Independent report

Defining the highest risk clinical subgroups upon community infection with SARS-CoV-2 when considering the use of neutralising monoclonal antibodies (nMABs) and antiviral drugs (updated March 2023)

Updated 19 September 2023

Introduction

In late 2021, at the request of Professor Jonathan Van Tam (the former Deputy Chief Medical Officer (DCMO)), an advisory group was constituted to identify a set of patient conditions (or cohorts) that were deemed to be at the very highest risk of an adverse COVID outcome, namely hospitalisation and death.

The first recommendations were published on 30 May 2022 and were designed to support the deployment of approved medications for treatment or prophylaxis, potentially across a range of scenarios, but the group was tasked at that time to focus on those in the community with clinically proven COVID-19.

The present report provides an update to the literature and advice offered in the context of an individual patient with a positive test for SARS-CoV-2.

Our approach was previously described, and this methodology was adhered to, in principle, on this occasion by the independent advisory group (IAG) (Appendix 4). Proposed changes arising from our update are included in Box 1 and Box 2 below. A short explanatory update is now included in Appendix 3 for each set of conditions, which is otherwise unchanged from the prior report - this makes it quickly obvious what is new and what remains constant to ease potential translation to policy in due course. An updated literature is provided in the footnotes to support this new advice. It is noteworthy that this update also gave consideration to other medical conditions now identified by recent data sets that might render a patient testing positive to be at higher risk of a relatively poorer outcome and thus be deemed especially vulnerable.

We evaluated papers published or in pre-print format, in the general and discipline specific literature, made available through to 1 December 2022 that might alter or confirm our prior recommendations. In particular we evaluated data contained in public health data sets, for example:

These provide evidence of poorer outcomes in conditions included in our original report but also conditions not originally covered by the remit of the IAG.

The advisory group was formed originally under terms of reference contained in Appendix 1 and constituted a range of clinical academics with requisite expertise. Notably, our remit is to focus primarily on those conditions in which immune compromise may constitute a major factor in defining risk of poor outcome.

Additional members have been co-opted to fill gaps based on expertise in specific disease cohorts gained via involvement in national studies of vaccine responses, as well as SARS-CoV-2 evolution and immune evasion. Particular attention was paid to develop a diverse and inclusive group to represent the clinical subgroups (Appendix 2).

We have continued to add members across a range of expertise, and in so doing we also sought to ensure interactivity with patient groups, professional societies and charities in evolving our guidance, which included consideration of new data proposed by such groups. Thus, the report update reflects input from across different areas allowing us to continue to be responsive to a dynamic environment.

A subsequent report (pre-exposure prophylaxis (PrEP) report), developed from this earlier work, provided a list of conditions that might be considered as most meritorious of receipt of prophylaxis on the basis of either predicted (or laboratory-proven) low protection by SARS-CoV-2 directed vaccine, or substantial harm in the event of SARS-CoV-2 re-infection despite vaccination (1 to 5). A parallel update for this report is ongoing and will be published shortly. The initial version of the report can be found on pages 972 to 987 of the ‘Committee papers’ available on the National Institute for Health and Care Excellence (NICE) webpage Tixagevimab plus cilgavimab for preventing COVID-19 [ID6136].

Recommendation update

The IAG first gave detailed consideration to the updated work contained in QCovid4, which considerably updated the data sets available for QCovid3 that in turn informed our prior disease selection. Briefly, this work used the QResearch database linked to national data on COVID-19 vaccination, high-risk patients prioritised for COVID-19 therapeutics, SARS-CoV-2 results, hospitalisation, cancer registry, systemic anticancer treatment, radiotherapy, and the national death registry. Significantly it refined the evaluation of mortality and hospitalisation following testing positive to SARS-CoV-2.

It identifies poor outcomes for subjects with a range of conditions already contained in our recommendations but added in particular diabetes (type 1 and 2), a range of cardiovascular conditions, and chronic obstructive pulmonary disease (COPD) to the list of potential vulnerable disease states, and offered further specific insight to neurologic and psychiatric conditions of potential concern.

Similarly, the IAG discussed the findings of Agrawal and others that analysed outcomes derived in a ‘4 nations’ approach using public health data sets that were broadly aligned with those detected in QCovid4.

1. New conditions worthy of consideration

Although our primary remit was to consider those diagnostic groups most at risk of adverse outcome on the basis of immunological vulnerability, our review of the evidence highlighted other conditions that could confer poorer outcomes on the basis of primary tissue pathology - for example, as a result of reduced respiratory, cardiovascular or renal reserve, peripheral cardiovascular pathology (for example, diabetes), immobility (for example, neurodegenerative disorders) and would merit consideration of antiviral interventions.

Parameters including age and obesity remained out of our remit and are not included in our recommendations though both remain significant risk factors in all data sets.

We identified several cardiovascular diseases, particularly heart failure, and cardiometabolic conditions (namely, diabetes (type 1 and type 2)) as additional risk factors. We do not make specific recommendations around these conditions noting deliberations elsewhere on behalf of policymakers.

Neurologic disorders have now been defined in detail in our updated report, particularly highlighting neurodegenerative disorders and immune diseases of the brain, which were previously covered in our section concerning immune-mediated inflammatory diseases (IMIDs).

Finally, some respiratory conditions - for example, COPD, severe asthma requiring immune suppression - have now been identified as conditions with higher risk of poorer outcome. Accordingly, we provide a standalone advisory ‘box’ to highlight these areas to more effectively support policy decisions.

2. Risk prediction algorithms

The QCovid 4 risk algorithm predicts mortality among people with a positive viral test. The IAG considered that the introduction of the use of a risk prediction tool, such as QCovid4, could offer value in the management of individuals at potential risk as it could individualise decision-making.

At this time, there remains limited evidence of the clinical effectiveness of this approach. Moreover, it is noted that this would require further validation and necessary interaction with other agencies - for example, NHS Digital - to ensure that it was feasible in primary care and that requisite data sets would be made readily available to allow optimal performance in primary care where this was likely to be of most value.

Whereas this sits out with our primary remit, the IAG considered that our report would be incomplete in its broader context without noting this potential approach to management and recommends that further research be performed to assess the role for risk prediction tools in allocation of therapeutics upon testing positive.

The updated recommendation of the advisory group on the groups of patients with highest risk is shown in Box 1.

Box 1: updated findings of the independent advisory group

See Risk factors for progression to severe COVID-19 in adults on the NICE website.

Box 2: pathway for PCR positive symptomatic cases aged older than 12 and younger than 18 years, greater than 40kg weight, and clinical concern

See Risk factors for progression to severe COVID-19 in young people aged 12 to 17 years on the NICE website.

Appendix 1: original terms of reference

This appendix sets out the original terms of reference of the COVID-19 Neutralising Monoclonal Antibodies (nMABs) and Antivirals Access Independent Advisory Group.

Background

Evidence is emerging and building in respect of the efficacy of nMABs and oral antivirals preventing progression to severe disease and death in both hospitalised and non-hospitalised patients with COVID-19. A number of nMAB products have entered the regulatory pipeline and are undergoing rolling review by the Medicines and Healthcare products Regulatory Agency (MHRA), with a number of products now having achieved a conditional marketing authorisation.

The NHS is therefore continuing to work to identify target populations and outline delivery pathways for these products. Supply is likely to be constrained and UK interim clinical commissioning policies will be required to ensure that access is provided to patients most likely to benefit from this treatment.

These interim clinical commissioning policies will be developed by the National Clinical Policy Team at NHS England and Improvement (NHSEI), with input from relevant national expert groups and updated as further guidance or evidence emerges.

The DCMO has requested that an advisory group chaired by Professor Iain McInnes and supported by the NHSE RAPID-C19 team identify a set of patient conditions (or cohorts) that are deemed to be at the very highest risk of an adverse COVID-19 outcome. This is to help support the adoption of approved medications for treatment or prophylaxis. The output would be a list of conditions or cohorts in order of greatest risk and an estimate of the population size of each, which will be used to inform the development of the UK clinical commissioning policies.

This document sets out the terms of reference for the IAG concerning use of nMABs and antiviral drugs in highest risk clinical subgroups upon community infection with SARS-CoV-2 in its role of identifying the patient cohorts at highest risk of an adverse COVID-19 and in supporting the development of relevant interim clinical commissioning policies.

Role

The group’s role is to review of high-risk cohorts suitable for treatment with nMABs and oral antivirals:

  1. The group will review all available literature, alerts from the Food and Drug Administration (FDA) and European Medicines Agency or other international medicines regulatory bodies, and any other relevant emergent data (trial or otherwise).

  2. The group will review the NICE COVID-19 rapid guideline on managing COVID-19.

  3. The group will review the data collected by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) and other real-world evidence, if appropriate.

  4. The group will draw upon its expertise in immunology, infectious diseases, and other relevant disciplines to identify patient groups at risk of adverse COVID-19 outcomes following a third (booster) vaccination.

Meeting schedule and governance

The group will meet twice initially to support development of the list of highest-risk cohorts. The group will then be reconvened as necessary to review new evidence or changes to national or international consensus statements and guidelines.

Notes will be taken of the meetings and shared with the group.

The group will report directly to the UK DCMO.

Confidentiality

Members are obliged to treat information shared and discussed within the group as clinically or commercially in confidence, as applicable. This may include, for example, commercially in confidence information on available medicines supply or pricing, or early research data prior to publication.

Review

Given the evolving nature of the COVID-19 pandemic in the UK, the above terms of reference may be subject to review or change.

Date: 14 April 2022 (first agreed on 28 October 2021, since subject to revisions up to date of publication).

