements, existence of a register of the target population, funding mechanisms and monitoring), a range of obstacles and enablers of high rates of vaccination coverage are identified. Obstacles to vaccination coverage include individuals’ and parents’ concerns or fears about vaccine safety and side effects, lack of trust, social norms, exposure to rumours and myths undermining confidence in vaccines, failure by some healthcare providers to counter these myths and provide evidence-informed advice, access barriers (e.g. poor availability, copayments), and failure to understand the underlying mechanisms that decrease vaccination confidence. Enablers include sources of reliable information about vaccination, exposure to positive media messages, building trust in institutions and providers, building confidence in vaccination, easy access and availability to healthcare services, ease of administration, active involvement and engagement by healthcare providers, and targeting of high-risk groups. There is a range of policy options that countries can implement to increase vaccination coverage. Communication strategies about the benefits of vaccination are important but need to be combined with opportunities for dialogue with vaccine hesitant groups and participatory approaches. These strategies need to be targeted not only at the uninformed (i.e. the lack of information) but also at the misinformed (when the information is incorrect) or disinformed (when information is spread with the intention to deceive). Vaccination is mandatory in some countries and recommended in others. When mandatory, it can be unpopular with some individuals or groups, which reinforces the case for good communication strategies to improve acceptability. One policy option is to allow individuals to opt out of vaccination subject to certain conditions to be determined depending on the institutional context (e.g. an exception process which includes a mandatory consultation and dialogue with a healthcare worker who can make individuals and parents aware of the risk of not being covered) but only if vaccination coverage levels are sufficiently high to ensure herd immunity. Family physicians are well positioned to improve child vaccination rates given frequent interactions with parents and children with other illnesses or attending check-ups. These interactions can be used as opportunities to raise awareness. Family physicians and nurses do not have to be the exclusive providers of vaccines. Better access could be achieved by improving availability of vaccines from other providers (e.g. pharmacists, providers of community services, subject to appropriate training) and ensuring equity- driven vaccination programmes. Healthcare and other workers engaging in communication and dialogue related to vaccination should be supported with specific training to address vaccine concerns from hesitant individuals, in particular in relation to safety and side effects.There is scope for strengthening the monitoring and the surveillance systems at international, national and sub-national level to ensure up-to-date data to guide policy and planning at a regional and country level that will optimise coverage and impact, and identifying areas where low coverage is concentrated. Finally, as a comprehensive programme considers populations and individuals, there is scope for close co-operation and better integration of public health and primary care services, strengthening accountability towards a population of primary care

EXPH (EXpert Panel on effective ways of investing in Health). Opinion on Benchmarking Access to Healthcare in the EU.

