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: independent advisory group report
Published 30 May 2022
An updated version of this report was published in March 2023: Higher-risk patients eligible for COVID-19 treatments: independent advisory group report (March 2023).
Introduction
At the request of the Deputy Chief Medical Officer (DCMO), an advisory group, supported by the NHS England RAPID-C19 team, 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-19 outcome, namely hospitalisation and death. The recommendations are to support the deployment of approved medications for treatment or prophylaxis, potentially across a range of scenarios, but the group was tasked to focus on those in the community with clinically proven COVID-19.
The advisory group sought to generate a list of conditions or cohorts of greatest risk of adverse outcome following COVID-19.
Our approach is described in detail below.
Briefly, we evaluated risk of poor outcome using QCOVID3 and ISARIC (International Severe Acute Respiratory Infection Consortium – Coronavirus Clinical Characterisation Consortium) data since these large population studies gave indicative risk groups based on community data relevant to our specific commission.
Next, we gathered an extensive literature of (mainly immunological) studies that examined the immunologic efficacy of vaccines in the context of either primary disease or therapeutics that might compromise immune competence. By this means we addressed:
- knowledge gaps
- lack of granularity when evaluating QCOVID3 and ISARIC datasets to determine who may be at greatest risk of hospitalisation and death despite vaccination
Finally, using primarily expert opinion in the absence of an adequate literature base, greatest capacity to benefit from a given therapeutic agent was considered.
The advisory group was formed under terms of reference contained in Appendix 1 and constituted a range of clinical academics with requisite expertise. To maximise continuity, some members had previously participated in the COVID-19 nMABs Access and Policy National Expert Group. Additional members were 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 continued to add members across a range of expertise, and in so doing we also sought to ensure interactivity with patient groups and charities in evolving our guidance, which included consideration of new data proposed by such groups. Thus, the report reflects input from across different areas allowing us to be responsive to a dynamic environment.
Methodology
Nomenclature
Terminology was problematic as we were asked to explore risk within groups already classified as clinically extremely vulnerable or overlapping with other defined cohorts such as for vaccination. Our report is therefore explanatory. Below is the nomenclature which was 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
For the purposes of this document, we mean those people whose immune system means they are at higher risk of serious illness from COVID-19.[footnote 1] 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.
General approach
The approach by the advisory group is described as follows:
- The advisory group agreed to work towards ensuring consistency with the policies formed by the COVID-19 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 1 or 2 doses of COVID-19 vaccination.[footnote 2] 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 Coronavirus Clinical Characterisation Consortium (ISARIC 4C) 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 an 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, haematologic datasets to optimise the contemporaneous nature of our advices. This literature is cited within the detailed disease descriptions (Appendix 3 and references).
- 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 Medicines and Healthcare products Regulatory Agency (MHRA)-approved ongoing OCTAVE and OCTAVE-DUO studies, that 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 less than 18 years old[footnote 3] shown in Figure 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
As noted above, 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 subgroups (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
- immune-mediated inflammatory diseases (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 rare 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 aged 12 to 17 years inclusive in all of these groups were considered separately.
Considerations around children and young people
The recommendations apply to individuals 18 years or older. In children and young people (CYP) aged less than 18 years old, the risks of hospitalisation or death from COVID are very low.[footnote 4] 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 (Figure 2). In PCR-positive, symptomatic cases aged 12 years and older and less than 18 years, it is recommended that clinicians should arrange an urgent multidisciplinary team (MDT) case discussion by referral to local paediatric infectious diseases service. Cases will be considered by the MDT using criteria shown in Figure 2, which contains our key recommendations in this area of practice.
Recommendations
The recommendation of the advisory group on the groups of patients of highest risk[footnote 5] is shown in Figure 1.
Figure 1: summary of key findings of the independent advisory group
Down’s syndrome and other genetic disorders
All individuals with Down’s syndrome or other chromosomal disorders known to affect immune competence (decision to treat to be at the discretion of the treating clinician).
Solid cancer
- metastatic or locally advanced inoperable cancer
- lung cancer (at any stage)
- people receiving any chemotherapy (including antibody-drug conjugates), PI3K inhibitors or radiotherapy[footnote 6] within 12 months
- people who have had cancer resected within 3 months[footnote 7] and who received no adjuvant chemotherapy or radiotherapy
- 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
Haematological diseases and recipients of haematological stem cell transplant (HSCT)
- allogeneic HSCT recipients in the last 12 months or active graft versus host disease (GVHD) regardless of time from transplant (including HSCT for non-malignant diseases)
- autologous HSCT recipients in the last 12 months (including HSCT for non-malignant diseases)
- individuals with haematological malignancies who have received CAR-T cell therapy in the last 24 months, or radiotherapy in the last 12 months
- individuals with haematological malignancies receiving systemic anti-cancer treatment (SACT) within the last 12 months
- all people who do not fit the criteria above, and are diagnosed with:
- myeloma (excluding monoclonal gammopathy of undetermined significance (MGUS))
- AL amyloidosis
- chronic B-cell lymphoproliferative disorders (chronic lymphocytic leukaemia, follicular lymphoma)
- myelodysplastic syndrome (MDS)
- chronic myelomonocytic leukaemia (CMML)
- myelofibrosis
- all people with sickle cell disease
- people with thalassaemia or rare inherited anaemia with any of the following (the decision to treat these patients will need to be at the individual patient level with input from the haematology consultant responsible for the management of the patient’s haematological condition):
- severe cardiac iron overload (T2 * less than 10ms on magnetic resonance imaging)
- severe to moderate iron overload (T2 * greater than or equal to 10ms on magnetic resonance imaging) plus an additional co-morbidity of concern (for example, diabetes, chronic liver disease or severe hepatic iron load on MRI)
- individuals with non-malignant haematological disorders (for example, aplastic anaemia or paroxysmal nocturnal haemoglobinuria) receiving B-cell depleting systemic treatment (for example, anti-CD20, anti-thymocyte globulin (ATG) and alemtuzumab) within the last 12 months
Renal disease
- renal transplant recipients (including those with failed transplants within the past 12 months), particularly those who have:
- received B cell depleting therapy within the past 12 months (including alemtuzumab, rituximab (anti-CD20), anti-thymocyte globulin)
- an additional substantial risk factor which would in isolation make them eligible for monoclonals or oral antivirals
- not been vaccinated prior to transplantation
- non-transplant renal patients who have received a comparable level of immunosuppression. Please refer to the section on ‘Immune-mediated inflammatory diseases’ below for a list of qualifying immunosuppressive therapies
- patients with chronic kidney disease (CKD) stage 4 or 5 (an eGFR less than 30ml per min per 1.73m2) without immunosuppression
Liver diseases
- people with cirrhosis Child-Pugh class A,B and C, whether receiving immune suppressive therapy or not. Those with decompensated liver disease (Child-Pugh B and C) are at greatest risk
- people with a liver transplant
- people with liver disease on immune suppressive therapy (including people with and without cirrhosis) – please refer to the section on ‘Immune-mediated inflammatory diseases’ below for a list of qualifying immunosuppressive therapies
Solid organ transplant recipients
Solid organ transplant recipients not in any of the above categories.