Update group remit

The remit of the update group was specified in November 2022 as follows:

To use the IAG expertise to analyse the QCovid4 data and any other relevant data to establish whether the existing high-risk group or COVID medicines delivery unit (CMDU) cohort is still appropriate about 6 months on from the publication of the IAG report in May, or whether it supports an expansion of the cohort. Given this, we are asked to propose which groups or characteristics should be included in such an expansion. The group is asked to specifically focus on conditions in which impaired immune competence is a likely contributor to the poor outcome either a priori, or by dint of reduced vaccine response leading to reduction in the protection afforded by the same in terms of hospitalisation or death upon subsequent infection.

The group is also asked to consider whether such data may require that the recommendations in the draft PrEP report also need updating ahead of publication, in light of this more recent data. This work will be contained in a further update to the PrEP report in January 2023.

Appendix 2: membership of the advisory group

  • Professor Iain McInnes (Chair), Vice Principal and Head of College, College of Medical, Veterinary and Life Sciences, University of Glasgow

  • Professor Anthony Kessel (supporting), Clinical Director National Clinical Policy, Specialised Commissioning, NHSEI

  • Professor Benedict Michael, Professor of Neuroscience and Honorary Consultant Neurologist, NIHR Health Protection Research Unit for Emerging and Zoonotic Infection, University of Liverpool

  • Professor Baba Inusa, Chair, National Haemoglobinopathy Panel, England, and Professor of Paediatric Haematology and Sickle cell disease, Guy’s and St Thomas’ NHS Foundation Trust

  • Professor Carl Goodyear, Professor of Translational Immunology, University of Glasgow

  • Professor Calum Semple, Professor of Child Health and Outbreak Medicine at University of Liverpool, and Consultant Respiratory Paediatrician at Alder Hey Children’s NHS Foundation Trust, Liverpool

  • Professor Carlo Palmieri, Professor of Translational Oncology and Medical Oncologist, Molecular and Clinical Cancer Medicine, University of Liverpool

  • Professor Claire Harrison, Professor of Myeloproliferative Neoplasms, Guy’s and St Thomas’ Hospital

  • Dr Charlie Tomson, Consultant Nephrologist, North Bristol NHS Trust

  • Dr David Lowe, Consultant Clinical Immunologist, Royal Free Hospital

  • Dr Dhivya Subramaniam (supporting), National Clinical Policy Fellow, NHSEI

  • Professor Eleanor Barnes, Professor of Hepatology and Experimental Medicine, Nuffield Department of Medicine, University of Oxford, Oxford University Hospitals NHS Foundation Trust

  • Dr Elizabeth Whittaker, Consultant in Paediatric Infectious Diseases and Immunology, Imperial College Healthcare NHS Trust, and Convenor, British Paediatric Allergy, Immunology and Infection Group

  • Professor Emma Thomson, Professor in Infectious Diseases, University of Glasgow

  • Dr Edward Carr, Post-doctoral Clinical Fellow, The Francis Crick Institute

  • Dr Emily Padfield, NHSE (supporting)

  • Professor Gary Middleton, Professor of Medical Oncology, University of Birmingham

  • Professor Jack Satsangi, Professor of Gastroenterology, University of Oxford

  • Professor Julia Hippisley-Cox, Professor of Clinical Epidemiology and General Practice, and Chair, COVID Risk Stratification Subgroup, NERVTAG

  • Dr Josh Wright, Consultant Haematologist, Sheffield Teaching Hospitals NHS Foundation Trust, and Lead Clinician, North East and Yorkshire Haemoglobinopathy Coordinating Centre

  • Dr Jane Collier, Consultant Hepatologist, Oxford University Hospitals NHS Foundation Trust

  • Professor Kwee Yong, Professor of Clinical Haematology, University College London Hospitals

  • Dr Katie Vinen, Kings College Hospital NHS Foundation Trust

  • Dr Laurie Tomlinson, Consultant Nephrologist, London School of Hygiene and Tropical Medicine

  • Professor Lennard Lee, Honorary Senior Research Fellow, Institute of Cancer and Genomic Sciences, University of Birmingham

  • Dr Lisa Spencer, Consultant Respiratory Physician, Liverpool University Hospitals NHS Foundation Trust

  • Professor Lucy Wedderburn, Professor in Paediatric Rheumatology, University College London

  • Professor Martin, Underwood Professor of Primary Care Research, Warwick Clinical Trials Unit, Warwick Medical School

  • Dr Matthias Schmid, Consultant Physician and Head of Department, Infection and Tropical Medicine, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, and Chair, Clinical Reference Group, Infectious Diseases, NHSE

  • Professor Matthew Snape, Professor in Paediatrics and Vaccinology, Oxford Vaccine Group

  • Professor Martin Turner, Professor of Clinical Neurology and Neuroscience, Nuffield Department of Clinical Neurosciences, University of Oxford, and Honorary Consultant Neurologist, Oxford University Hospitals NHS Foundation Trust

  • Dr Michelle Willicombe, Consultant Nephrologist, Imperial College Healthcare NHS Trust

  • Dr Nick Kennedy, Consultant Gastroenterologist, University of Exeter

  • Dr Nick Powell, Consultant Gastroenterologist, Imperial College London

  • Professor Paul Moss, Professor of Haematology, University of Birmingham

  • Dr Paul Cockwell, Consultant Physician, University Hospital Birmingham

  • Dr Rupert Beale, Immunologist and Clinical Nephrologist, and Clinical Researcher, Crick Institute

  • Dr Siraj Misbah, Consultant Immunologist, and Chair, Blood and Infection Programme, Care, NHSE

  • Professor Stefan Siebert, Professor of Inflammation Medicine and Rheumatology, University of Glasgow

  • Dr Sean Lim, Associate Professor and Honorary Consultant in Haematological Oncology, University of Southampton

  • Dr Stephen McAdoo, Consultant Nephrologist, Imperial College London

  • Professor Thushan de Silva, Professor and Honorary Consultant Physician in Infectious Diseases, University of Sheffield

  • Professor Tariq Ahmed, Consultant Gastroenterologist, University of Exeter

  • Dr Tom Marjot, Clinical Fellow in Hepatology, Oxford University Hospitals NHS Foundation Trust

  • Professor Chris Griffiths, University of Manchester

  • Professor Richard Warren, University of Manchester

Appendix 3: key evidence base and explanatory notes upon which disease sub-classification is based

Solid cancer

QCOVID demonstrated that the delivery of chemotherapy within 12 months is a proven risk factor for increased mortality compared with those not receiving chemotherapy with a confirmed SARS-CoV-2 infection in the pre-vaccination era (adjusted hazard ratio in women, chemotherapy group A 2.30 (1.35 to 3.94), group B 3.52 (2.29 to 5.42), group C 17.31 (6.52 to 45.98) and in men group A 1.74 (1.1 to 2.75), group B 3.50(2.54 to 4.82), group C 3.37 (1.17 to 9.64).[footnote 1]

Importantly, in the post-vaccination era this enhanced risk remains for chemotherapy groups B and C (3.63 (2.57 to 5.12) and 4.30 (1.06 to 17.51) respectively).[footnote 2] The grouping used in QCOVID was based on the risk of grade 3/4 febrile neutropenia or lymphopenia. Thus, the following chemotherapies were included in group A (less than 10% risk) - weekly taxanes, cisplatin, 5FU single agent, capecitabine single agent, pemetrexed and raltitrexed. Many of these agents are given in combination with group B drugs (for example, 5FU and capecitabine with oxaliplatin or irinotecan). Pemetrexed is given with high dose steroids and has a mechanism of action similar to methotrexate which is used for its anti-inflammatory effect through alterations in lymphocyte subsets and suppression of T cell activity.

Importantly, group A included many non-chemotherapy agents thus likely diluting out any adverse effect of the chemotherapies. Given these uncertainties and in particular the need to make rapid treatment decisions in which the exact regimen and associated concomitant medications may not be immediately available (for example, 3 weekly taxane is in group B) it is felt that the safest approach is to include all chemotherapies in the high-risk group. COVID-19 vaccination is effective in the majority of patients with solid cancer.

Based on neutralisation studies only 6.6% of those receiving immunotherapy, 16.2% receiving chemotherapy and 11.2% of those receiving chemo-immunotherapy (the latter almost all lung cancer patients - a high risk group in its own right) within 4 weeks, had an inadequate response.[footnote 3] In patients with solid cancers, neutralising antibody titres (NAbTs) were the same as age-matched non-cancer patients and this included antibodies against the delta variant.[footnote 4] This implies that while the increased risk of chemotherapy may be somewhat blunted by the development of neutralising antibodies, the significant enhanced risk is not eliminated due to the immunosuppressive impact of chemotherapy in spite of an apparently adequate B cell response.

The QCOVID data did not separately analyse chemotherapy administered in an adjuvant context post-resection, and thus in people with no active cancer, from those receiving cancer in the locally advanced or metastatic settings or whether patients with active cancer not receiving chemotherapy also have an enhanced risk compared with those with no active cancer.

Theoretically, active locally advanced or metastatic disease is clearly a risk in its own right as a result of the profound immunosuppression driven by active cancer secondary to the generation of highly T cell suppressive populations such as Tregs and myeloid-derived suppressor cells (MDSCs). Tregs in severe COVID-19 infection bear striking resemblance to tumour-infiltrating Tregs.[footnote 5] They overexpress FoxP3 and Treg effector molecules, and given their similarity with suppressive tumour Tregs, it suggests that they may limit the antiviral response during the cytokine storm phase thus contributing to the secondary disease re-expansion, given that all samples in this study were from severe patients profiled during that time.

