Guidance
Rationales
- Assessment in the community
- Management in hospital
- Antivirals
- Sotrovimab
- Corticosteroids
- Tocilizumab
- Baricitinib
- Azithromycin
- Budesonide (inhaled)
- Colchicine
- Doxycycline
- Ivermectin
- Tixagevimab plus cilgavimab
- Vitamin D
- Prevention and management of venous thromboembolism (VTE) prophylaxis
- Diagnosing and treating COVID-19-associated pulmonary aspergillosis (CAPA)
Rationales
Assessment in the community
Identifying severe COVID-19
This recommendation is based on the expert panel's consensus view. The panel agreed that using pulse oximetry to measure oxygen saturation threshold levels is appropriate for helping to identify people with acute COVID-19 in primary or community care, and to predict outcomes such as hospitalisation. NHS England has guidance on pulse oximetry in assessment in adults in the community. The panel agreed that it is appropriate to cross-refer to this guidance for adults but not for children. The panel's recommended oxygen saturation level for children and young people was based on their consensus view that oxygen saturation levels below 91% in room air at rest are appropriate to assess the severity of illness and detect early deterioration in this group.
Care planning
Some benefits and risks of hospital admission may be similar for all patients (for example, improved diagnostic tests and access to treatments, or better contact with families in the community), but others may be personal to the individual (such as loss of access to carers who can anticipate needs well in someone unable to communicate themselves, or risks of spreading COVID-19).
Management in hospital
Early treatment escalation planning for non-invasive respiratory support
Based on their experience, the panel concluded that to improve outcomes for patients, it was important to ensure that existing management is optimised for people who need escalation of respiratory support.
Recommendations 3.2.10 and 3.2.11
Evidence shows that, for people in hospital with COVID-19 who are not intubated and have higher oxygen needs, awake prone positioning reduces the need for intubation compared with standard care. There is no evidence showing that awake prone positioning improves other outcomes compared with standard care. Although evidence is limited and of low to very low certainty, the panel agreed that awake prone positioning may be beneficial for this population.
The panel noted that awake prone positioning may not be suitable for everyone, and some people may find it difficult or uncomfortable to be in a prone position. They emphasised the importance of involving the person in decisions to try awake prone positioning.
The panel agreed that more research is needed to guide treatment and made a recommendation for research for trials done in the UK with a focus on patient-reported outcomes.
Delivering non-invasive respiratory support
Evidence does not show that high-flow nasal oxygen (HFNO) has treatment benefits over conventional oxygen therapy for people in whom escalation to invasive mechanical ventilation would be appropriate. So, the panel agreed that it should not be used as the preferred treatment option for this population.
The panel acknowledged that although HFNO should not be routinely offered as the main form of respiratory support, it may be considered in some situations.
Evidence from a clinical trial suggests that there may be some treatment benefits with continuous positive airway pressure (CPAP) for people who have hypoxaemia and when mechanical ventilation is not immediately needed. These benefits are mostly for intubation outcomes (including likelihood of needing tracheal intubation and IMV), but there are uncertainties in the evidence. In this clinical trial, hypoxaemia was defined as less than or equal to 94% using pulse oximetry.
Based on their experience, the panel agreed that it is important to closely review people with COVID-19 having CPAP. This is to ensure that CPAP is not used for longer than necessary and that treatment is escalated when needed.
Evidence showed no statistically significant benefits between HFNO compared with conventional oxygen. The panel acknowledged that although HFNO should not be the main form of respiratory support, it may be considered in some situations so made a recommendation for research on the use of HFNO where treatment would not be escalated beyond non-invasive respiratory support. The panel used their expertise to inform the recommendation on when to consider HFNO and proposed a recommendation for research to explore which treatment methods are effective for weaning people with COVID-19 from CPAP and the acceptability and safety of these methods.
Antivirals
Remdesivir
For adults in hospital, remdesivir can improve how long adults needing low-flow supplemental oxygen live compared with standard care, but the evidence is highly uncertain. The cost-effectiveness estimates for remdesivir are only likely to be within what NICE considers an acceptable use of NHS resources for adults in hospital who have a high risk of serious illness. So, remdesivir is recommended for treating COVID-19 in this group.
There is limited clinical evidence comparing remdesivir with standard care for treating severe COVID-19 in babies, children and young people. So, the cost-effectiveness estimates are highly uncertain. But there are limited treatment options licensed for the groups covered, and the number who would have remdesivir is very small. So, remdesivir is recommended for treating COVID-19 in these groups.