Immune-mediated inflammatory disorders
- people who have received a B-cell depleting therapy (anti-CD20 drug for example rituximab, ocrelizumab, ofatumab, obinutuzumab) in the last 12 months
- people who have been treated with cyclophosphamide (IV or oral) in the 6 months prior to positive PCR
- people who are on biologics[footnote 8] or small molecule JAK-inhibitors (except anti-CD20 depleting monoclonal antibodies) or who have received these therapies within the last 6 months
- people who are on corticosteroids (equivalent to greater than 10mg per day of prednisolone) for at least the 28 days prior to positive PCR
- people who are on current treatment with mycophenolate mofetil, oral tacrolimus, azathioprine/mercaptopurine (for major organ involvement such as kidney, liver and/or interstitial lung disease), methotrexate (for interstitial lung disease) and/or ciclosporin
- people who exhibit at least one of: (a) uncontrolled or clinically active disease (that is required recent increase in dose or initiation of new immunosuppressive drug or IM steroid injection or course of oral steroids within the 3 months prior to positive PCR); and/or (b) major organ involvement such as significant kidney, liver or lung inflammation or significantly impaired renal, liver and/or lung function)
Immune deficiencies
- common variable immunodeficiency (CVID)
- undefined primary antibody deficiency on immunoglobulin (or eligible for Ig)
- hyper-IgM syndromes
- Good’s syndrome (thymoma plus B-cell deficiency)
- severe combined immunodeficiency (SCID)
- autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome)
- primary immunodeficiency associated with impaired type 1 interferon signalling
- x-linked agammaglobulinaemia (and other primary agammaglobulinaemias)
- any person with secondary immunodeficiency receiving, or eligible for, immunoglobulin replacement therapy
HIV/AIDS
- people with high levels of immune suppression, have uncontrolled or untreated HIV (high viral load) or present acutely with an AIDS defining diagnosis
- people 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, alcoholic dependency)[footnote 9]
Rare neurological and severe complex life-limiting neurodisability conditions
An NHS England and Improvement (NHSEI) expert group has identified the key conditions are:
- multiple sclerosis[footnote 10]
- motor neurone disease
- myasthenia gravis
- Huntington’s disease
Figure 2: pathway for PCR-positive symptomatic cases aged older than 12 and younger than 18 years, greater than 40kg weight, and clinical concern
Non-hospitalised individuals in the 12 to 18 years of age range considered at high risk from COVID-19 and to be prioritised for consideration of treatment with neutralising monoclonal antibodies when symptomatic and SARS-CoV-2 PCR positive. Concerned clinicians should refer for regional MDT case discussion through local established pathways, who will confirm eligibility and consider risk benefit and whether to proceed with offer of treatment.
Children and young people at substantial risk
Complex life-limiting neurodisability with recurrent respiratory infections or compromise.
Children and young people at significant risk if 2 or more of these risk factors are present
Primary immunodeficiency:
- common variable immunodeficiency (CVID)
- primary antibody deficiency on immunoglobulin (or eligible for immunoglobulin replacement)
- hyper-IgM syndromes
- Good’s syndrome (thymoma plus B-cell deficiency)
- severe combined immunodeficiency (SCID)
- autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome)
- primary immunodeficiency associated with impaired type I interferon signalling
- x-linked agammaglobulinaemia (and other primary agammaglobulinaemias)
Secondary immunodeficiency:
- HIV CD4 count less than 200 cells per mm3
- solid organ transplant
- HSCT within 12 months, or with GVHD
- CAR-T therapy in last 24 months
- induction chemotherapy for acute lymphoblastic leukaemia (ALL), non-Hodgkin’s lymphoma, chemotherapy for acute myeloid leukaemia (AML), relapsed and/or refractory leukaemia or lymphoma
Immunosuppressive treatment:
- chemotherapy within the last 3 months
- cyclophosphamide within the last 3 months
- corticosteroids greater than 2mg per kg per day for 28 days in last 4 weeks
- B cell depleting treatment in the last 12 months
Other conditions:
- high BMI (greater than 95th centile)
- severe respiratory disease (for example, cystic fibrosis or bronchiectasis with FEV1 less than 60%)
- tracheostomy or long-term ventilation
- severe asthma (paediatric intensive care unit (PICU) admission in 12 months)
- neurodisability and/or neurodevelopmental disorders
- severe cardiac disease
- severe chronic kidney disease
- severe liver disease
- sickle cell disease or other severe haemoglobinopathy
- trisomy 21
- complex or chromosomal genetic or metabolic conditions associated with significant comorbidity
- multiple congenital anomalies associated with significant comorbidity
Appendix 1: terms of reference
This appendix sets out the 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 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 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 NHS England 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 independent advisory group 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 high-risk cohorts suitable for treatment with nMABs and oral antivirals:
-
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).
-
The group will review the National Institute for Health and Care Excellence (NICE) COVID-19 rapid guideline on managing COVID-19.
-
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.
-
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).
Appendix 2: membership of the advisory group
The members of the advisory group are:
-
Professor Iain McInnes (Chair), Vice Principal and Head of College, College of Medical, Veterinary and Life Sciences, University of Glasgow
-
Professor Carl Goodyear, Professor of Translational Immunology, University of Glasgow
-
Dr Rupert Beale, Immunologist and Clinical Nephrologist, Clinical Researcher at Crick Institute
-
Professor Julia Hippisley-Cox, Professor of Clinical Epidemiology and General Practice, Chair of COVID Risk Stratification Subgroup, New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG)
-
Professor Eleanor Barnes, Professor of Hepatology and Experimental Medicine Nuffield Department of Medicine, University of Oxford OUH Hospital NHS Trust
-
Dr David Lowe, Consultant Clinical Immunologist, Royal Free Hospital
-
Dr Siraj Misbah, Consultant Immunologist and Chair, Blood and Infection Programme of Care, NHS England
-
Dr Matthias Schmid, Consultant Physician and Head of Department Infection and Tropical Medicine, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Chair of Clinical Reference Group Infectious Diseases, NHS England
-
Professor Gavin Screaton, Head of Medical Sciences Division, University of Oxford
-
Professor Calum Semple, Professor of Child Health and Outbreak Medicine at University of Liverpool, Consultant Respiratory Paediatrician at Alder Hey Children’s Hospital. Chair CO-CIN (a SAGE subgroup), and NERVTAG member
-
Professor Martin Underwood, Professor of Primary Care Research Warwick Clinical Trials Unit, Warwick Medical School
-
Professor Lucy Wedderburn, Professor in Paediatric Rheumatology, University College London
-
Dr Elizabeth Whittaker, Honorary Clinical Senior Lecturer Faculty of Medicine, Department of Infectious Disease, Imperial College London
-
Professor Matthew Snape, Professor in Paediatrics and Vaccinology, Oxford Vaccine Group
-
Dr Thushan de Silva, Senior Clinical Lecturer and Honorary consultant Physician in Infectious Diseases, University of Sheffield
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Professor Paul Moss, Professor of Haematology, University of Birmingham
-
Dr Sean Lim, Associate Professor and Honorary Consultant in Haematological Oncology, University of Southampton
-
Professor Gary Middleton, Professor of Medical Oncology, University of Birmingham
-
Professor Emma Thomson, Professor in Infectious Diseases, University of Glasgow
-
Professor Jack Satsangi, Professor of Gastroenterology, University of Oxford
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Professor Anthony Kessel (supporting), Clinical Director National Clinical Policy, Specialised Commissioning NHSEI
-
Dr Dhivya Subramaniam (supporting), National Clinical Policy Lead, NHS England and NHS Improvement
Co-opted members
Co-opted members of the advisory group are:
-
Professor Stefan Siebert, University of Glasgow, Professor of Inflammation Medicine and Rheumatology
-
Professor Tariq Ahmed, University of Exeter, Consultant Gastroenterologist
-
Dr Nick Kennedy, University of Exeter, Consultant Gastroenterologist
-
Dr Nick Powell, Imperial College London, Consultant Gastroenterologist
-
Dr Paul Cockwell, University Hospital Birmingham, Consultant Physician
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Dr Charlie Tomson, North Bristol NHS Trust, Consultant Nephrologist
-
Dr Katie Vinen, King’s College Hospital NHS Foundation Trust, Consultant Nephrologist
-
Dr Michelle Willicombe, Imperial College Healthcare NHS Trust, Consultant Nephrologist
-
Dr Stephen McAdoo, Imperial College London, Consultant Nephrologist
-
Dr Laurie Tomlinson, London School of Hygiene and Tropical Medicine, Consultant Nephrologist
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Dr Edward Carr, The Francis Crick Institute, Post-doctoral Clinical Fellow
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Dr Tom Marjot, Oxford University NHS Trust, Clinical Fellow in Hepatology
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Dr Jane Collier, Oxford University NHS Trust, Consultant Hepatology
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Professor Kwee Yong, University College London Hospitals, Professor of Clinical Haematology
-
Professor Claire Harrison, Guy’s and St Thomas’ Hospital, Professor of Myeloproliferative Neoplasms
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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
-
Dr Josh Wright, Consultant Haematologist, Sheffield Teaching Hospitals NHS Foundation Trust; Lead Clinician North East and Yorkshire Haemoglobinopathy Coordinating Centre
-
Professor Carlo Palmieri, Professor of Translational Oncology and Medical Oncologist, Molecular and Clinical Cancer Medicine, University of Liverpool
Appendix 3: key evidence base 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 11]
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 12] 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 13] In patients with solid cancers, neutralising antibody titres were the same as age-matched non-cancer patients and this included antibodies against the delta variant.[footnote 14] 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 15] 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 antiviral 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 16] 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 17] This data strongly suggests that the presence of increasing levels of disease activity cumulatively increases 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 18]).