There is abundant evidence on the critical role of MDSCs in dampening the anti-viral T cell response in severe COVID-19 infection through arginine depletion, transforming growth factor beta (TGF-beta) and Inducible Nitric Oxide Synthase (iNOS) production, all mechanisms used by MDSCs to potently suppress anti-cancer immune responses.[footnote 6] Thus, a patient with active cancer is primed for a poor T cell response on exposure to COVID-19 infection with the threat of more severe disease. In updated UK Coronavirus Cancer Monitoring Project (UKCCMP) data under consideration (pre-vaccination era) in 2,786 cancer patients with documented infection those receiving palliative chemotherapy within 4 weeks of infection were at much greater risk than those receiving neoadjuvant, adjuvant or radical chemotherapy, indeed suggesting an added risk component of active cancer per se (36.6% mortality rate versus 17.1% respectively (odds ratio 0.44 (0.27 to 0.71)).

Early CCC19 data included 45% cancer patients in remission: in multivariable analysis adjusted for age, sex, smoking status and obesity the odds ratio of mortality (using no active disease as reference) for present cancer which was stable or responding and using no evidence of active disease as reference was 1.79 (1.09 to 2.95) and in those with active progressing cancer 5.20 (2.77 to 9.77).[footnote 7] These data strongly suggest that the presence of increasing levels of disease activity cumulatively increase risk. This analysis did not correct for receipt of chemotherapy but in a recent analysis using the Optum HER repository of 507,307 patients with COVID-19 of whom 14,287 had cancer, 4,296 of whom received treatment within 3 months of COVID diagnosis, metastatic cancer (using non-metastatic solid cancer as reference) was an independent predictor of increased hospitalisation (odds ratio 1.37 (1.24 to 1.52) and 30-day mortality (odds ratio 2.36 (1.96 to 2.84) even after adjusting for use of chemotherapy or immunotherapy.[footnote 8]

The use of chemotherapy was associated with increased risk of hospitalisation (odds ratio 1.4) and 30-day mortality (odds ratio 1.84) after adjusting for the presence or absence of metastatic disease. Thus, chemotherapy delivery enhances risk independent of cancer status, but metastatic solid cancer also increases risk independently of chemotherapy and numerically the increased risk is greater than for chemotherapy in the preceding 3 months.

Importantly data that has just been submitted for publication on the efficacy of third dose booster vaccination in cancer patients from the UK coronavirus cancer project. The cancer cohort was identified from Public Health England’s rapid registration dataset. Given that this data is under review, full details cannot be made available to the public. However, there is reduced vaccine effectiveness against breakthrough and symptomatic infections in people with a diagnosis of cancer within 12 months (in solid cancer most notable in those with respiratory tract cancers) or receiving chemotherapy or radiotherapy within 12 months. It is to be noted that separate data also under review from the consortium has shown a significant waning of vaccine efficacy after second dose vaccine at 3 to 6 months in cancer patients, an effect markedly blunted in those without cancer.

Most importantly, on multivariate analysis, cancer patients were at significantly increased risk of hospitalisation and death after third booster vaccination especially in younger age groups but there was still a discernible detrimental effect in the over 80s. Although not broken down by haematological versus solid cancer only lymphoma patients had markedly less protection against breakthrough and symptomatic infections. Data from more than 20,000 cancer patients hospitalised with COVID between March 2020 and August 2021 from the Clinical Information Network (CIN) and the ISARIC WHO Clinical Characterisation Protocol (CCP) UK demonstrated that younger patients were at the highest relative risk of death from COVID-19 compared to those non-cancer patients of a similar age.[footnote 9] However, the absolute risk of death remained the highest in the older cancer patients.

This age effect was also found in a recent meta-analysis of 81 studies that recruited more than 81,000 patients. Fourteen of these studies provided data on the median or mean age of cancer patients and non-cancer patients with COVID-19. On univariate regression, when assessing the impact of age on the comparison of cancer and control patients, the relative risk of mortality significantly decreased as age increased (exp (b) 0.96; 95% confidence interval (CI), 0.922 to 0.994; probability (p) = 0.028) - that is, a greater difference in the relative risk of mortality was seen between cancer patients and controls of younger ages.[footnote 10]

Given the increases in the risk of hospitalisation or death in people with cancer (an obvious limitation is that at this stage full confirmation has not been possible as to whether all deaths were due to coronavirus infection), the differential breakthrough efficacy data, the waning vaccine effect in cancer patients after second dose (unknown after third) and the generalised immunosuppression of active cancer, this strongly suggests that all patients with present solid cancer (or treated with curative intent in the preceding 3 months) regardless of the receipt of therapy should be considered as vulnerable and highest priority. Solid cancer patients receiving chemotherapy and radiotherapy within 12 months should also considered as in the highest priority category. Those whose cancers were resected with curative intent and received no adjuvant chemotherapy or adjuvant therapy are, on first principles, likely to be less at risk. But, given this data, those within 12 months from diagnosis who have not received any adjuvant therapy should still be considered to be more vulnerable than the non-cancer population.

Justification for priority

Priority is justified as follows.

In the absence of clear data that vaccination equalises risk of severe disease in those with metastatic cancer with its attendant virus-relevant immunosuppression and given this risk is not equalised in vaccinated chemotherapy recipients, we propose that all patients with metastatic or locally advanced solid cancer or lung cancer at any stage be considered at high risk. Cancer patients in receipt of recent chemotherapy or radiotherapy within 12 months should also be considered high priority. People who have had cancer resected within 3 months and receiving no adjuvant chemotherapy or radiotherapy are considered to be priority group 2. Those people who have had cancer resected within 3 to 12 months and receiving no adjuvant chemotherapy or radiotherapy are expected to be at less risk (and thus less priority) but still at increased risk compared with the non-cancer populations.

Given the risk in these patients is still elevated even though vaccination is effective, and given that metastatic patients are at high risk because of mechanisms that prevent effective viral clearance, we suggest both groups of patients be considered for antiviral therapy if they fulfil the appropriate criteria.

March 2023 update

The following datasets have been added to the literature, and given this data we deem no update to our recommendations should be made currently.

A meta-analysis of 81 studies involving 61,532 patients with cancer found the relative risk of mortality from COVID-19 among patients with vs without cancer when age and sex were matched was 1.69 (95% CI, 1.46 to 1.95; p less than 0.001; I2 = 51.0%).[footnote 11] The relative risk of mortality in patients with cancer vs control patients was associated with decreasing age (exp (b) 0.96; 95% CI, 0.92 to 0.99; p = 0.03). Compared with other cancers, lung cancer (relative risk 1.68; 95% CI, 1.45 to 1.94; p less than 0.001; I2 = 32.9%), and hematologic cancer (relative risk 1.42; 95% CI, 1.31 to 1.54; p less than 0.001; I2 = 6.8%) were associated with a higher risk of death. Chemotherapy was associated with the highest overall pooled case fatality rate of 30% (95% CI, 25% to 36%; I2 = 86.97%; range, 10% to 100%), and endocrine therapy was associated with the lowest at 11% (95% CI, 6% to 16%; I2 = 70.68%; range, 0% to 27%).

This data predominately relates to the pre-vaccination era but reinforces the risk groups selected.[footnote 12] Updated data being prepared for publication on cancer patients receiving active anticancer therapy and hospitalised between 17 January 2020 and 1 January 2022 from the CIN and ISARIC CCP UK demonstrate mortality was higher for cancer patients, with younger patients continuing to have the highest relative risk.

While mortality fell through the pandemic, it remained higher for cancer patients during the alpha and delta wave. Mortality fell less for cancer patients as compared to non-cancer patients. This data covers the period before and after the introduction of vaccine of the SARS-CoV-2 pandemic, and indicates that despite the introduction of vaccination, cancer patients remain at higher risk than non-cancer patients if hospitalised from COVID-19. Meanwhile, the new QCOVID model (QCovid4) using data recorded during the Omicron wave in England continues to demonstrate that the delivery of chemotherapy within 12 months remains a risk factor for increased mortality compared with those not receiving chemotherapy with a confirmed SARS-CoV-2 infection in the post-vaccination era.[footnote 13] In addition, radiotherapy within the last 6 months as well as blood and respiratory cancers also were risk factors for increased mortality.[footnote 14]

The observation with regard to higher mortality for cancer patients within CCP UK as well as within QCovid4 in the period following the introduction of vaccination is supported by data published by the UK Coronavirus Cancer Evaluation Project, which assessed the efficacy of third dose booster vaccination in cancer patients.[footnote 15] The cancer cohort was identified from Public Health England’s rapid registration dataset. There was evidence of an increase in vaccine effectiveness against breakthrough and symptomatic infections for most cancer subtypes following the third dose booster. However, vaccine effectiveness against breakthrough infections, symptomatic infections and coronavirus hospitalisation was lower in cancer patients as compared to population control: 59.1% vs 77.25%, 62.8% vs 80.53%, and 80.5% vs 89.81%, respectively.

Vaccine effectiveness was higher following third dose boosters in solid organ malignancies for breakthrough and symptomatic infections (66.0%, 95% CI: 65.5 to 66.4 and 69.6%, 95% CI 69.2 to 70.1, respectively) compared to individuals with haematological malignancies (53.2%, 95% CI: 52.8 to 53.6 and 56.0%, 95% CI: 55.5 to 56.4). Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Patients with lymphoma had low levels of protection from symptomatic disease.

