COVID-19: Risk factors for progression to severe infection

Risk factors for progression to severe COVID‑19 in adults defined by the independent advisory group commissioned by the Department of Health and Social Care (June 2023).

Down’s syndrome and other genetic disorders

All individuals with Down’s Syndrome or other chromosomal disorders known to affect immune competence.

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 within 12 months
• people who have had cancer resected within 3 months 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 until the lymphocyte count is within the normal range
• Individuals with haematological malignancies receiving systemic anti‑cancer treatment (SACT) within the last 12 months, or radiotherapy in 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
  • any mature T-cell malignancy
• all people with sickle cell disease
• people with thalassaemia or rare inherited anaemia with any of the following:
  • severe cardiac iron overload (T2 * less than 10ms)
  • severe to moderate iron overload (T2 * greater than or equal to 10ms) 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
• non-transplant renal patients who have received a comparable level of immunosuppression
• patients with chronic kidney stage (CKD) 4 or 5 (an estimated glomerular filtration rate (eGFR) less than 30ml per min per 1.73m²) without immunosuppression

Liver diseases

• people with cirrhosis Child-Pugh (CP) class A,B and C, whether receiving immune suppressive therapy or not. Those with decompensated liver disease (CP 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)

Solid organ transplant recipients

Solid organ transplant recipients not in any of the above categories.

Immune mediated inflammatory disorders

(diseases in which autoimmune or autoinflammation-based pathways are implicated in disease, for example, inflammatory arthritis, connective tissue diseases, inflammatory skin diseases, inflammatory gastrointestinal disease)

• 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 or relevant COVID test
• people who are on corticosteroids (equivalent to 10mg or more per day of prednisolone) for at least the 28 days prior to positive PCR or relevant COVID test
• People who are on biologics or small molecule JAK inhibitors
• people who are on current treatment with mycophenolate mofetil, oral tacrolimus, azathioprine, mercaptopurine, or similar agents (for major organ involvement such as kidney, gastro-intestinal tract, liver, lung, brain), methotrexate (for interstitial lung disease or asthma only) and/or ciclosporin. No minimum dose threshold is suggested
• People who are on current treatment (or within the last 6 months) with S1P modulators (fingolimod, ponesimod or siponimod), or alemtuzumab or cladribine within the last 12 months
• 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) other high risk comorbidities (for example, body mass index (BMI) greater than 30, diabetes mellitus, hypertension, major organ involvement such as significant kidney, liver or lung inflammation or significantly impaired renal, liver and/or lung function)

Respiratory

• asthma in people on oral corticosteroids (defined above). Any asthma patient taking immunosuppressants for their asthma including but not exclusively methotrexate, ciclosporin. Frequent exacerbations requiring 4 or more courses of prednisolone per year, usually 40 mg per day for 5 days or more
• COPD on long term home non-invasive ventilation (NIV). Patients on long term oxygen therapy. People with moderate or severe disease (FEV1 less than or equal to 50% predicted) who have required 4 or more courses of prednisolone 30mg for 5 days or greater in last 12 months
• interstitial lung disease (ILD) - all patients with idiopathic pulmonary fibrosis
• sub-types of ILD - for example, connective tissue disease related, sarcoidosis, hypersensitivity pneumonitis, NSIP (non specific interstitial pneumonia) who have received a B-cell depleting therapy in last 12 months, or IV or oral cyclophosphamide in the 6 months prior to testing positive for COVID-19. Any ILD patient on current treatment with corticosteroids, mycophenolate mofetil, azathioprine, tacrolimus, cyclosporin or methotrexate. No minimum dose criteria
• any people with any type of ILD who may not be on treatment due to intolerance but has severe disease with an FVC predicted less than 60%
• NIV and tracheostomy ventilated - all patients requiring this type of support regardless of the underlying disorder (which might include COPD, obesity hypoventilation syndrome, scoliosis, bronchiectasis, neurodisability and genetic muscular diseases [refer to neurology section])
• lung cancer patients, refer to ‘Solid cancer’ section above
• lung transplant patients (refer to solid organ transplant section)
• pulmonary hypertension (PH): groups 1 and 4 from PH classification