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 the 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. While data from more than 20,000 cancer patients hospitalised with COVID between March 2020 and August 2021 from the Clinical Information Network (CIN) and International Severe Acute Respiratory and Emerging Infections Consortium WHO Coronavirus Clinical Characterisation Consortium (ISARIC-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 19] 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; 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 20]
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.
Haematological diseases and recipients of haematological stem cell transplant
Allogeneic HSCT recipients in the last 12 months or active GVHD regardless of time from transplant (including HSCT for non-malignant diseases).
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 21] 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 22] Receipt of vaccines within the first 12 months following HSCT results in lower antibody titres,[footnote 23] both in autologous and allogeneic HSCT recipients.[footnote 24] Severe chronic graft versus host disease (GVHD) was also found to be a risk factor for poor humoral immunogenicity in allogeneic HSCT recipients,[footnote 25] in keeping with prior data on the higher risk of infection and poor immunogenicity of other vaccines in the context of GVHD.[footnote 26] Current guidance recommends commencing post-HSCT re-vaccination courses with SARS-CoV-2 vaccines as early as 2 to 3 months following transplant[footnote 27] 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 either received 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 28] with lack of immune reconstitution to vaccine preventable diseases.[footnote 29] 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 30]
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 1 and/or 2 doses of vaccinations. In particular:
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 31] Accordingly, the majority of patients have either an undetectable or markedly reduced antibody response when vaccinated within 12 months of anti-CD20 administration.[footnote 32] 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.
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 33] Limited data suggests improved antibody levels are observed early after BTK inhibitor, ibrutinib withdrawal.[footnote 34] 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 35]
Anti-CD38 monoclonal antibody or BMCA 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 around 80% of patients with myeloma and inferior responses are reported for patients on anti-CD38 and BCMA-targeted therapies in 2 large studies.[footnote 36]
Chemotherapy recipients
Patients with acute leukaemias and aggressive lymphomas have an increased risk of 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 37] 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 fivefold reduction in antibody level for patients vaccinated on treatment compared to those vaccinated more than a month after completion.[footnote 38]
Other SACT
Data describing the impact of other therapies on vaccination response in conditions such as the myeloproliferative neoplasms and myelodysplastic syndromes tend to comprise of smaller cohorts and can be conflicting.[footnote 39]
Individuals with chronic myeloid leukaemia (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 40] as also evidenced by experience in the CML community. However, they have not been specifically excluded for pragmatism.
All patients who do not fit the criteria above and are diagnosed with myeloma (excluding MGUS), AL amyloidosis, chronic B-cell lymphoproliferative disorders (for example, chronic lymphocytic leukaemia, follicular lymphoma) or myelodysplastic syndrome (MDS), or chronic myelomonocytic leukaemia, or myelofibrosis.
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 41] 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 42] 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 43] Similarly, poor vaccine responses have also observed in AL amyloidosis.[footnote 44]
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 45] 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 46]
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
- have 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 immune-mediated inflammatory diseases). 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 disease (CKD) stage 4 or 5 (an eGFR less than 30ml per min per 1.73m2) without immunosuppression are at high risk and should be considered for either neutralising monoclonals or oral antivirals. Although there is 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 47] 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:
- Bell and others, The impact of vaccination on incidence and outcomes of SARS-CoV-2 infection in patients with kidney failure in Scotland
- Describing the population experiencing COVID-19 vaccine breakthrough following second vaccination in England: a cohort study from OpenSAFELY
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 48]
The global burden of CLD is enormous, with cirrhosis affecting more than 122 million people worldwide, of whom 10 million have decompensated disease.[footnote 49] 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 50] 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 51] 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 52] This finding was confirmed in a larger international cohort using the SECURE-Cirrhosis and COVID-Hep registries where the odds ratio for death for NAFLD patients was 1.01 (95% CI 0.57 to 1.79)[footnote 53]). 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 54] 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 55] 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 56] 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 suggests that liver transplant patients are not at increased risk of severe COVID-19 mortality as compared to non liver transplant patients.[footnote 57] Case fatality rates are broadly consistent across cohort studies from the first wave of the pandemic at around 20%.[footnote 58]
Similarly, 2 independent cohorts of patients with autoimmune hepatitis on immune suppressive therapy have been shown not to be at increased of death, unless they also have CP B-C cirrhosis.[footnote 59] 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 60] Patients with CLD but without cirrhosis, and patients with NAFLD make robust immune responses to COVID-19 vaccines.[footnote 61] Together, this data suggests 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 2021) to indicate that molnupiravir is associated with liver toxicity. Patients with CLD, 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.
Immune-mediated inflammatory disorders
In the immune-mediated inflammatory diseases (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 62] 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 63] and other immune-mediated neurological disease such as multiple sclerosis.[footnote 64] Together, the available data on outcomes after infection in this patient group suggest that there are subgroups of patients (based on either disease state or treatment) at a higher risk of severe life-threatening COVID-19.[footnote 65] This data allows definition of subgroups that should be prioritised for either nMABs or oral antivirals upon confirmation of COVID-19 infection.[footnote 66]
We highlight the following priority groups:
- patients who have received a B cell depleting therapy (anti-CD20) within the last year[footnote 67]
- patients who are on or have received steroids within 28 days (10mg daily prednisolone equivalent or more, including budesonide)[footnote 68]
- patients treated with mycophenolate,[footnote 69] cyclophosphamide, cyclosporin, JAK inhibitors or tacrolimus
- patients with uncontrolled or unstable clinically active disease and/or flaring disease[footnote 70]
In defining active disease,[footnote 71] we suggest a pragmatic approach of including patients requiring escalation of systemic therapy as an outpatient 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 72] 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 73] However, evidence is at present lacking for correlation of these attenuated responses with either de novo breakthrough or recurrent COVID-19 infection.[footnote 74]
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
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 75] a substantial proportion of patients will experience mild disease.[footnote 76] 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 77] Since these patients are also at greater risk of prolonged viraemia and the development of viral escape mutants,[footnote 78] there is clear justification for considering early treatment with monoclonal antibodies and/or oral antiviral agents in this group.[footnote 79] Prolonged infection with intra-host viral evolution otherwise poses significant risks for infection control and public health.[footnote 80]
Because of insufficient data it is not possible to produce a risk hierarchy for the various PID listed in Figure 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 81] 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.