The lowest vaccine effectiveness for solid cancers was seen in those with respiratory and intrathoracic organ cancers (breakthrough infection: 51.60%, symptomatic infection: 55.73%).[footnote 16] Following multivariable adjustment, individuals with cancer with a positive coronavirus test were at an increased risk of hospitalisation and death compared to the population control (odds ratio 3.38, 3.01, respectively; p less than 0.001 for both) following a third dose booster, especially in younger age groups, although there was still a discernible detrimental effect in the over 80s.[footnote 17] Effectiveness of third dose was not assessed by stage of cancer. Taken together, this data indicates that while vaccination has reduced the risk of death, there is likely attenuation of vaccine effectiveness for patients with cancer, varying by cancer type.

Serological studies have shown significant waning of vaccine efficacy (positive PCR test) after the second vaccine dose at 3 to 6 months in cancer patients (47.0%, 46.3 to 47.6) versus a control population (61.4%, 61.4 to 61.5) based on data from the UK Coronavirus Cancer Evaluation Project.[footnote 18] The greatest levels of waning was observed in those with a diagnosis of lymphoma or leukaemia, in those who were diagnosed with cancer within 12 months of data cut-off, and in those who had received systemic anticancer treatments or radiotherapy.[footnote 19] While data from 28 cancers patients where anti-S IgG titres were available at 3 time points (post-vaccination (2 doses), pre-booster and 4 weeks post-booster) found the waning of immunity at 4 to 6 months post-full vaccination, that could be rescued to above pre-vaccination titters after booster vaccination.[footnote 20]

The CAPTURE study found that a third dose of vaccination boosted the neutralising response against omicron in patients with cancer (n=199), but the effect was blunted in patients with blood cancer compared to those with solid cancer.[footnote 21] While only a few patients with solid cancer lacked nAb titres against omicron after 3 vaccine doses, a substantial proportion of patients with blood cancer, especially those on B-cell-depleting therapies or with progressive cancer, did not mount a response.[footnote 22] Further data from the CAPTURE study found that at a median of 18 days (6 to 67 days) after a fourth vaccine dose, the proportion of patients with haematological malignancies (n=80) with detectable NAbTs titres (wild-type, Delta, and Omicron BA.1 and BA.2) and T-cell response increased compared with that after the third vaccine dose. Receipt of B cell-depleting therapies within the 12 months before vaccination was associated with the greatest risk of not having detectable NAbTs.[footnote 23] Currently precise correlates of protection from breakthrough infection remains undefined, after 3 and 4 vaccine doses in patients with cancer.

Haematological diseases and recipients of haematological stem cell transplant

Autologous HSCT recipients in the last 12 months (including HSCT for non-malignant diseases).

A high mortality risk was observed in HSCT recipients with COVID-19 in the pre-vaccine era, with 30-day survival of 68% (95% CI 58, 77) in allogeneic HSCT recipients and 67% (95% 55, 78) in autologous HSCT recipients.[footnote 24] Allogeneic HSCT recipients with COVID-19 less than 12 months from transplant had a greater risk of mortality (hazard ratio 2.67, 95% CI 1.33, 5.36).

Several studies have demonstrated lower antibody induction following mRNA SARS-CoV-2 vaccines in HSCT recipients compared to healthy controls, with limited data from other vaccine types.[footnote 25], [footnote 26] Receipt of vaccines within the first 12 months following HSCT results in lower antibody titres,[footnote 27], [footnote 28] both in autologous and allogeneic HSCT recipients.[footnote 29] Severe chronic GVHD was also found to be a risk factor for poor humoral immunogenicity in allogeneic HSCT recipients,[footnote 30] in keeping with prior data on the higher risk of infection and poor immunogenicity of other vaccines in the context of GVHD.[footnote 31] Current guidance recommends commencing post-HSCT re-vaccination courses with SARS-CoV-2 vaccines as early as 2 to 3 months following transplant,[footnote 32], [footnote 33] and HSCT recipients are likely to remain at risk of poor SARS-CoV-2 immune reconstitution in the first year post-transplant.

Individuals with haematological malignancies who have received either CAR-T cell therapy in the last 24 months or radiotherapy in the last 6 months.

Prolonged humoral immunodeficiency in recipients of chimeric antigen receptor-modified T cell (CAR-T) therapy is well documented,[footnote 34] with lack of immune reconstitution to vaccine preventable diseases.[footnote 35] Studies on SARS-CoV-2 vaccine immunogenicity in CAR-T recipients are limited, but available data suggests antibody induction that may be even lower than in HSCT recipients.[footnote 36], [footnote 37], [footnote 38]

Individuals with haematological malignancies receiving systemic anti-cancer treatment (SACT) within the last 12 months.

A range of SACT have been shown to impair antibody responses to one and or 2 doses of vaccinations. In particular:

1. Anti-CD20 monoclonal antibody therapy and other B-cell depletion agents

Anti-CD20 monoclonal antibody therapy is associated with marked peripheral B cell depletion of which full recovery can take up to a year.[footnote 39] Accordingly, the majority of patients have either an undetectable or markedly reduced antibody response when vaccinated within 12 months of anti-CD20 administration.[footnote 40], [footnote 41], [footnote 42] Cell depletion is also a recognised phenomenon for therapies such as ATG and anti-CD52 (alemtuzumab). Thus individuals treated with these agents are anticipated to have reduced immune responses.

2. Venetoclax or Bruton tyrosine kinase (BTK) inhibitors

Antibody response is reduced or absent in more than half of patients on either of these drugs.[footnote 43], [footnote 44], [footnote 45], [footnote 46] Limited data suggests improved antibody levels are observed early after BTK inhibitor, ibrutinib withdrawal.[footnote 47] Venetoclax is often administered in combination with anti-CD20, so its sole effects are difficult to assess, but recovery of associated B-cell depletion can occur as early as 30 days after drug withdrawal.[footnote 48]

3. Anti-CD38 monoclonal antibody or BCMA targeted therapy

These agents are utilised by patients with multiple myeloma in whom an increased mortality rate with COVID-19 was noted prior to vaccination. Anti-S IgG antibodies have been reported in about 80% of patients with myeloma and inferior responses are reported for patients on anti-CD38 and BCMA-targeted therapies in 2 large studies.[footnote 49], [footnote 50]

4. Chemotherapy recipients

Patients with acute leukaemias and aggressive lymphomas have an increased risk severe COVID-19 infection (hazard ratio 3.49, 95% CI 1.56, 7.81 for acute myeloid leukaemia and 2.56 (1.34, 4.89) for aggressive B-NHL) in the pre-vaccination period.[footnote 51] Data describing vaccine responses in the absence of anti-CD20 is lacking. Vaccine responses from patients with Hodgkin lymphoma indicate a seronegative rate of 10% and around a 5-fold reduction in antibody level for patients vaccinated on treatment compared to those vaccinated more than a month after completion.[footnote 52]

5. Other SACT

Data describing the impact of other therapies on vaccination response in conditions such as the myeloproliferative neoplasms and myelodysplastic syndromes tends to comprise of smaller cohorts and can be conflicting.[footnote 53]

Individuals with CML in molecular response, or those who are receiving first or second line tyrosine-kinase inhibitor (TKI) therapy demonstrate detectable and durable vaccine responses,[footnote 54] as also evidenced by experience in the CML community (see American Society of Hematology’s COVID-19 and CML: frequently asked questions. However, they have not been specifically excluded for pragmatism.

Individuals with indolent B-cell malignancies have an increased risk of severe outcome from COVID-19 (hazard ratio 2.19 (95% CI 1.07, 4.48).[footnote 55] A third of individuals with chronic or indolent B-cell lymphoproliferative disorders have undetectable or reduced antibody responses to vaccination irrespective of timing of systemic treatment.[footnote 56] The patients who are most likely to have reduced antibody responses are those who have reduced serum immunoglobulin and reduced peripheral blood B cell counts, which may help identify those most at risk.[footnote 57] Similarly, poor vaccine responses have also been observed in AL amyloidosis.[footnote 58]

Individuals with myeloproliferative neoplasms have tended to demonstrate better vaccine responses compared to those with B-cell malignancies, but as the cohorts tended to be small, where data suggests that individuals with these subtypes may have impaired responses such as in myelodysplastic syndrome or myelofibrosis,[footnote 59] they are included as high risk.

A recent European registry data reported the outcomes of 113 COVID-19 cases in vaccinated individuals with haematologic malignancies, wherein 70% had severe or critical infections.[footnote 60]

March 2023 update

There continues to be a paucity of data describing the clinical outcomes of COVID-19 infection in vaccinated individuals described within this category. Further, the immune response to COVID-19 vaccination within each group is heterogeneous so precise risk delineation is difficult. No changes are proposed to the existing prioritisation groupings with 2 exceptions:

1. Individuals with haematological malignancies who have received CAR-T cell therapy in the last 24 months.

It is apparent from clinical experience that recipients of CAR-T cell therapy may be cytopenic for a period exceeding 24 months, and recovery of lymphocyte counts is associated with improved vaccine immune response.[footnote 61] In view of this, the following change to the prioritisation grouping is proposed:

Individuals with haematological malignancies who have received CAR-T cell therapy in the last 24 months, or until the lymphocyte count is within the normal range.[footnote 62]

2. Inclusion of individuals with mature T-cell malignancies.

The primary reasons for inclusion of T-cell malignancies are that these are malignancies and there is limited knowledge of their vaccine response. The PROSECO study observed antibody responses comparable to those with Hodgkin lymphoma after second, third and fourth vaccine doses[footnote 63] (when vaccinated more than 6 months from systemic anti-cancer treatment, but there were less than 10 cases in that cohort). Despite their inclusion, it is likely that their risk of severe COVID-19 disease is less that those with B-cell malignancies given that these patients tend not be hypogammaglobulinaemic or B-cell depleted from B-cell directed therapy. We advise the need for discretion by clinical teams caring for these patients in the application of this guidance.