For evidence and information on how this decision was made, see NICE's technology appraisal guidance on remdesivir and tixagevimab plus cilgavimab.
Molnupiravir
There is evidence from 2 randomised controlled trials that treatment with molnupiravir within 5 days of symptom onset reduces the risk of hospitalisation or death compared with placebo in adults who do not need supplemental oxygen and have at least 1 risk factor for development of severe COVID-19 disease. However, there is uncertainty about the generalisability of the evidence to current clinical practice because the trials only included people who were not vaccinated against COVID-19, and took place before the emergence of the Omicron (B.1.1.529) variant. Clinicians should refer to the NHS England Interim Clinical Commissioning Policy for the most up-to-date information about people prioritised for treatment with antivirals.
Two trials were included in the evidence, and both trials only included people aged 18 and above. Pregnant women were also excluded from the study population.
The summary of product characteristics states that molnupiravir is of low risk for mutagenicity or genotoxicity in adults. However, the safety and efficacy of molnupiravir has not been established in children and young people or pregnant women. Based on this, and the absence of these groups from the study populations, the panel concluded that there is no evidence on the efficacy and safety of molnupiravir for children and young people, or pregnant women, and so it cannot be recommended for them.
Sotrovimab
There is some evidence suggesting that sotrovimab is likely to be effective at treating mild COVID-19 compared with standard care. Its likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources for people in whom nirmatrelvir plus ritonavir is contraindicated or unsuitable. So, sotrovimab is recommended for this group. For evidence and information on how this decision was made, see NICE's technology appraisal guidance on nirmatrelvir plus ritonavir, sotrovimab and tocilizumab.
Corticosteroids
There is evidence to support using corticosteroids for people with COVID-19 who need supplemental oxygen, or who have a level of hypoxia that needs supplemental oxygen but who are unable to have or tolerate it. It is now established standard practice to offer dexamethasone. The growing evidence base, combined with its widespread availability, ease of administration and acceptable safety profile, supports its continued use. Hydrocortisone and prednisolone are suitable alternatives if dexamethasone cannot be used or is unavailable. The course duration recommended, for up to 10 days unless there is a clear indication to stop early, is based on that used in clinical trials. This includes being discharged from hospital or a hospital supervised virtual COVID ward. (Being on a hospital-supervised virtual COVID ward is not classed as being discharged from hospital.)
Evidence suggests that, in people with COVID-19 who do not need supplemental oxygen, corticosteroids may increase the risk of needing invasive mechanical ventilation and death at 28 days. The recommendation therefore cautions against using corticosteroids for people not on supplemental oxygen, unless there is another medical indication to do so.
Tocilizumab
Clinical evidence suggests that tocilizumab is effective at treating severe COVID-19 compared with standard care. Tocilizumab is recommended because the likely cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. For evidence and information on how this decision was made, see NICE's technology appraisal guidance on nirmatrelvir plus ritonavir, sotrovimab and tocilizumab.
Baricitinib
There is evidence to support the use of baricitinib for moderate to severe COVID-19 in adults in hospital. It shows that baricitinib reduces mortality, duration of hospital stay and disease severity. Corticosteroids are part of standard treatment for COVID‑19 in the UK, and there is evidence of an additional benefit when baricitinib is also used.
Baricitinib is not licensed for treating COVID-19. Off-label use of baricitinib for COVID-19 may be an option for adults who cannot have tocilizumab (for example, when tocilizumab is not available, the person cannot tolerate intravenous administration, or there are other important patient preferences or circumstances). The panel noted that, when there is clinical deterioration despite treatment with tocilizumab, it may be appropriate to also add baricitinib.
Based on the evidence supporting the use of baricitinib for moderate to severe COVID‑19 in adults, the panel agreed that, in the event of severe or deteriorating illness, it could also be considered for children and young people 2 years and over. This is after careful clinical risk assessment and shared decision making that includes expert input from paediatricians and paediatric infectious disease specialists.
Azithromycin
The evidence suggests that azithromycin is no better than standard care at reducing risk of death in people in hospital with COVID-19. Limited evidence also suggests that azithromycin does not reduce the risk of hospitalisation or death in people with COVID-19 in the community. There is no evidence for azithromycin use for COVID‑19 in children. The panel did not think there were reasons to expect different results in this group, so agreed that the recommendation applies to all age groups. They also noted the risk of antimicrobial resistance with azithromycin.