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 82] 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 83] QCOVID cohort data in the UK indicates that despite vaccination, PLWH have an increased risk of hospitalisation or death, although it did not differentiate between different risk factor.[footnote 84] However, other studies have suggested that PLWH with well-controlled HIV had no different risk of death compared to non-HIV patients.[footnote 85] There is 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 86]
Overall, it appears that patients with a CD4 less than 200 cells per mm3 and high viral load (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 the 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.
Recommendations for children and young people older than 12 years old and up to 17 years old
The evidence grade for this policy is all D. In the 12 to 18 year age group, 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 2 per million for the 12,023,568 CYP living in England).[footnote 87] 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 88] 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 the 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 sub-cutaneous 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.
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Egan C, Turtle L, Thorpe M, Harrison EM, Semple MG, Docherty AB, and others. Hospital admission for symptomatic COVID-19 and impact of vaccination: analysis of linked data from the Coronavirus Clinical Information Network and the National Immunisation Management Service. Anaesthesia. 2022. ↩
-
Hippisley-Cox J, Coupland CA, Mehta N, Keogh RH, Diaz-Ordaz K, Khunti K, and others. Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study. BMJ. 2021;374:n2244. ↩
-
Tomic S, Dokic J, Stevanovic D, Ilic N, Gruden-Movsesijan A, Dinic M, and others. Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients. Front Immunol. 2021;12:614599.
Reizine F, Lesouhaitier M, Gregoire M, Pinceaux K, Gacouin A, Maamar A, and others. SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage. J Clin Immunol. 2021;41(3):515-25.
Kuderer NM, Choueiri TK, Shah DP, Shyr Y, Rubinstein SM, Rivera DR, and others. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395(10241):1907-18.
Mariana Chavez-MacGregor XL, Hui Zhao, Paul Scheet, Sharon H Giordano Evaluation of COVID-19 Mortality and Adverse Outcomes in US Patients With or Without Cancer. JAMA Oncol. 2022.
Drake T PC, Turtle L, Harrison E, Docherty A, Greenhalf B, and others. LBA60 - Prospective data of >20,000 hospitalised patients with cancer and COVID-19 derived from the International Severe Acute Respiratory and emerging Infections Consortium WHO Coronavirus Clinical Characterisation Consortium: CCP-CANCER UK. Annals of Oncology. 2021.
Khoury E NS, Madsen W, Turtle L, Davies G, Palmieri C. Differences in Outcomes and Factors Associated With Mortality Among Patients With SARS-CoV- 2 Infection and Cancer Compared With Those Without Cancer: A Systematic Review and Meta-analysis. JAMA Network Open. In press. ↩ -
SAGE. ISARIC: Comparison of children and young people admitted with SARS-CoV-2 across the UK in the first and second pandemic waves – prospective multicentre observational cohort study, 9 September 2021. Paper prepared by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) for SAGE. 2021.
Smith C, Odd, D, Harwood, R and others. Deaths in children and young people in England after SARS-CoV-2 infection during the first pandemic year. Nat Med (2021).
Ward JL, Harwood R, Smith C and others. Risk factors for PICU admission and death among children and young people hospitalised with COVID-19 and PIMS-TS in England during the first pandemic year. Nat Med (2021). ↩ -
Particular clinical attention should be given in the presence of co-morbidities that confer risk of poorer outcomes and that may be more prevalent in the context of the listed categories and conditions. ↩
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Patients with thyroid cancer who have undergone radio-iodine ablation will be eligible for treatment. ↩
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Patients with basal cell carcinomas who have undergone local excision or topical treatment are not considered to be at sufficiently high risk to be eligible for treatment. ↩
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People on monotherapy with biologics as maintenance therapy in IMIDs (including anti-IL17A, anti- IL-6R, anti-BLyS, anti-TNF, anti-IL12/23, vedolizumab and abatacept) appear not be at significantly increased risk of severe COVID-19 on available evidence but may have variable responses to currently available vaccines; physician discretion is advised in the context of patients in receipt of combination immune modification. ↩
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The use of CD4 counts to assess eligibility for treatment applies only to those patients for whom CD4 counts are used to monitor for treatment compliance and/or levels of immune compromise. Where CD4 counts are not known, but concerns remain around potential immune compromise, discussion with the patient’s HIV team is advised. ↩
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Many of the immune modifying therapeutics used in MS are already covered in the other recommendations under the wider category of IMIDs to which the clinician is referred. ↩
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Clift AK, Coupland CAC, Keogh RH, Diaz-Ordaz K, Williamson E, Harrison EM, and others. Living risk prediction algorithm (QCOVID) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study. BMJ. 2020;371:m3731. ↩
-
Hippisley-Cox J, Coupland CA, Mehta N, Keogh RH, Diaz-Ordaz K, Khunti K, and others. Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study. BMJ. 2021;374:n2244. ↩
-
Oosting SF, van der Veldt AAM, GeurtsvanKessel CH, Fehrmann RSN, van Binnendijk RS, Dingemans AC, and others. mRNA-1273 COVID-19 vaccination in patients receiving chemotherapy, immunotherapy, or chemoimmunotherapy for solid tumours: a prospective, multicentre, non-inferiority trial. Lancet Oncol. 2021;22(12):1681-91. ↩
-
Shepherd PbS. Adaptive immunity to SARS-CoV-2 infection and vaccination in cancer patients: The CAPTURE study. Annals of Oncology 2021;32. ↩
-
Galvan-Pena S, Leon J, Chowdhary K, Michelson DA, Vijaykumar B, Yang L, and others. Profound Treg perturbations correlate with COVID-19 severity. Proc Natl Acad Sci U S A. 2021;118(37). ↩
-
Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485-98.
Agrati C, Sacchi A, Bordoni V, Cimini E, Notari S, Grassi G, and others. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ. 2020;27(11):3196-207.
Sacchi A, Grassi G, Bordoni V, Lorenzini P, Cimini E, Casetti R, and others. Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome. Cell Death Dis. 2020;11(10):921.
Tomic S, Dokic J, Stevanovic D, Ilic N, Gruden-Movsesijan A, Dinic M, and others. Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients. Front Immunol. 2021;12:614599.
Reizine F, Lesouhaitier M, Gregoire M, Pinceaux K, Gacouin A, Maamar A, and others. SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage. J Clin Immunol. 2021;41(3):515-25. ↩ -
Kuderer NM, Choueiri TK, Shah DP, Shyr Y, Rubinstein SM, Rivera DR, and others. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395(10241):1907-18. ↩
-
Mariana Chavez-MacGregor XL, Hui Zhao, Paul Scheet, Sharon H Giordano Evaluation of COVID-19 Mortality and Adverse Outcomes in US Patients With or Without Cancer. JAMA Oncol. 2022. ↩
-
Drake T PC, Turtle L, Harrison E, Docherty A, Greenhalf B, and others. LBA60 - Prospective data of >20,000 hospitalised patients with cancer and COVID-19 derived from the International Severe Acute Respiratory and emerging Infections Consortium WHO Coronavirus Clinical Characterisation Consortium: CCP-CANCER UK. Annals of Oncology. 2021. ↩
-
Khoury E NS, Madsen W, Turtle L, Davies G, Palmieri C. Differences in Outcomes and Factors Associated With Mortality Among Patients With SARS-CoV- 2 Infection and Cancer Compared With Those Without Cancer: A Systematic Review and Meta-analysis. JAMA Network Open. In press. ↩
-
Sharma A, Bhatt NS, St Martin A, Abid MB, Bloomquist J, Chemaly RF, and others. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8(3):e185-e93. ↩
-
Maneikis K, Sablauskas K, Ringeleviciute U, Vaitekenaite V, Cekauskiene R, Kryzauskaite L, and others. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8):e583-e92.
Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Chen P, and others. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine. 2021;74:103705. ↩ -
Maneikis K, Sablauskas K, Ringeleviciute U, Vaitekenaite V, Cekauskiene R, Kryzauskaite L, and others. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8):e583-e92.
Redjoul R, Le Bouter A, Beckerich F, Fourati S, Maury S. Antibody response after second BNT162b2 dose in allogeneic HSCT recipients. Lancet. 2021;398(10297):298-9. ↩ -
Maneikis K, Sablauskas K, Ringeleviciute U, Vaitekenaite V, Cekauskiene R, Kryzauskaite L, and others. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8):e583-e92. ↩
-
Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Chen P, and others. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine. 2021;74:103705. ↩
-
Cordonnier C, Einarsdottir S, Cesaro S, Di Blasi R, Mikulska M, Rieger C, and others. Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19(6):e200-e12. ↩
-
British Society of Blood and Marrow Transplantation and Cellular Therapy and COVID 2021.
European Society for Blood and Marrow Transplantation and COVID-19. 2021. ↩ -
Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, and others. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):449-59. ↩
-
Walti CS, Krantz EM, Maalouf J, Boonyaratanakornkit J, Keane-Candib J, Joncas-Schronce L, and others. Antibodies against vaccine-preventable infections after CAR-T cell therapy for B cell malignancies. JCI Insight. 2021;6(11). ↩
-
Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Chen P, and others. Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine. 2021;74:103705.
Dhakal B, Abedin S, Fenske T, Chhabra S, Ledeboer N, Hari P, and others. Response to SARS-CoV-2 vaccination in patients after hematopoietic cell transplantation and CAR T-cell therapy. Blood. 2021;138(14):1278-81.
Ram R, Hagin D, Kikozashvilli N, Freund T, Amit O, Bar-On Y, and others. Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study. Transplant Cell Ther. 2021;27(9):788-94. ↩ -
Anolik JH, Friedberg JW, Zheng B, Barnard J, Owen T, Cushing E, and others. B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny. Clin Immunol. 2007;122(2):139-45. ↩
-
Maneikis K, Sablauskas K, Ringeleviciute U, Vaitekenaite V, Cekauskiene R, Kryzauskaite L, and others. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8):e583-e92.
Herishanu Y, Avivi I, Aharon A, Shefer G, Levi S, Bronstein Y, and others. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165-73.
Lim SH, Campbell N, Johnson M, Joseph-Pietras D, Collins GP, O’Callaghan A, and others. Antibody responses after SARS-CoV-2 vaccination in patients with lymphoma. Lancet Haematol. 2021;8(8):e542-e4. ↩ -
Maneikis K, Sablauskas K, Ringeleviciute U, Vaitekenaite V, Cekauskiene R, Kryzauskaite L, and others. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8):e583-e92.
Herishanu Y, Avivi I, Aharon A, Shefer G, Levi S, Bronstein Y, and others. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165-73.
Lim SH, Campbell N, Johnson M, Joseph-Pietras D, Collins GP, O’Callaghan A, and others. Antibody responses after SARS-CoV-2 vaccination in patients with lymphoma. Lancet Haematol. 2021;8(8):e542-e4.
Parry H, McIlroy G, Bruton R, Ali M, Stephens C, Damery S, and others. Antibody responses after first and second COVID-19 vaccination in patients with chronic lymphocytic leukaemia. Blood Cancer J. 2021;11(7):136. ↩ -
Lim SH, Campbell N, Johnson M, Joseph-Pietras D, Collins GP, O’Callaghan A, and others. Antibody responses after SARS-CoV-2 vaccination in patients with lymphoma. Lancet Haematol. 2021;8(8):e542-e4. ↩
-
Dave N, Gopalakrishnan S, Mensing S, Salem AH. Model-Informed Dosing of Venetoclax in Healthy Subjects: An Exposure-Response Analysis. Clin Transl Sci. 2019;12(6):625-32. ↩
-
Van Oekelen O, Gleason CR, Agte S, Srivastava K, Beach KF, Aleman A, and others. Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma. Cancer Cell. 2021;39(8):1028-30.
Ramasamy K, Sadler R, Jeans S, Weeden P, Varghese S, Turner A, and others. Immune response to COVID-19 vaccination is attenuated by poor disease control and antimyeloma therapy with vaccine driven divergent T-cell response. Br J Haematol. 2022. ↩ -
Passamonti F, Cattaneo C, Arcaini L, Bruna R, Cavo M, Merli F, and others. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol. 2020;7(10):e737-e45. ↩
-
Lim SH, Campbell N, Johnson M, Joseph-Pietras D, Collins GP, O’Callaghan A, and others. Antibody responses after SARS-CoV-2 vaccination in patients with lymphoma. Lancet Haematol. 2021;8(8):e542-e4.
Lim Shea. Immune responses against SARS-CoV-2 variants after two and three doses of vaccine in B-cell malignancies: UK PROSECO study (In press). Nat Cancer. 2022. ↩ -
Maneikis K, Sablauskas K, Ringeleviciute U, Vaitekenaite V, Cekauskiene R, Kryzauskaite L, and others. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021;8(8):e583-e92.
Cattaneo D, Bucelli C, Cavallaro F, Consonni D, Iurlo A. Impact of diagnosis and treatment on response to COVID-19 vaccine in patients with BCR-ABL1-negative myeloproliferative neoplasms. A single-center experience. Blood Cancer J. 2021;11(11):185.
Pimpinelli F, Marchesi F, Piaggio G, Giannarelli D, Papa E, Falcucci P, and others. Lower response to BNT162b2 vaccine in patients with myelofibrosis compared to polycythemia vera and essential thrombocythemia. J Hematol Oncol. 2021;14(1):119. ↩ -
Claudiani S, Apperley JF, Parker EL, Marchesin F, Katsanovskaja K, Palanicawandar R, and others. Durable humoral responses after the second anti-SARS-CoV-2 vaccine dose in chronic myeloid leukaemia patients on tyrosine kinase inhibitors. Br J Haematol. 2021. ↩
-
Passamonti F, Cattaneo C, Arcaini L, Bruna R, Cavo M, Merli F, and others. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol. 2020;7(10):e737-e45. ↩
-
Lim SH, Campbell N, Johnson M, Joseph-Pietras D, Collins GP, O’Callaghan A, and others. Antibody responses after SARS-CoV-2 vaccination in patients with lymphoma. Lancet Haematol. 2021;8(8):e542-e4.
Parry H, McIlroy G, Bruton R, Ali M, Stephens C, Damery S, and others. Antibody responses after first and second COVID-19 vaccination in patients with chronic lymphocytic leukaemia. Blood Cancer J. 2021;11(7):136. ↩ -
Lim Shea. Immune responses against SARS-CoV-2 variants after two and three doses of vaccine in B-cell malignancies: UK PROSECO study (In press). Nat Cancer. 2022. ↩
-
Liebers N, Schonland SO, Speer C, Edelmann D, Schnitzler P, Krausslich HG, and others. Seroconversion Rates After the Second COVID-19 Vaccination in Patients With Systemic Light Chain (AL) amyloidosis. Hemasphere. 2022;6(3):e688. ↩
-
Pimpinelli F, Marchesi F, Piaggio G, Giannarelli D, Papa E, Falcucci P, and others. Lower response to BNT162b2 vaccine in patients with myelofibrosis compared to polycythemia vera and essential thrombocythemia. J Hematol Oncol. 2021;14(1):119.