Renal diseases

Renal transplant recipients who test positive for SARS-CoV-2 remain at very high risk of hospitalisation and death despite vaccination. Among renal transplant recipients there are groups of patients who are at particular risk as a consequence of B-cell depleting therapy or the presence of other risk factors.

The highest risk transplant recipients (including those with failed transplants within the past 12 months) should comprise those who:

  • have had B cell depleting therapy within the past 12 months (including alemtuzumab, rituximab [anti-CD20], anti-thymocyte globulin)
  • have an additional substantial risk factor which would in isolation make them eligible for monoclonals or oral antivirals
  • not been vaccinated prior to transplantation

This group will comprise a small number of glomerulonephritis and vasculitis patients who will have received comparable immunosuppression comprising rituximab or B cell depletion within preceding 6 months and/or high doses of cyclophosphamide with steroids (see also remarks in the section concerning IMIDs). Solid organ transplant recipients not in any of the above categories should be considered for either neutralising monoclonals or molnupiravir. If transplant recipients require subsequent admission the alternative agent should be made available.

Patients with chronic kidney stage (CKD) 4 or 5 (an eGFR less than 30 ml per min per 1.73m2) without immunosuppression are at high risk and should be considered for either neutralising monoclonals or oral antivirals. Although there are no trial data for use of molnupiravir in CKD stage 4 or 5, the course of the drug is short and in this high-risk group we consider the benefits of use to outweigh the risks. We note a paper reporting a phase 1 trial concluded: “very little molnupiravir or EIDD-1931 was detected in urine” suggesting that the kidneys are not a major route of excretion for the pro-drug or active drug.[footnote 64] Uncertainties on drug dosing in patients with CKD stage 4 or 5 should be addressed through a mandated post authorisation surveillance study in patients with CKD and through pharmacokinetic studies. Details on the Pfizer protease inhibitor are at present unavailable, but we note that Ritonavir inhibits cytochrome P450 and hence is relatively contraindicated in patients receiving Tacrolimus (most transplant patients), Sirolimus, Cyclosporin or Voclosporin.

Patients with CKD stage 3 without immunosuppression and CKD stage 1 or 2 with minimal or no immunosuppression are not at sufficiently elevated risk to warrant community antivirals currently (unless they satisfy other criteria).

Further evidence

Relevant data considered includes a submitted paper from the Scottish Renal Registry (made available to the working group with permission and now published) and from the OpenSAFELY Collaborative:

March 2023 update

There is not judged to be a new literature that would substantially change the original recommendations. Data from QCovid4 and OpenSAFELY (Changes in COVID-19-related mortality across key demographic and clinical subgroups: an observational cohort study using the OpenSAFELY platform on 18 million adults in England) suggest patients with advanced kidney disease remain at elevated risk of poor outcomes and indeed low vaccine responses. The only minor change from previous recommendations concerns the proviso on vaccination timing for transplant patients which has been removed.

Liver diseases

The advisory group considered particularly the following at risk groups:

  • patients with liver cirrhosis (Child-Pugh (CP) class A, B and C)
  • patients with liver disease on immune suppressive therapy
  • liver transplant recipients

By corollary, the advisory group recommend that patients with chronic liver disease (CLD) or abnormal liver function tests who do not fall into the above 3 categories should not be prioritised for therapy as there is no clear evidence of either poor clinical outcomes, or poor response to SARS-CoV-2 vaccines. Patients with hepatocellular cancer (HCC) should be prioritised as defined in the solid cancer section. HCC has been identified as a risk factor for mortality following SARS-CoV-2 infection.[footnote 65]

The global burden of CLD is enormous, with cirrhosis affecting more than 122 million people worldwide, of whom 10 million have decompensated disease.[footnote 66] Advanced liver disease is associated with immune dysregulation and coagulopathy which may contribute to the more severe COVID-19 disease course. The main cause of death in liver patients with COVID-19 is pulmonary disease followed by liver related mortality.[footnote 67] CLD may have overlapping risk factors for severe COVID-19, particularly in non-alcoholic fatty liver disease (NAFLD) that is commonly associated with obesity and other co- morbidities. NAFLD is highly prevalent in the UK population (more than 20%).[footnote 68] However, in a series of 155 consecutive COVID-19 inpatients enriched for FLD (43%) and significant fibrosis (45%), these factors were not independently associated with mortality.[footnote 69] This finding was confirmed in a larger international cohort using the SECURE-Cirrhosis and COVID-Hep registries where the odds ratio for death for NALFD patients was 1.01 (95% CI 0.57 to 1.79).[footnote 70] Together this data suggests that NAFLD per se is not a risk factor for SARS-CoV-2 mortality.

Mortality and morbidity from SARS-CoV-2 increases with the severity of cirrhosis as measured by CP class. In the international SECURE-Cirrhosis and COVID-Hep registries, which consisted of more than 1,200 hospitalised liver patients with SARS-CoV-2 infection, there was a stepwise increase in the frequency of intensive care unit admission, renal replacement therapy, invasive ventilation and death that was associated with increasing CP score. Compared to COVID-19 patients with CLD, but without cirrhosis, patients with CP A cirrhosis had an increased odds ratio for death (1.90 (1.03 to 3.52)), CP B 4.14 (95% CI 2.24 to 7.65), and CP C 9.32 (95% CI 4.8 to 18.08).[footnote 71] CP C patients had only a 10% survival once ventilated.

The SECURE-Cirrhosis and COVID-Hep registries included a large proportion of liver patients without cirrhosis who had no increased risk of COVID-19 mortality compared to matched control patients without liver disease. Similar findings were described in a French national cohort study of 15,746 patients with CLD, though this study found no increase in mortality for CP A cirrhosis.[footnote 72] In the French study, and also in the SECURE-Cirrhosis and COVID-Hep registries, alcohol-induced liver disease was particularly associated with increased mortality. Chronic liver disease (OpenSAFELY adjusted hazard ratio 1.75) and liver cirrhosis (QResearch mortality odds ratio 3) was also found to be associated with increased mortality in 2 large UK primary care datasets.[footnote 73] Together, this data suggests that increasing severity of liver cirrhosis is associated with increasing SARS-CoV-2 mortality.

Liver transplant and autoimmune liver disease on immune suppressive therapy recipients

Published international SECURE-Cirrhosis and COVID-Hep registries and Spanish registry data suggest that liver transplant patients are not at increased risk of severe COVID-19 mortality as compared to non-liver transplant patients.[footnote 74] Case fatality rates are broadly consistent across cohort studies from the first wave of the pandemic at around 20%.[footnote 75]

Similarly, 2 independent cohorts of patients with autoimmune hepatitis on immune suppressive therapy have been shown not to be at increased risk of death, unless they also have CP B-C cirrhosis.[footnote 76] In a UK Public Health England analysis of approximately 6,700 transplant recipients (blood and solid organ) who had not received a COVID-19 vaccine, 7% (466) contracted COVID-19 and 40% (189) died within 28 days of a positive COVID test.

However, solid organ transplant patients, and studies including only liver transplant populations have shown that these patients make a weak or absent immune response to COVID-19 vaccines.[footnote 77] Patients with CLD but without cirrhosis, and patients with NAFLD make robust immune responses to COVID-19 vaccines.[footnote 78] Together, these data suggest that liver transplant and liver disease patients on immune suppressive therapy may not be at increased risk of SARS-CoV-2 mortality - however, these subgroups are particularly likely to make poor COVID-19 vaccine responses.

Patients with liver cirrhosis are at increased risk of COVID-19 death and COVID-19 vaccine no or low response and should be prioritised for treatment. The risk of death after SARS-CoV-2 infection increases with liver disease stage, as measured by Child-Pugh class.

Liver transplant, autoimmune liver disease and other liver patients on immune suppressive therapy are at high risk of vaccine low or non-response and should be prioritised for treatment.

Patients with CLD or abnormal liver function tests who do not fall into the above categories should not be prioritised for therapy.

Molnupiravir may be offered to liver patients as there is no published data (as of November 21) to indicate that molnupiravir is associated with liver toxicity. Patients with chronic liver disease, who are not on immune suppressive drugs, and/or who do not have liver cirrhosis should not be prioritised for treatment, unless they have other co-morbidities that would mean that they meet inclusion criteria that are defined by others for therapy. Abnormal liver function tests and thrombocytopenia are commonly associated with liver disease and should not necessarily be used as a contraindication for therapy.

March 2023 update

No change in prior recommendations is currently considered necessary on the basis of recent literature.