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 I 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 mm³and 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)

Neurological disorders

• Conditions associated with neuromuscular respiratory failure requiring chronic ventilatory support:
  • motor neurone disease
  • Duchenne muscular dystrophy
  • Conditions that require use of specific immunotherapies:
    • multiple sclerosis (MS)
    • myasthenia gravis (MG)
    • other immune mediated disorders
• Dementia and neurodegenerative disorders when associated with severe frailty (for example, levels 7 or 8 on Clinical Frailty Scale, as part of a personalised care plan):
  • Alzheimer’s disease, vascular disease, Lewy body disease, or frontotemporal atrophy
  • Parkinson’s Disease
  • Huntington’s disease
  • progressive supranuclear palsy and multiple system atrophy
  • motor neurone disease
  • multiple sclerosis and other immune-mediated nerological disorders

Pathway for PCR (or relevant COVID test) positive symptomatic cases aged older than 12 and younger than 18 years, greater than 40 kg weight, and clinical concern: defined by the independent advisory group commissioned by the Department of Health and Social Care (March 2023)

Children and young people (CYP) at substantial risk

• Complex life-limiting neurodisability with recurrent respiratory infections or compromise.

CYP at significant risk if 2 or more or 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 (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
• bronchopulmonary dysplasia - decisions should be made taking in to account degree of prematurity at birth and chronological age

1. This advice is gathered from evidence in people over 18 years - risks for those under 18 years are summarised in Box 2.
2. Physician discretion is advised for each of the conditions provided and decision to treat should follow evaluation of individual circumstances.
3. Please refer also to IMID section.
4. IMIDs comprise diseases in which auto-immune or auto-inflammation based pathways are implicated in disease for example, inflammatory arthritis, connective tissue diseases, inflammatory skin diseases, inflammatory gastrointestinal disease.
5. Please cross refer to the ‘Respiratory’ section in Box 1.
6. The IAG gave detailed consideration to the risks posed by TNF inhibitors and other cytokine inhibitors, including JAK inhibitors, used in rheumatology, dermatology and gastroenterology practice. As detailed in the appendix, there is consistent evidence of reduced serology responses in a variety of IMIDs to some these medications, but little consistent evidence as yet of increased severity of outcomes upon infection.
7. Please cross reference to advice in the sections on in Box 1 on IMIDs, solid cancer and neurology. Note also advice regarding glucocorticoids in evaluation in IMID section.
8. Note, exceptionally, that frequent exacerbations requiring 4 or more courses of prednisolone per year, usually 40mg per day for 5 days or more, may render an asthma patient eligible.
9. Patients using continuous positive airway pressure (CPAP) only for treatment of obstructive sleep apnoea (OSA) are not deemed to be particularly high risk and do not require prioritised access to treatments for COVID-19 disease.
10. Refer to respiratory section for details.
11. 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.
12. These should be managed according to the recommendations contained in the broader section on immune-mediate inflammatory disorders with the individual drugs - for example, rituximab, ocrelizumab, used as the ‘gatekeeper’, rather than the specific diagnosis.
13. For example, levels 7 or 8 on Clinical Frailty Scale, as part of a personalised care plan.
14. Complex congenital heart disease and severe bronchopulmonary dysplasia are rare and as such do not offer a readily available dataset upon which to base advice. As such, we propose a practical approach to adopt clinical criteria similar to those used to administer palivizumab for respiratory syncytial virus (RSV) prevention in the same groups of very young infants. Where clinical judgement of other individual patient circumstances not covered above strongly suggests that prophylaxis would prevent serious outcome upon SARS-CoV-2 infection in infants who are at particular risk of complications from this virus, use of appropriate antiviral approaches should be considered by an MDT.