Chowdhury O, Bruguier H, Mallett G, Sousos N, Crozier K, Allman C, and others. Impaired antibody response to COVID-19 vaccination in patients with chronic myeloid neoplasms. Br J Haematol. 2021;194(6):1010-5. ↩ -
Pagano L, Salmanton-Garcia J, Marchesi F, Busca A, Corradini P, Hoenigl M, and others. COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA). J Hematol Oncol. 2021;14(1):168. ↩
-
Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut N, and others. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2. Antimicrob Agents Chemother. 2021. ↩
-
Mallet V, Beeker N, Bouam S, Sogni P, Pol S, Demosthenes research g. Prognosis of French COVID-19 patients with chronic liver disease: A national retrospective cohort study for 2020. J Hepatol. 2021;75(4):848-55. ↩
-
Collaborators GBDC. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3):245-66. ↩
-
Lavarone M, D’Ambrosio R, Soria A, Triolo M, Pugliese N, Del Poggio P, and others. High rates of 30-day mortality in patients with cirrhosis and COVID-19. J Hepatol. 2020;73(5):1063-71.
Marjot T, Moon AM, Cook JA, Abd-Elsalam S, Aloman C, Armstrong MJ, and others. Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study. J Hepatol. 2021;74(3):567-77. ↩ -
Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, and others. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11-20. ↩
-
Lopez-Mendez I, Aquino-Matus J, Gall SM, Prieto-Nava JD, Juarez-Hernandez E, Uribe M, and others. Association of liver steatosis and fibrosis with clinical outcomes in patients with SARS-CoV-2 infection (COVID-19). Ann Hepatol. 2021;20:100271. ↩
-
Marjot T, Moon AM, Cook JA, Abd-Elsalam S, Aloman C, Armstrong MJ, and others. Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study. J Hepatol. 2021;74(3):567-77. ↩
-
Marjot T, Moon AM, Cook JA, Abd-Elsalam S, Aloman C, Armstrong MJ, and others. Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study. J Hepatol. 2021;74(3):567-77. ↩
-
Mallet V, Beeker N, Bouam S, Sogni P, Pol S, Demosthenes research g. Prognosis of French COVID-19 patients with chronic liver disease: A national retrospective cohort study for 2020. J Hepatol. 2021;75(4):848-55. ↩
-
Hippisley-Cox J, Coupland CA, Mehta N, Keogh RH, Diaz-Ordaz K, Khunti K, and others. Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study. BMJ. 2021;374:n2244.
Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, and others. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430-6. ↩ -
Colmenero J, Rodriguez-Peralvarez M, Salcedo M, Arias-Milla A, Munoz-Serrano A, Graus J, and others. Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients. J Hepatol. 2021;74(1):148-55.
Webb GJ, Marjot T, Cook JA, Aloman C, Armstrong MJ, Brenner EJ, and others. Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study. Lancet Gastroenterol Hepatol. 2020;5(11):1008-16. ↩ -
Colmenero J, Rodriguez-Peralvarez M, Salcedo M, Arias-Milla A, Munoz-Serrano A, Graus J, and others. Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients. J Hepatol. 2021;74(1):148-55.
Ravanan R, Callaghan CJ, Mumford L, Ushiro-Lumb I, Thorburn D, Casey J, and others. SARS-CoV-2 infection and early mortality of waitlisted and solid organ transplant recipients in England: A national cohort study. Am J Transplant. 2020;20(11):3008-18. ↩ -
Marjot T, Buescher G, Sebode M, Barnes E, Barritt ASt, Armstrong MJ, and others. SARS-CoV-2 infection in patients with autoimmune hepatitis. J Hepatol. 2021;74(6):1335-43. ↩
-
Boyarsky BJ, Werbel WA, Avery RK, Tobian AAR, Massie AB, Segev DL, and others. Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA. 2021;325(21):2204-6.
Rabinowich L, Grupper A, Baruch R, Ben-Yehoyada M, Halperin T, Turner D, and others. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients. J Hepatol. 2021;75(2):435-8. ↩ -
Wang J, Hou Z, Liu J, Gu Y, Wu Y, Chen Z, and others. Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study. J Hepatol. 2021;75(2):439-41. ↩
-
MacKenna Bea. Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune modifying therapies: a nationwide cohort study in the OpenSAFELY platform. 2021(medRxiv). ↩
-
Bjornsson AH, Grondal G, Kristjansson M, Jonsdottir T, Love TJ, Gudbjornsson B, and others. Prevalence, admission rates and hypoxia due to COVID-19 in patients with rheumatic disorders treated with targeted synthetic or biologic disease modifying antirheumatic drugs or methotrexate: a nationwide study from Iceland. Ann Rheum Dis. 2021;80(5):671-2.
Blanch-Rubio J, Soldevila-Domenech N, Tio L, Llorente-Onaindia J, Ciria-Recasens M, Polino L, and others. Influence of anti-osteoporosis treatments on the incidence of COVID-19 in patients with non-inflammatory rheumatic conditions. Aging (Albany NY). 2020;12(20):19923-37.
Michelena X, Borrell H, Lopez-Corbeto M, Lopez-Lasanta M, Moreno E, Pascual-Pastor M, and others. Incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs. Semin Arthritis Rheum. 2020;50(4):564-70.
Bower H, Frisell T, Di Giuseppe D, Delcoigne B, Ahlenius GM, Baecklund E, and others. Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population: a nationwide Swedish cohort study. Ann Rheum Dis. 2021. ↩ -
Middleton RM, Craig EM, Rodgers WJ, Tuite-Dalton K, Garjani A, Evangelou N, and others. COVID-19 in Multiple Sclerosis: Clinically reported outcomes from the UK Multiple Sclerosis Register. Mult Scler Relat Disord. 2021;56:103317. ↩
-
Andersen KM, Bates BA, Rashidi ES, Olex AL, Mannon RB, Patel RC, and others. Long-term use of immunosuppressive medicines and in-hospital COVID-19 outcomes: a retrospective cohort study using data from the National COVID Cohort Collaborative. Lancet Rheumatol. 2022;4(1):e33-e41.
Izadi Z, Brenner EJ, Mahil SK, Dand N, Yiu ZZN, Yates M, and others. Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19. JAMA Netw Open. 2021;4(10):e2129639. ↩ -
Bower H, Frisell T, Di Giuseppe D, Delcoigne B, Ahlenius GM, Baecklund E, and others. Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population: a nationwide Swedish cohort study. Ann Rheum Dis. 2021.
Izadi Z, Brenner EJ, Mahil SK, Dand N, Yiu ZZN, Yates M, and others. Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19. JAMA Netw Open. 2021;4(10):e2129639.
Mandl P, Tobudic S, Haslacher H, Karonitsch T, Mrak D, Nothnagl T, and others. Response to SARS-CoV-2 vaccination in systemic autoimmune rheumatic disease depends on immunosuppressive regimen: a matched, prospective cohort study. Ann Rheum Dis. 2022.
Mrak D, Tobudic S, Koblischke M, Graninger M, Radner H, Sieghart D, and others. SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity. Ann Rheum Dis. 2021;80(10):1345-50.
Bonelli MM, Mrak D, Perkmann T, Haslacher H, Aletaha D. SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response. Ann Rheum Dis. 2021;80(10):1355-6.
Simader E, Tobudic S, Mandl P, Haslacher H, Perkmann T, Nothnagl T, and others. Importance of the second SARS-CoV-2 vaccination dose for achieving serological response in patients with rheumatoid arthritis and seronegative spondyloarthritis. Ann Rheum Dis. 2022;81(3):416-21.