Immune-mediated inflammatory disorders

In the IMIDs (primarily affecting joint, bowel and skin, though the principles of therapeutic considerations are consistent for other inflammatory disorders, including connective tissue diseases), there is now emerging population-based evidence to suggest that these patients are overall at a modestly increased risk of severe life-threatening COVID-19.[footnote 79] The defined risk is most apparent in inflammatory joint diseases, in which hospital admissions and mortality are reportedly elevated; and less apparent in inflammatory bowel disease with borderline increased hospitalisation rates, with no excess mortality. However, it should be noted that other datasets (all pre-vaccination) have not shown a clearly elevated overall risk in these disease settings.[footnote 80] and other IMID such as multiple sclerosis.[footnote 81] Together the available data on outcomes after infection in this patient group suggest that there are sub-groups of patients (based on either disease state or treatment) at a higher risk of severe life threatening COVID-19[footnote 82]. These data allow definition of sub-groups that should be prioritised for either nMABs or oral antivirals upon confirmation of COVID-19 infection.[footnote 83]

We highlight the following priority groups:

  • patients who have received a B cell depleting therapy (anti-CD20) within the last year[footnote 84]
  • patients who are on or have received steroids within 28 days (10mg daily prednisolone equivalent or more, including budesonide)[footnote 85]
  • patients treated with mycophenolate,[footnote 86] cyclophosphamide, cyclosporin, JAK inhibitors or tacrolimus
  • patients with uncontrolled or unstable clinically active disease and/or flaring disease[footnote 87]

In defining active disease,[footnote 88] we suggest a pragmatic approach of including patients requiring escalation of systemic therapy as an out-patient and/or hospital admission. It is important to note that monotherapy with targeted therapies, biological agents (other than rituximab and other B cell targeted therapy) or immunomodulators commonly used in IMID has generally not been associated with increased risk of adverse clinical outcomes[footnote 89] in the pre-vaccination setting, although large datasets have suggested an increased age and sex-adjusted risk of death for people with rheumatoid arthritis/systemic lupus erythematosus (SLE)/psoriasis of 1.3 (1.21 to 1.38). At present therefore and on balance, the high proportion of IMID patients in established remission on maintenance therapy with these agents do not represent a group requiring prioritisation on current evidence (grade B/C).

Reduced serological responses to vaccination has been noted in all IMID, and also associated with specific therapies, most notably anti-CD20 therapy in the 9 to 12 months preceding vaccination.[footnote 90] However, evidence is at present lacking for correlation of these attenuated responses with either de novo breakthrough or recurrent COVID-19 infection.[footnote 91]

We define as areas requiring further evaluation:

  • the incidence and severity of infection in vaccinated patients on advanced therapies including a broad base of biologics
  • relationship of COVID-19 infection incidence and severity to serological response or non-response to vaccines
  • emerging data on cell-mediated responses to vaccination
  • combination therapy outcomes (in particular infliximab (and other TNFi), or thiopurines or methotrexate)
  • outcomes on JAK inhibitor therapies

March 2023 update

Since our last report, several reports of relevance inform this area. A report prepared for the UK Joint Committee on Vaccination and Immunisation identified risk factors for severe COVID-19 outcomes (that is, COVID-19-related hospitalisation or death) in individuals who had completed their primary COVID-19 vaccination schedule and had received the first booster vaccine. Older people, those with multimorbidity (which is high in IMIDs), and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalisation and death after the initial vaccine booster. Of the latter (which also included rare neurologic conditions and renal disease), specific mention is made of rheumatoid arthritis and SLE.[footnote 92]

In QCovid 4, rheumatoid arthritis and SLE were once again highlighted as associated with poorer outcomes for death and hospitalisation. In principle, poorer clinical outcomes could reflect impaired host defence as function of immune dysregulation a priori, or as a consequence of immune suppressive treatment. In both the Agrawal report and QCovid4 analyses, immune suppression alone predicted poorer clinical outcomes. We have focused our remarks therefore on therapeutics used in the IMID space. That said, general risk factors - for example, age - remain relevant to increased mortality and morbidity in the IMIDs and support the inclusion of this as a mitigating factor in decision-making called out in Box 1.

In inflammatory bowel disease, recent UK studies have added evidence addressing these issues.[footnote 93] Attenuated serological responses to second and third vaccine responses, together with increased breakthrough COVID-19 infections have been reported in patients on anti-TNF therapies with a correlation between neutralising antibody concentrations and time to reported breakthrough infection. The reduced serological responses to 3 doses, characterised as ‘vaccine escape’, were seen in patients on infliximab monotherapy, infliximab together with thiopurine therapy, and patients on thiopurine monotherapy, but not in patients on other biologics used in inflammatory bowel disease.

Of note, both serological as well as T-cell responses to vaccination were noted in patients on JAK-inhibition. Similar data exists for use of JAK inhibitors and TNF inhibitors for other conditions,[footnote 94] though in this data we do not yet have clear evidence of impaired clinical outcomes in consequence. It seems that in general there is reduced serological response upon anti-TNF and perhaps other biologic disease modifying therapeutics and also in recipients of JAK inhibitors. This may lead to higher rates of infection. However, it is not yet certain that this leads to more severe outcomes, including death. More data is required before the IAG can determine whether these agents should be called out specifically for prioritisation.

Poor outcomes in inflammatory myopathy are more likely in older patients, males, higher co-morbidity, higher disease activity and with immune suppressant therapy (prednisolone greater than 7.5mg) and rituximab.[footnote 95] Interrogation of the EULAR COVID-19 Registry of COVID-19 in CYP with rheumatic and musculoskeletal diseases (RMDs) showed that the majority of CYP were not hospitalised: consistent with the adult literature, people with severe systemic RMDs and obesity were more likely to be hospitalised.[footnote 96] An SLR used to inform the EULAR recommendations concerning risk and prognosis of SARS-CoV-2 infection in RMDs found that disease activity (potentially confounded by corticosteroid use), rituximab and possibly JAK inhibitors were associated with worse COVID-19 prognosis.[footnote 97]

The group has also now made specific consideration of the main risks for dermatology patients and highlight especially patients on rituximab (pemphigus vulgaris). Methotrexate is used for psoriasis and atopic dermatitis (AD) and azathioprine for AD (although the use is diminishing) but we consider the risks here as commensurate with that to use in rheumatology. The use of JAKs is increasing for AD and is starting for alopecia areata (AA) although this affects a younger population. We are unaware of increased risk for the use of biologic agents anti-IL-4/IL-13 - the AD COVID register was the main source for this comment, but predominantly comprises young patients and as such this may reflect low overall exposure. Omalizumab (anti-IgE) is used in urticaria but thus far we are unaware of enhanced risk.

At present these findings do not support the prioritisation for early treatment (and prophylaxis - see additional report) in patients on anti-TNF therapies or JAK inhibitors - physician discretion is however advised in this group and further research data are urgently required.

Primary and other acquired immune deficiencies

Primary immunodeficiency disorders

While patients with primary immunodeficiency disorders (PID) do have a higher case fatality rate with SARS-CoV-2 (31.6%; general population around 2.9%),[footnote 98] a substantial proportion of patients will experience mild disease.[footnote 99] In addition to increasing age and pre-infection lymphopenia, risk factors predisposing to severe disease in the general population are also applicable to this group. Patients with autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) and Good’s syndrome commonly have anti-type I interferon antibodies which are implicated in severe COVID-19. These risks are further compounded by the high likelihood of poor vaccine-induced immune responses.[footnote 100] Since these patients are also at greater risk of prolonged viraemia and the development of viral escape mutants,[footnote 101] there is clear justification for considering early treatment with monoclonal antibodies and/or oral antiviral agents in this group.[footnote 102] Prolonged infection with intra-host viral evolution otherwise poses significant risks for infection control and public health.[footnote 103]

Because of insufficient data it is not possible to produce a risk hierarchy for the various PID listed in Box 1 above. Patients with any of these disorders should be considered to be in the highest priority group.

Due to similarities in immunological risk, vaccine response and treatment response,[footnote 104] we also propose the inclusion of all patients with secondary immune deficiency requiring (or eligible for) immunoglobulin therapy, if not otherwise included in other disease cohorts.

March 2023 update

The following datasets on vaccination responses, the impact of vaccination on hospitalisation and mortality from COVID-19 and the outcome of community-based treatment in patients with primary immunodeficiency and secondary antibody deficiency have been added to the literature. The emerging data on the presence of antibodies to SARS-CoV-2 spike protein in therapeutic immunoglobulin should be taken into account in determining eligibility for pre-exposure prophylaxis. On balance, there is no new data which materially warrants a change in previous recommendations for community-based treatment of patients with primary immunodeficiency.

1. Vaccination responses and impact of vaccination on hospitalisation and mortality

Seroconversion following 2 doses of COVID vaccine (either mRNA-1273, BioNTech 162b2 or ChAdOx1) in patients with primary immunodeficiency disorders (PID) has ranged between 54.8% and 81%, with significant variations between individual disorders (common variable immunodeficiency 52.2% to 81%, x-linked agammaglobulinaemia (XLA) 0% to 15%). The presence of antibodies to SARS-CoV-2 spike protein in these patients correlated well with the presence of neutralising antibodies.[footnote 105]

T-cell responses following 2 doses of COVID vaccine were detected in 46.2% to 67% of patients with PID. While antibody responses were predictably absent in most patients (greater than 85%) with XLA, it was noteworthy that all patients developed a robust SARS-CoV-2 specific T-cell response.[footnote 106]

Data from the UK COV-AD consortium has shown a positive impact of COVID vaccination on reducing hospitalisation and mortality for patients with primary and secondary immunodeficiency. Compared with March to July 2020, hospitalisation rates (53.3% vs 17.9%) and mortality (20% vs 3.4%) have significantly fallen during the period January 2021 to April 2022, albeit while remaining elevated in comparison to the general population.[footnote 107]

2. Pre-exposure prophylaxis

With regard to considerations on pre-exposure prophylaxis, there is now well-validated evidence of the presence of significant concentrations of SARS-CoV-2 anti-spike antibody levels in most commercial preparation of polyclonal therapeutic immunoglobulin as a result of vaccination and natural infection in the donor plasma pool. These levels approach or exceed levels of antibodies present in convalescent plasma and hyperimmune globulin and exhibit NAbTs comparable to those found in healthy controls.[footnote 108]

3. Outcome of community-based treatment

Little data has been published on the response to community-based treatment in patients with primary immunodeficiency and secondary antibody deficiency. However, in a large real-world study of use of nirmaltrevir or ritonavir (4,737 treated patients), we note that the beneficial effect of drug treatment in reducing the cumulative end-point of severe COVID-19 or death was particularly evident for those with ‘immunosuppression’ (hazard ratio 0.29 vs 0.65 for those without immunosuppression).[footnote 109]

A pre-print reports that patients with antibody deficiency commonly remain PCR positive for greater than 28 days even after receiving treatment and that this is predicted by lower B cell counts, lower serum IgA concentration and lower serum IgM concentration.[footnote 110] However, no concerning viral mutations were identified (albeit only relatively few samples were available for this analysis) and patients generally made a clinical recovery.