Faced with growing evidence that some groups within European Union Member States have been unable to achieve access to necessary healthcare, the European Union has committed to action to reduce levels of unmet need, most recently as an element of the European Pillar of Social Rights. In response, the Expert Panel on Effective Ways of Investing in Health has been requested to propose a series of quantitative and qualitative benchmarks for assessing progress in reducing unmet need for healthcare and to discuss means by which EU funds or other mechanisms might be used to improve access to healthcare. A first step is to define need for healthcare. This is the ability to benefit from it, meaning that the individual in question has a condition that causes him or her to be in less than good health but also that there is a treatment available that can improve their health, whether curative, life-sustaining or enhancing, or merely palliative. While recognising that there may be clinical reasons, such as low levels of cost effectiveness, for denying treatment in the face of limited resources, treatment should never be withheld on moral grounds. In practice, however, there are many challenges involved in measuring unmet need for particular interventions, precluding its routine use. Consequently, a pragmatic solution involves the use of survey data in which individuals are asked whether they have experienced a need for healthcare but were unable to obtain that care. These data are collected throughout the European Union annually in the Survey of Income and Living Conditions (EU-SILC), with subsidiary questions that ask about the reasons for unmet need. The report of the Panel recognises that this approach has a number of limitations, and also that there are other sources of data that provide insights into the extent to which you need for healthcare is being met, including comparative data on outcomes related to healthcare, but for the present, the EU-SILC data are the only timely and comparable source of information available across all Member States. Using this measure, the Panel draws attention to persisting evidence of relatively high rates of unmet need in some Member States, and some groups within them. The Panel notes that, consistent with the political objective of achieving convergence within the European Union, there is a strong argument for setting a target for unmet need that is close to that already achieved by the most privileged group within the best performing Member State. However, given the very differing starting positions, the Panel considers that this is, for the present time, unrealistic. It is beyond the scope of the Panel to propose a precise target for reduction in unmet need, given that this will require the commitment of financial and other resources. Instead, the Panel has proposed a mechanism for setting such a target. This involves setting a benchmark of the median value achieved by the best performing Member States, with the expectation that those Member States not yet achieving it should narrow the gap by a given percentage, which might be around 50%, over a defined period of time, which might be three years. Such a target would be ambitious, requiring a significantly faster rate of reduction and has been achieved in recent years in many Member States but, in our view, would be achievable. The Panel was also asked to identify second level indicators. Taking a pragmatic approach, based on the availability of data, it proposes that this should follow the questions that are included in the EU-SILC data. These provide information on affordability, availability, and acceptability of health services. The Panel did, however, note the importance of developing additional sources of data that can be collected regularly to provide more detailed insights into the levels, patterns, and determinants of unmet need for healthcare across the European Union. The Panel was requested to identify qualitative measures of unmet need. This is particularly challenging, given the many and diverse reasons for unmet need for healthcare, both among and within Member States. The Panel was not convinced that a standard reporting system was appropriate. Rather, it was recommended that each Member State identify those groups that are most likely to be disadvantaged, according to factors such as age, gender, education, ethnicity, or employment status, analyse the appropriate data, and prepare a report on the level and pattern of unmet need among disadvantaged groups, accompanied by recommendations for action. The Panel also note the value of shadow reports produced by civil society organisations in other areas and encourages the production of such reports. Finally, the Panel reviews the scope for using European Union funds to improve access to healthcare. It notes that, as the problems facing each Member State differ, as well as the extent to which each of them is eligible for different forms of support. However, it notes that there are many opportunities for using vehicles such as Structural Funds, research funds, and European Reference Networks

EXPH (EXpert Panel on effective ways of investing in Health). Opinion on Tools and Methodologies for Assessing the Performance of Primary Care.

The report "Tools and methodologies for assessing the performance of primary care” starts with a definition of the role and goals of primary care, based on previous opinions by the EXPH. From the primary care definition formulated in 2014, 8 domains and dimensions of primary care can be defined. Additionally, the domains of primary care organisation and human resources are added, so that 10 dimensions are eventually identified. This opinion uses the adapted framework of structure, process and outcome as developed by Donabedian. Starting from the question "How is primary care structured?", a performance assessment system for primary care is defined, focusing on how access to primary care services occurs, how providers of primary care are organised, and how resources are managed in the system. With regards to the processes through which primary care is delivered, coordination of care and integration are described. When it comes to "outcomes" of primary care, the opinion examines relevance, equity, quality and financial sustainability. The need for using professional, contextual and policy evidence, when describing quality of care is emphasized. All these dimensions are translated into indicators: presenting on the one hand, a set of comparative key-indicators, and on the other hand, descriptive additional indicators. The EXPH proposes examples of comparative key-indicators related to the 10 domains of primary care that are identified. The procedural steps that are required for a performance assessment system are explored including: multi-dimensionality, shared design, evidence-based, benchmarking of results, timeliness and transparent disclosure. To ensure the selection of a set of indicators that are relevant to each health system, three criteria are proposed; alignment of indicators with objectives of the health system, ability to routinely collect the indicator, the validity and reliability of information. As a reality check, recent experiences from European countries, as documented by the EU Expert Group on Health Systems Performance Assessment, are considered. Actual problems and bottle necks in performance assessment in primary care are debated in the discussion, paying special attention to the importance of context when outcomes are reported. Finally, the report formulates recommendations for further development of the framework in the European Union

EXPH (EXpert Panel on effective ways of investing in Health). Opinion on Benchmarking Access to Healthcare in the EU.