Bonelli M, Mrak D, Tobudic S, Sieghart D, Koblischke M, Mandl P, and others. Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: a randomised controlled trial. Ann Rheum Dis. 2022.
Landewe RB, Machado PM, Kroon F, Bijlsma HW, Burmester GR, Carmona L, and others. EULAR provisional recommendations for the management of rheumatic and musculoskeletal diseases in the context of SARS-CoV-2. Ann Rheum Dis. 2020;79(7):851-8.
Kroon FPB, Najm A, Alunno A, Schoones JW, Landewe RBM, Machado PM, and others. Risk and prognosis of SARS-CoV-2 infection and vaccination against SARS-CoV-2 in rheumatic and musculoskeletal diseases: a systematic literature review to inform EULAR recommendations. Ann Rheum Dis. 2022;81(3):422-32.
Hasseli R, Mueller-Ladner U, Hoyer BF, Krause A, Lorenz HM, Pfeil A, and others. Older age, comorbidity, glucocorticoid use and disease activity are risk factors for COVID-19 hospitalisation in patients with inflammatory rheumatic and musculoskeletal diseases. RMD Open. 2021;7(1).
Regierer AC, Hasseli R, Schafer M, Hoyer BF, Krause A, Lorenz HM, and others. TNFi is associated with positive outcome, but JAKi and rituximab are associated with negative outcome of SARS-CoV-2 infection in patients with RMD. RMD Open. 2021;7(3).
Gianfrancesco M, Hyrich KL, Al-Adely S, Carmona L, Danila MI, Gossec L, and others. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020;79(7):859-66.
Strangfeld A, Schafer M, Gianfrancesco MA, Lawson-Tovey S, Liew JW, Ljung L, and others. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2021;80(7):930-42.
Sparks JA, Wallace ZS, Seet AM, Gianfrancesco MA, Izadi Z, Hyrich KL, and others. Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry. Ann Rheum Dis. 2021;80(9):1137-46.
Briggs FBS, Gianfrancesco MA, George MF. More on Covid-19 in Immune-Mediated Inflammatory Diseases. N Engl J Med. 2020;383(8):796-7.
Sattui SE, Conway R, Putman MS, Seet AM, Gianfrancesco MA, Beins K, and others. Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study. Lancet Rheumatol. 2021;3(12):e855-e64.
Ugarte-Gil MF, Alarcon GS, Izadi Z, Duarte-Garcia A, Reategui-Sokolova C, Clarke AE, and others. Characteristics associated with poor COVID-19 outcomes in individuals with systemic lupus erythematosus: data from the COVID-19 Global Rheumatology Alliance. Ann Rheum Dis. 2022. ↩ -
Avouac J, Drumez E, Hachulla E, Seror R, Georgin-Lavialle S, El Mahou S, and others. COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study. Lancet Rheumatol. 2021;3(6):e419-e26. ↩
-
Strangfeld A, Schafer M, Gianfrancesco MA, Lawson-Tovey S, Liew JW, Ljung L, and others. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2021;80(7):930-42. ↩
-
Consortium FRSSSCI, contributors. Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients. Ann Rheum Dis. 2020. ↩
-
Strangfeld A, Schafer M, Gianfrancesco MA, Lawson-Tovey S, Liew JW, Ljung L, and others. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2021;80(7):930-42.
Al. U-Ge. OP0286. Characteristics associated with severe COVID-19 outcomes in Systemic Lupus Erythematosus (SLE): results from the COVID-19 Global Rheumatology Alliance (COVID-19 GRA). BMJ. 2021. ↩ -
Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, and others. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. 2020;370:m3249. ↩
-
MacKenna Bea. Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune modifying therapies: a nationwide cohort study in the OpenSAFELY platform. 2021(medRxiv).
Ungaro RC, Brenner EJ, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, and others. Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut. 2021;70(4):725-32.
Ungaro RC, Brenner EJ, Agrawal M, Zhang X, Kappelman MD, Colombel JF, and others. Impact of Medications on COVID-19 Outcomes in Inflammatory Bowel Disease: Analysis of More Than 6000 Patients From an International Registry. Gastroenterology. 2022;162(1):316-9 e5. ↩ -
Bonelli MM, Mrak D, Perkmann T, Haslacher H, Aletaha D. SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response. Ann Rheum Dis. 2021;80(10):1355-6.
Chiang TP, Connolly CM, Ruddy JA, Boyarsky BJ, Alejo JL, Werbel WA, and others. Antibody response to the Janssen/Johnson & Johnson SARS-CoV-2 vaccine in patients with rheumatic and musculoskeletal diseases. Ann Rheum Dis. 2021;80(10):1365-6.
Connolly CM, Chiang TP, Boyarsky BJ, Ruddy JA, Teles M, Alejo JL, and others. Temporary hold of mycophenolate augments humoral response to SARS-CoV-2 vaccination in patients with rheumatic and musculoskeletal diseases: a case series. Ann Rheum Dis. 2022;81(2):293-5.
Ammitzboll C, Bartels LE, Bogh Andersen J, Risbol Vils S, Elbaek Mistegard C, Dahl Johannsen A, and others. Impaired Antibody Response to the BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine in Patients With Systemic Lupus Erythematosus and Rheumatoid Arthritis. ACR Open Rheumatol. 2021;3(9):622-8.
Boekel L, Steenhuis M, Hooijberg F, Besten YR, van Kempen ZLE, Kummer LY, and others. Antibody development after COVID-19 vaccination in patients with autoimmune diseases in the Netherlands: a substudy of data from two prospective cohort studies. Lancet Rheumatol. 2021;3(11):e778-e88.
Medeiros-Ribeiro AC, Aikawa NE, Saad CGS, Yuki EFN, Pedrosa T, Fusco SRG, and others. Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: a phase 4 trial. Nat Med. 2021;27(10):1744-51.
Benucci M, Damiani A, Infantino M, Manfredi M, Grossi V, Lari B, and others. Presence of specific T cell response after SARS-CoV-2 vaccination in rheumatoid arthritis patients receiving rituximab. Immunol Res. 2021;69(4):309-11.
Simeng Lin NAK, Aamir Saifuddin and others. Preprint. COVID-19 vaccine-induced antibodies are attenuated and decay rapidly in infliximab treated patients. Research Square. 2021.
Chapman TP, Reves J, Torres J, Satsangi J. Anti-SARS-CoV-2 Antibody Responses in Patients With IBD Treated With Biologics: Are We Finding CLARITY? Gastroenterology. 2021;161(6):2057-9.
Kennedy NA, Goodhand JR, Bewshea C, Nice R, Chee D, Lin S, and others. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut. 2021;70(5):865-75.
Sakuraba A, Luna A, Micic D. Serologic Response to Coronavirus Disease 2019 (COVID-19) Vaccination in Patients With Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-analysis. Gastroenterology. 2022;162(1):88-108 e9.
Krasselt M, Wagner U, Nguyen P, Pietsch C, Boldt A, Baerwald C, and others. Humoral and Cellular Response to COVID-19 Vaccination in Patients with Autoimmune Inflammatory Rheumatic Diseases under Real-life Conditions. Rheumatology (Oxford). 2022.
Schreiber K, Graversgaard C, Petersen R, Jakobsen H, Bojesen AB, Krogh NS, and others. Reduced Humoral Response of SARS-CoV-2 Antibodies following Vaccination in Patients with Inflammatory Rheumatic Diseases-An Interim Report from a Danish Prospective Cohort Study. Vaccines (Basel). 2021;10(1).
Bugatti S, De Stefano L, Balduzzi S, Greco MI, Luvaro T, Cassaniti I, and others. Methotrexate and glucocorticoids, but not anticytokine therapy, impair the immunogenicity of a single dose of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic inflammatory arthritis. Ann Rheum Dis. 2021;80(12):1635-8.