High risk groups with HIV/AIDS

The risk of COVID-19 related hospitalisation or death for people living with HIV (PLWH) is thought to be increased although this may differ depending on their level of control of HIV. UK population cohort data has suggested an increased risk of death[footnote 111] and a US cohort study of over 16,000 PLWH identified an increased rate of hospitalisation and death from COVID-19 identifying CD4 less than 200, high viral load and associated other risk factors similar to general population including older age, diabetes, obesity and CKD.[footnote 112] QCOVID cohort data in UK indicates that despite vaccination, PLWH have an increased risk of hospitalisation or death although it did not differentiate between different risk factor.[footnote 113] However, other studies have suggested that PLWH with well-controlled HIV had no different risk of death compared to non-HIV patients.[footnote 114] There are data showing that vaccination in the 30 to 55 year age group is similar to general population although no data exists in older PLWH or patients with severe immunocompromise.[footnote 115]

Overall, it appears that patients with a CD4 less than 200 cells per mm3 and high VL (untreated or non-compliant treatment) or acutely presenting with an AIDS-defining diagnosis have the highest risks followed by patients with CD4 less than 350. There is currently no evidence that oral antivirals interact with antiretroviral medication (Liverpool COVID-19 Drug Interactions). While there is currently no data available on use of nMABs or oral antivirals, it is suggested that based on the above results, PLWH should be considered as high-risk patients.

Highest priority may be given if the level of immune suppression is high and if patients have uncontrolled or untreated HIV (high viral load) or present acutely with an AIDS defining diagnosis. Patients in that group may be considered for nMAB treatment. PLWH on treatment for HIV with CD4 less than 350 cells per mm3 and stable on HIV treatment or CD4 greater than 350 cells per mm3 and additional risk factors (for example, age, diabetes, obesity, cardiovascular, liver or renal disease, homeless, alcoholics) are in second risk category.

The advisory group considers that PLWH with stable HIV on treatment and CD4 greater than 350 cells per mm3 and no additional risk factors may not require to be in a high-risk group.

Neurological diseases: March 2023 update

In our prior report this was an area of potential risk and poor outcome that was being addressed by an NHSEI expert group. In this update we now offer specific and considerably revised advice on the basis of recent literature and comparability with the way in which other conditions were addressed. The previously named 4 disorders would appear rather arbitrary and could potentially exclude otherwise deserving diagnostic groups, though they had been previously derived for expediency from the COVID-19 Neutralising Monoclonal Antibodies Access and Policy National Expert Group. It should be recognised that none of the diagnoses themselves involves a primary immunodeficiency, but rather it is the complications of advanced or refractory disease in these, and also many other neurological conditions, that increases the risk from COVID infection.

In general, the evidence available around specific disorders is limited, but ‘dementia’ (and its principal causes) and ‘Parkinson’s disease’ are both highlighted specifically in QCovid4 and as such are now included in our guidelines. It is recognised that use in these settings would be part of a personalised care plan.

The broader category of a ‘primary neurological disorder’ mainly presents a risk on the basis of falling into one of 3 categories:

  1. Those neuromuscular disorders needing chronic ventilatory support - that is, NIV or tracheostomy. This applies to some cases of MND but also Duchenne MD and such conditions should be regarded as included in this recommendation as meritorious of treatment.

  2. Use of specific high-risk immunotherapies. Applies to some but not all cases of MS and myasthenia (MG) but also other rarer conditions such as neuromyelitis optica (NMO), refractory autoimmune encephalitis, and rare peripheral neuropathies. These can all be managed within the broader section on immune-mediate inflammatory disorders with the individual drugs - for example, rituximab, ocrelizumab as the gatekeeper, not the specific diagnosis.

  3. Dementias and other neurodegenerative disorders when associated with severe frailty, not because the conditions are inherently associated with immunocompromise.

Respiratory disease: March 2023 update

COVID-19 infection predominantly causes hospitalisation and/or death due to its effects on the lungs causing a viral pneumonitis or pneumonia. In some this will lead to respiratory failure. Patients with lung disease often have pre-existing reduced lung function and if they become infected with COVID-19 they are at a disadvantage from the onset.[footnote 116] Their impaired lung function means they are less able to tolerate the infection in the first place due to a lack of respiratory reserve. Their pre COVID-19 infection lung impairment can also lead to poor exercise tolerance meaning some would not be candidates for admission to an intensive therapy unit (ITU) and invasive ventilation. Both factors can lead to poorer outcomes post infection.

In addition, a number of respiratory diseases are treated with corticosteroids (short frequent bursts or long term) or other immunosuppressant drugs which are likely to impact any vaccine-driven immune protection. Personalised vaccine outcome data on many individual respiratory diseases is lacking, although some studies are pending or planned.

New data has emerged, however, in QCovid4 and other publications - for example, Agrawal and others, 2022 - highlighting several respiratory diseases as having poor outcomes even in vaccinated or partially vaccinated cohorts in the UK. This guidance, now updated, contains a respiratory disease-specific box reflecting the inherent risks respiratory patients face.

Specific subtypes of patients with airways disease - COPD[footnote 117] and asthma - have been added to the list of those eligible to access COVID-19 treatments. Those with the least respiratory reserve and those requiring either long term or frequent short courses of oral corticosteroids are most likely to have capacity to benefit. Use of oral corticosteroids, for any underlying disease, has consistently been shown to badly impact on outcomes after COVID-19 infection (see other disease sections).

Many forms of lung fibrosis or interstitial lung disease are considered eligible for COVID-19 treatments. Many require treatment with oral corticosteroids or other immunosuppressant drugs. In addition, patients with idiopathic pulmonary fibrosis are included, not due to drug induced immunosuppression per se but a combination of often significantly poor lung reserve, older age (with its associated likely immune senescence), and a high co-existing co-morbid rate of other higher risk (in a COVID-19 infection setting) diseases like diabetes and hypertension.[footnote 118]

Patients with pulmonary hypertension (PH) enter the mix of those considered at higher risk. These are patients who will have been seen and formerly diagnosed at one of the UK’s highly specialised PH centres and covers patients from groups 1 and 4 of the PH classification. Group 1 includes pulmonary arterial hypertension (PAH), heritable PH, PH due to drugs and toxins, and PH due to systemic diseases - for example, connective tissue diseases. Group 4 includes PH due to chronic blood clots in the lungs, also known as chronic thromboembolic PH or CTEPH. Their potentially increased risk of a poor outcome after a COVID-19 infection lies in their severely compromised cardiorespiratory status caused by their disease. All formerly diagnosed PH patients are in fact likely at risk, but other categories are broadly covered by other disease sections of this document.

Finally, it is clearly outlined in this new section that all patients who require long-term NIV, for any underlying disease, merit access to COVID-19 treatments. There is no COVID vaccine response data in this field but any patient needing NIV clearly has a very low respiratory reserve. They can often not get through one night without ventilatory support before they tip into type 2 respiratory failure. Adding a COVID-19 pneumonia will carry poor prognostic significance.

NIV is most commonly used to treat patients with genetic muscle diseases - for example, Duchenne muscular dystrophy, motor neurone disease, scoliosis, COPD, bronchiectasis and obesity hypoventilation syndrome. Neurological disorders requiring ventilatory support are already covered by the neurology section. Obese patients requiring NIV are particularly at risk not just due to their ventilatory compromise but also due to its underlying cause. In multiple COVID-19 datasets, obesity itself is a risk factor for a poor outcome if infected with COVID-19. Post-May 2022 Intensive Care National Audit and Research Centre (ICNARC) data showed, of critical care admitted patients, 35% and 12.4% had BMI of 30 to 40, and greater than 40, respectively. Of those intubated, 34.7% and 12.9% had BMI of 30 to 40, and greater than 40, respectively. It is not unreasonable to suspect that some of these patients had compromised ventilatory function before they contracted COVID-19.

In summary, this new addition of a respiratory disease section in this guideline reflects emerging data and provides clearer advice to clinicians of how to identify those with respiratory diseases suspected to be most at risk of a poor outcome after COVID-19 infection.

Recommendations for CYP older than 12 years and up to 17 years

Risks of hospitalisation or death from COVID are low compared to adults: 25 deaths in England March 2020 to February 2021 attributed to SARS-CoV-2 (estimated mortality of 2 per million for the 12,023,568 CYP living in England).[footnote 119] Evidence from more than 1,000 UK immunosuppressed CYP suggests very low rates of hospitalisation (4 in 1,022), no PICU admissions and no deaths.[footnote 120] Within this group, risk rises with age, with 15 to 17 year olds more at risk than 12 year olds. It is anticipated that few CYP will meet criteria for treatment in the community.