Faced with growing evidence that some groups within European Union Member States have been unable to achieve access to necessary healthcare, the European Union has committed to action to reduce levels of unmet need, most recently as an element of the European Pillar of Social Rights. In response, the Expert Panel on Effective Ways of Investing in Health has been requested to propose a series of quantitative and qualitative benchmarks for assessing progress in reducing unmet need for healthcare and to discuss means by which EU funds or other mechanisms might be used to improve access to healthcare. A first step is to define need for healthcare. This is the ability to benefit from it, meaning that the individual in question has a condition that causes him or her to be in less than good health but also that there is a treatment available that can improve their health, whether curative, life-sustaining or enhancing, or merely palliative. While recognising that there may be clinical reasons, such as low levels of cost effectiveness, for denying treatment in the face of limited resources, treatment should never be withheld on moral grounds. In practice, however, there are many challenges involved in measuring unmet need for particular interventions, precluding its routine use. Consequently, a pragmatic solution involves the use of survey data in which individuals are asked whether they have experienced a need for healthcare but were unable to obtain that care. These data are collected throughout the European Union annually in the Survey of Income and Living Conditions (EU-SILC), with subsidiary questions that ask about the reasons for unmet need. The report of the Panel recognises that this approach has a number of limitations, and also that there are other sources of data that provide insights into the extent to which you need for healthcare is being met, including comparative data on outcomes related to healthcare, but for the present, the EU-SILC data are the only timely and comparable source of information available across all Member States. Using this measure, the Panel draws attention to persisting evidence of relatively high rates of unmet need in some Member States, and some groups within them. The Panel notes that, consistent with the political objective of achieving convergence within the European Union, there is a strong argument for setting a target for unmet need that is close to that already achieved by the most privileged group within the best performing Member State. However, given the very differing starting positions, the Panel considers that this is, for the present time, unrealistic. It is beyond the scope of the Panel to propose a precise target for reduction in unmet need, given that this will require the commitment of financial and other resources. Instead, the Panel has proposed a mechanism for setting such a target. This involves setting a benchmark of the median value achieved by the best performing Member States, with the expectation that those Member States not yet achieving it should narrow the gap by a given percentage, which might be around 50%, over a defined period of time, which might be three years. Such a target would be ambitious, requiring a significantly faster rate of reduction and has been achieved in recent years in many Member States but, in our view, would be achievable. The Panel was also asked to identify second level indicators. Taking a pragmatic approach, based on the availability of data, it proposes that this should follow the questions that are included in the EU-SILC data. These provide information on affordability, availability, and acceptability of health services. The Panel did, however, note the importance of developing additional sources of data that can be collected regularly to provide more detailed insights into the levels, patterns, and determinants of unmet need for healthcare across the European Union. The Panel was requested to identify qualitative measures of unmet need. This is particularly challenging, given the many and diverse reasons for unmet need for healthcare, both among and within Member States. The Panel was not convinced that a standard reporting system was appropriate. Rather, it was recommended that each Member State identify those groups that are most likely to be disadvantaged, according to factors such as age, gender, education, ethnicity, or employment status, analyse the appropriate data, and prepare a report on the level and pattern of unmet need among disadvantaged groups, accompanied by recommendations for action. The Panel also note the value of shadow reports produced by civil society organisations in other areas and encourages the production of such reports. Finally, the Panel reviews the scope for using European Union funds to improve access to healthcare. It notes that, as the problems facing each Member State differ, as well as the extent to which each of them is eligible for different forms of support. However, it notes that there are many opportunities for using vehicles such as Structural Funds, research funds, and European Reference Networks

EXPH (Expert Panel on effective ways of investing in Health). Opinion on Application of the ERN model in European cross-border healthcare cooperation outside the rare diseases area.