Sieiro Santos C, Calleja Antolin S, Moriano Morales C, Garcia Herrero J, Diez Alvarez E, Ramos Ortega F, and others. Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases. RMD Open. 2022;8(1).
Lin S, Kennedy NA, Saifuddin A, Sandoval DM, Reynolds CJ, Seoane RC, and others. Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab. Nat Commun. 2022;13(1):1379.
Jena A, Mishra S, Deepak P, Kumar MP, Sharma A, Patel YI, and others. Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: Systematic review and meta-analysis. Autoimmun Rev. 2022;21(1):102927. ↩ -
Papagoras C, Fragoulis GE, Zioga N, Simopoulou T, Deftereou K, Kalavri E, and others. Better outcomes of COVID-19 in vaccinated compared to unvaccinated patients with systemic rheumatic diseases. Ann Rheum Dis. 2021. ↩
-
Shields AM, Burns SO, Savic S, Richter AG, Consortium UPC-. COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience. J Allergy Clin Immunol. 2021;147(3):870-5 e1. ↩
-
Egan C, Turtle L, Thorpe M, Harrison EM, Semple MG, Docherty AB, and others. Hospital admission for symptomatic COVID-19 and impact of vaccination: analysis of linked data from the Coronavirus Clinical Information Network and the National Immunisation Management Service. Anaesthesia. 2022.
SAGE. ISARIC: Comparison of children and young people admitted with SARS-CoV-2 across the UK in the first and second pandemic waves – prospective multicentre observational cohort study, 9 September 2021. Paper prepared by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) for SAGE. 2021.
Quinti I, Lougaris V, Milito C, Cinetto F, Pecoraro A, Mezzaroma I, and others. A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia. J Allergy Clin Immunol. 2020;146(1):211-3 e4.
Meyts I, Bucciol G, Quinti I, Neven B, Fischer A, Seoane E, and others. Coronavirus disease 2019 in patients with inborn errors of immunity: An international study. J Allergy Clin Immunol. 2021;147(2):520-31. ↩ -
Delmonte OM, Bergerson JRE, Burbelo PD, Durkee-Shock JR, Dobbs K, Bosticardo M, and others. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity. J Allergy Clin Immunol. 2021;148(5):1192-7.
Hagin D, Freund T, Navon M, Halperin T, Adir D, Marom R, and others. Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity. J Allergy Clin Immunol. 2021;148(3):739-49.
Abo-Helo N, Muhammad E, Ghaben-Amara S, Panasoff J, Cohen S. Specific antibody response of patients with common variable immunodeficiency to BNT162b2 coronavirus disease 2019 vaccination. Ann Allergy Asthma Immunol. 2021;127(4):501-3.
Shields AMea. SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings From The COV-AD Study. (Preprint) Journal of Clinical Immunology.
Brown LK, Moran E, Goodman A, Baxendale H, Bermingham W, Buckland M, and others. Treatment of chronic or relapsing COVID-19 in immunodeficiency. J Allergy Clin Immunol. 2022;149(2):557-61 e1. ↩ -
Kemp SA, Collier DA, Datir RP, Ferreira I, Gayed S, Jahun A, and others. SARS-CoV-2 evolution during treatment of chronic infection. Nature. 2021;592(7853):277-82. ↩
-
Brown LK, Moran E, Goodman A, Baxendale H, Bermingham W, Buckland M, and others. Treatment of chronic or relapsing COVID-19 in immunodeficiency. J Allergy Clin Immunol. 2022;149(2):557-61 e1.
Malsy J, Veletzky L, Heide J, Hennigs A, Gil-Ibanez I, Stein A, and others. Sustained Response After Remdesivir and Convalescent Plasma Therapy in a B-Cell-Depleted Patient With Protracted Coronavirus Disease 2019 (COVID-19). Clin Infect Dis. 2021;73(11):e4020-e4. ↩ -
Kemp SA, Collier DA, Datir RP, Ferreira I, Gayed S, Jahun A, and others. SARS-CoV-2 evolution during treatment of chronic infection. Nature. 2021;592(7853):277-82.
Choi B, Choudhary MC, Regan J, Sparks JA, Padera RF, Qiu X, and others. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med. 2020;383(23):2291-3.
Rambaut A LN, Pybus O, Barclay W, Barrett J, Carabelli A, and others. Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. 2021. ↩ -
Shields AMea. SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings From The COV-AD Study. (Preprint) Journal of Clinical Immunology.
Brown LK, Moran E, Goodman A, Baxendale H, Bermingham W, Buckland M, and others. Treatment of chronic or relapsing COVID-19 in immunodeficiency. J Allergy Clin Immunol. 2022;149(2):557-61 e1.
Rodionov RN, Biener A, Spieth P, Achleitner M, Holig K, Aringer M, and others. Potential benefit of convalescent plasma transfusions in immunocompromised patients with COVID-19. Lancet Microbe. 2021;2(4):e138. ↩ -
Shapiro AE, Bender Ignacio RA, Whitney BM, Delaney JA, Nance RM, Bamford L, and others. Factors associated with severity of COVID-19 disease in a multicenter cohort of people with HIV in the United States, March-December 2020. medRxiv. 2021. ↩
-
Hippisley-Cox J, Coupland CA, Mehta N, Keogh RH, Diaz-Ordaz K, Khunti K, and others. Risk prediction of covid-19 related death and hospital admission in adults after covid-19 vaccination: national prospective cohort study. BMJ. 2021;374:n2244. ↩
-
Bhaskaran K, Rentsch CT, MacKenna B, Schultze A, Mehrkar A, Bates CJ, and others. HIV infection and COVID-19 death: a population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform. Lancet HIV. 2021;8(1):e24-e32. ↩
-
Diez C, Del Romero-Raposo J, Mican R, Lopez JC, Blanco JR, Calzado S, and others. COVID-19 in hospitalized HIV-positive and HIV-negative patients: A matched study. HIV Med. 2021;22(9):867-76. ↩
-
Frater J, Ewer KJ, Ogbe A, Pace M, Adele S, Adland E, and others. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV. 2021;8(8):e474-e85.
Woldemeskel BA, Karaba AH, Garliss CC, Beck EJ, Wang KH, Laeyendecker O, and others. The BNT162b2 mRNA Vaccine Elicits Robust Humoral and Cellular Immune Responses in People Living with HIV. Clin Infect Dis. 2021. ↩ -
Swann OV, Holden KA, Turtle L, Pollock L, Fairfield CJ, Drake TM, and others. Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study. BMJ. 2020;370:m3249.
Ward JL, Harwood R, Smith C, Kenny S, Clark M, Davis PJ, and others. Risk factors for PICU admission and death among children and young people hospitalized with COVID-19 and PIMS-TS in England during the first pandemic year. Nat Med. 2022;28(1):193-200.
Harwood R, Yan H, Talawila Da Camara N, Smith C, Ward J, Tudur-Smith C, and others. Which children and young people are at higher risk of severe disease and death after hospitalisation with SARS-CoV-2 infection in children and young people: A systematic review and individual patient meta-analysis. EClinicalMedicine. 2022;44:101287.
Smith C, Odd D, Harwood R, Ward J, Linney M, Clark M, and others. Deaths in children and young people in England after SARS-CoV-2 infection during the first pandemic year. Nat Med. 2022;28(1):185-92. ↩ -
Shaunak M, Patel R, Driessens C, Mills L, Leahy A, Gbesemete D, and others. COVID-19 symptom surveillance in immunocompromised children and young people in the UK: a prospective observational cohort study. BMJ Open. 2021;11(3):e044899. ↩