Studies of nMABs and/or antivirals have largely been in adults and there is minimal data to assess benefit of nMABs to those younger than 18 years old, even in symptomatic inpatients. Due to low numbers of severely unwell CYP, it is challenging to estimate the risks vs benefit, or number needed to treat to prevent one hospitalisation or death. Administration of an intravenous or subcutaneous drug to CYP in hospital brings its own burden and requires specialised paediatric teams. Nevertheless, equity of care for those deemed to be at risk is vital. For use of oral antivirals (molnupiravir or other) at present there is no published trial data including CYP, and no data on patients younger than 18 years old, so no policy can be proposed for oral antivirals in this age group.

March 2023 update

There have been no significant publications of datasets in children which would result in an update to the prior recommendation.

One large dataset in the USA identified similar risk factors to those which informed the previous recommendations for CYP. There are 2 small observational studies demonstrating safety of monoclonals against COVID in children. They are too small to comment on efficacy.

The first study retrospectively collected data on the use of sotrovimab, casirivimab/imdevimab and bamlanivimab in 53 children. Median patient age was 5.4 years (range 0 to 13.8, interquartile range = 6.2). In 36 patients, the reason for MAB treatment was the underlying condition, and in 8 patients, the reason was the disease severity, and in 5 patients both. Seven children required ITU, and there was one death. The treatments were well tolerated. The most frequently reported pre-existing conditions were:

  • immunodeficiency (49%)
  • malignancy (45%)
  • cardiac disease (21%)
  • hematologic disease (19%)
  • chronic lung disease (19%)
  • chronic liver disease (9%)
  • kidney disease (9%)
  • diabetes (2%)

All patients had at least one pre-existing condition, and all but 4 patients (8%) had multiple pre-existing conditions.

The second study retrospectively presented data on MAB use in 73 children between 24 days and 18 years of age. They included patients with:

  • BMI greater than or equal to the 95th percentile for age and gender
  • chronic renal failure, including hemodialysis or peritoneal dialysis
  • uncontrolled diabetes mellitus (HbA1c greater than 9% or 75 mmol/mol) or chronic complications
  • primary and secondary immunodeficiencies
  • hemoglobinopathies
  • cerebral vascular diseases (including high blood pressure with organ damage)
  • neurodevelopment and degenerative diseases
  • COPD or other respiratory chronic conditions (for example, asthma, pulmonary fibrosis or condition requiring oxygen therapy not for SARS-CoV-2)
  • chronic hepatopathy

They also included:

  • neonates and infants (age less than 1 year)
  • casirivimab and imdevimab
  • bamlanivimab plus etesevimab
  • sotrovimab

There were no significant adverse events, and all children survived.[footnote 121] Paxlovid can now be accessed on a per patient basis for post-pubescent adolescents in line with the Commissioning Medicines for Children policy.

Appendix 4: general approach retained from prior IAG report

The advisory group agreed to work towards ensuring consistency with the policies formed by the COVID-19 Neutralising Monoclonal Antibodies (nMABs) Access and Policy National Expert Group. That group had identified 10 clinical groups at risk, but at a general level. We re-examined the QCOVID risk stratification tool under the leadership of Professor Julia Hippisley-Cox as had been previously applied by that nMABs group.

The QCovid3 risk stratification tool is derived from a population-based cohort record linkage study that used primary care data to derive and validate risk prediction algorithms to estimate risk of COVID-19 mortality and hospitalisation in UK adults following one or 2 doses of COVID-19 vaccination.[footnote 122] In this respect it interrogated the population most relevant to our commissioned task. Critically, as this dataset had not altered in the interim it meant that our focus remained upon the prioritised groups set out below. This also ensured continuity with the prior advice received for policy setting.

In addition, the advisory group evaluated additional data from ISARIC Comprehensive Clinical Characterisation Consortium (ISARIC4C)) led by Professor Calum Semple. The advisory group accepted the principle previously established that once risk magnitude was established for a given (set of) conditions, consideration was given to clinical capacity to benefit from introduction of a nMAB, or of an antiviral.

We did not conduct a conventional systematic literature review due to limitations of time and resource, but nevertheless performed a thorough literature review of clinical and immunologic functional studies that informed the likelihood of vaccine efficacy in the distinct clinical subgroups.

The advisory group also sought data from cohort datasets in preparation - for example, renal datasets and haematologic datasets - to optimise the contemporaneous nature of our advices. This literature is cited within the detailed disease descriptions (Appendix 3 and footnotes).

The advisory group discussed in detail the potential for serology to support decision-making. There are currently reported population and observational studies defining the potential for levels of protection afforded by serology levels, and several pre and post-vaccine immunophenotyping studies in patient subgroups at special risk - for example, the MHRA-approved ongoing OCTAVE and OCTAVE-DUO studies, which might inform the use of such testing. The consensus, however, was that at present, no given level of antibody levels could correlate sufficiently with levels of protection for general clinical use. Given that the recommendations concerned those in the community in whom ready access to anti-SARS-CoV-2 serology was not available, the group elected to defer further consideration of the matter until more data was available and, potentially, clinical capacity to offer community serology monitoring.

The advisory group generated advice focused mainly on individuals aged 18 and over. Since many of our disease groups cross into younger cohorts, we co-opted paediatric expertise and offered indicative guidelines for individuals aged younger than 18 years old (12 to 17) shown in Box 2. We did not consider children under the age of 12 years. The advisory group was not tasked with estimating the separate impact of older age in addition to underlying conditions rendering individuals vulnerable, but recognises that this should be a factor in policy evaluation. The advisory group did not address the issue of pregnancy in the context of therapeutics or prophylaxis, except in relation to known contraindications during pregnancy.

Approach to the use of available data

The advisory group built recommendations on the QCovid3 risk stratification approach, with additional data derived from ISARIC and disease specific cohorts and studies as cited throughout this report.

Designated disease sub-groups (non-mutually exclusive) were formed to highlight the key rationale for prioritisation within a given disease setting, based on currently available data within and across disciplines as follows:

  • solid organ cancer
  • haematological diseases and recipients of haematological stem cell transplant (HSCT)
  • renal conditions
  • liver conditions
  • IMIDs
  • primary and acquired immune deficiencies

For the other rarer diseases, it was determined by consensus that further granularity by disease or condition was unlikely to afford significant quantitative impact on the use of either nMABs or antivirals. These conditions, including Down’s syndrome and other complex or chromosomal genetic disorders, sickle cell disease (ultimately included in haematologic recommendation) and select neurological disorders, were therefore included in the evaluation of consideration of optimal approach - namely, nMAB or antiviral - but were not further defined on the basis of risk category. Implicit in our consensus on recommending this reductive approach is our recognition of need for discretion by topic experts in the application of this guidance to the groups of patients for whom they care. As noted above, all of the disease-specific advice applies for those aged 18 years and older, while those 12 to 17 years inclusive in all of these groups were considered separately.

Considerations around CYP

The recommendations apply to individuals 18 years or older. In CYP aged less than 18 years old, the risks of hospitalisation or death from COVID are very low.[footnote 123] Therefore most ‘at risk’ CYP considered for treatment will not be within the same risk category relative to adults. To enable treatment for individual cases where needed and ensure access to care, we propose a specific approach for those less than 18 years old (Box 2). In PCR positive, symptomatic cases aged 12 years and older and less than 18 years, it is recommended clinicians should arrange an urgent MDT case discussion by referral to local paediatric infectious diseases service. Cases will be considered by the MDT using criteria shown in Box 2 which contains our key recommendations in this area of practice.

Nomenclature

Terminology remains problematic in this area - below is the nomenclature which we have applied, which is empiric but sensitive to the contemporary language being used in policy.

COVID-19

Disease caused by SARS-CoV-2 infection, disambiguated from long COVID, paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS) and multisystem inflammatory syndrome in children (MIS-C)

Severe COVID-19

Acute disease requiring admission to hospital with infection or high probability of SARS-CoV-2 infection and requiring support of any organ system, typically but not exclusively respiratory failure. The advisory group recognises that death alone does not recognise the impact of severe COVID-19 which can lead to a substantial burden of life-changing morbidity caused by the complications of acute severe COVID-19. However, much of the data available to inform this review only reports hospital admission or death as the outcome measure. We do not include long COVID in this definition. However, we did consider the risk of chronic or relapsing infection with persistent viral replication due to failure of immunological control, as seen in some forms of immunocompromise.

Highest risk clinical subgroups upon community infection

Identifiable groups of people (all ages) who in the community remain, for whatever reason, at the very highest risk of severe COVID-19, despite availability of COVID-19 vaccination.[footnote 124] We are aware that different advisory groups and policy teams have chosen to use a variety of phrases to indicate high risk groups as they relate to different policies. That said, our choice of phrase highest risk clinical subgroups is carefully chosen to indicate those who remain at the highest risk of severe COVID-19 (that is, the ultimate risk) despite full adherence with community-wide public health measures including vaccination.

Medication for treatment

A medicine given once features (symptoms or signs) of disease have been identified by an affected person or clinician, with the intent of modifying severity or reducing complications of that disease.

Medication for prophylaxis

A medication that is given to a person or group of people on the basis of known exposure or likelihood of exposure, with the intent of prevention or modification of disease. Prophylaxis is usually reserved for use where the consequence of infection for a person or group of people is likely to be severe, either because of particular susceptibility of the people, or the inherent nature of the infection. This is because the balance of risk-to-benefit for prophylaxis is different to treatment, as by chance some of the people who will receive medication will not go on to become infected or if infected will not experience severe disease, yet they risk experiencing side effects as a result of taking the medication.

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