European Reference Networks (ERNs) were created by the Directive on the Application of Patients’ Rights in Cross-Border Healthcare. They offer a means by which patients with rare and complex diseases can gain access to highly specialised knowledge from across the European Union. The Expert Panel has been asked to advise on areas that can benefit most from the ERN model, options for the new networks in the longer term and the roles that they might assume, and how best national health systems could integrate networks into their national frameworks. ERNs are still a very new concept, having been launched in March 2017. So far, 24 have been established, bringing together over 300 hospitals from 26 Member States. Given the short time that they have been operating, the Expert Panel concluded that it was premature to draw any conclusions on their effectiveness. Instead, it sought to understand how other networks with similar goals have operated within member states and the lessons that have been learned, coupled with interviews with two of the coordinators of existing ERNs. The Expert Panel concluded that, while ERNs have considerable potential to improve the care of patients with rare diseases across the EU, both through advice on the management of individual patients, as well as through collaboration on research and development of guidelines, it is not yet possible to ascertain the extent to which these goals will be achieved. The Expert Panel also identified several issues which, even at this stage, appeared to need to be addressed, including long-term financial sustainability and the implementation of effective IT systems. Turning to the specific questions asked of the Expert Panel, we firstly concluded that the current criteria for establishing a ERN, as a means of improving the management of patients with rare and complex diseases, was appropriate. The ERN concept does not address other issues raised for our consideration, such as remote areas and border regions, or the development of new medicines or interventions, for which there are alternative and more appropriate mechanisms. We were also asked about the scope to extend the scope of ERNs to other areas such as the care of people who are homeless or emergency situations. In both cases, we believe that there are better alternative mechanisms to achieve the intended goals. Secondly, we examined the scope of the ERNs, and in particular their relationship with research and guideline development. Given the current state of implementation, it is not possible to come to a definitive conclusion, but we were persuaded by the arguments that there is considerable scope for incorporating these additional roles beyond the immediate objective of providing advice on individual patients. This will, however, require dedicated resources, some of which will have to come from other sources. Thirdly, while reinforcing the importance of ERN is to link with national health systems, the diversity of systems within Member States makes it impossible to provide detailed guidelines for how this can best be made to work. This is another area where it will be important to monitor the implementation of the existing ERNs and disseminate the lessons that arise from their experiences

EXPH (EXpert Panel on effective ways of investing in Health), Opinion on Innovative payment models for high-cost innovative medicines.

The growth of pharmaceutical expenditures due to new high-cost innovative medicines, under the current institutional framework, creates financial challenges to health systems. The recognition that the current path of growth cannot be continued indefinitely leads to the search of new ways to ensure that innovation “that matters” is produced, that patients have access to innovation and that health systems are financially sustainable. This context leads to the discussion of innovative payment models for new medicines that improves the way the three above-mentioned objectives are met. It is unlikely that a single payment model will be optimal for all situations. Some broad principles should be observed when defining specific payment models for innovative medicines and deciding on rewarding R&D in pharmaceutical products: • Greater price and cost transparency, including the acknowledgement that high prices (high costs to payers) may or may not have underlying high costs of R&D. • Revisit the promotion of innovation through patent law and market exclusivity, as other mechanisms to promote and reward high-value innovations can and should be devised. This is particularly true when clear areas of neglected attention can be identified in a consensual way. The patent system is the current best option for decentralized innovation efforts when consumers are price sensitive, but not necessarily otherwise. This opens space to explore new models of promoting innovation that will encompass novel payment models which may or may not be associated with different rules in R&D funding (say, making use of prize-awarding mechanisms). • Develop methodologies to measure the social value of pharmaceutical products and systematically use such methods, for instance in the context of Health Technology Assessment. • Have an assessment of exercise of market power in each price negotiation, as insurance protection set by health systems reduces the role of consumer’s price sensitivity in limiting price increases of new products under patent protection. • Set better rewards for higher therapeutic value added, so that innovation efforts are directed to the more relevant areas. • Payment systems should evolve in the direction of paying for acquisition of a service (treatment) and not of a product (pill). • Explore non-linear payment systems, including bundling, price-volume agreements, differentiation across geographies, and across indications, ensuring the conditions required for all parties to benefit. • Create dialogue platforms involving all relevant stakeholders