Budesonide (inhaled)
Trial evidence suggests some benefit with inhaled budesonide in reducing how long it takes to recover from COVID-19. However, this evidence is limited because it comes from only 2 trials, 1 of which was very small and stopped early. Also, the population in the trials was mainly older people, which limits its generalisability to other age groups. The panel concluded that more research is needed to address these issues, and that inhaled budesonide should therefore only be used as part of a clinical trial. They also made a recommendation for research to address this.
Colchicine
The evidence from trials of colchicine to treat COVID-19 in adults, both in hospital and community settings, shows no beneficial effect on all-cause mortality or need for mechanical ventilation compared with standard care. It also shows no effect on duration of hospital stay or hospitalisation. The evidence also shows that colchicine causes statistically significantly more adverse events than standard care within 21 days of starting treatment in hospital or 30 days in the community. There is no evidence for children or young people. Therefore, colchicine should not be used to treat COVID-19 in people of any age.
Doxycycline
There is evidence from 1 trial in the community of doxycycline for COVID-19 in people 65 years and over and in people 50 years and over with comorbidities. The results suggest that, compared with standard care alone, doxycycline plus standard care does not reduce the risk of hospitalisation and death, admission to intensive care, the need for mechanical ventilation or oxygen, or significant adverse events in these groups. The results also suggest that it does not improve symptoms or recovery.
There is no evidence for doxycycline use in the community for COVID-19 in people under 65 years or people under 50 years with comorbidities. But, it is unlikely that the results in these groups will differ, so the panel agreed that the recommendation applies to all age groups in the community. They also noted the risks of side effects and antimicrobial resistance with doxycycline. There was no evidence found for doxycycline use in hospital settings.
Ivermectin
Overall, there is a high degree of uncertainty about whether ivermectin is more effective than control (standard care, placebo or both) for managing COVID-19 in hospital or community settings. The panel raised concerns about the quality of the studies on ivermectin. They noted that most of the evidence is of low or very low certainty, with some that is of moderate certainty. The panel also noted the uncertainty about the overall safety and the possibility of rare serious adverse reactions with ivermectin. Because of the uncertainty in the evidence (including small sample sizes and issues with study quality), the panel agreed that ivermectin should only be used to treat COVID-19 in ongoing well-conducted clinical trials. The panel were aware of at least 1 ongoing trial, the results of which may improve the certainty of the evidence on the effectiveness of ivermectin for managing COVID-19.
Tixagevimab plus cilgavimab
Evidence suggests that it is highly uncertain that tixagevimab plus cilgavimab is effective against Omicron variants of COVID-19. Because of this, it is not possible to reliably estimate its cost effectiveness, so it is not recommended. For evidence and information on how this decision was made, see NICE's technology appraisal guidance on remdesivir and tixagevimab plus cilgavimab.
Vitamin D
The panel agreed that the clinical-effectiveness evidence for vitamin D for treating COVID-19 is uncertain, but suggests that there is no clear evidence of benefit. The studies included diverse populations with different COVID-19 severity, and used varying dosages of vitamin D and definitions of standard care. This means the evidence may not be generalisable to the UK.
The panel noted that the daily doses used in the studies were far higher than the standard doses used to prevent or treat vitamin D deficiency in the UK. They also noted that there was limited evidence from the studies on the adverse effects of these doses of vitamin D. The panel pointed out the potential adverse effects of a vitamin D overdose, such as raised plasma and urine concentrations of calcium and phosphate, and nausea and vomiting (see the BNF for more details on adverse effects).
The panel highlighted that existing guidance recommends taking vitamin D to maintain muscle and bone health. They agreed that vitamin D is important and well established for this.
The panel agreed that, until there is more evidence on the effects of vitamin D for treating COVID-19, it should only be used for treating COVID-19 as part of a clinical trial. The panel noted that the study populations did not include pregnant women or older populations who may be at more risk of severe COVID-19 outcomes. They also did not include children and young people under 18 years. So, they agreed that more research is also needed in the area and made a recommendation for research on vitamin D for treating COVID-19.
Prevention and management of venous thromboembolism (VTE) prophylaxis
In hospital
The panel agreed that all people with COVID-19 have an increased risk of VTE. Initial risk assessment for these people (as soon as possible after admission or by the time of their first consultant review) should focus on identifying people whose bleeding risk contraindicates pharmacological VTE prophylaxis.
The panel agreed that a risk assessment tool published by a national UK body, professional body or peer-reviewed journal should be prioritised for use.
Recommendation 5.3.2 and 5.3.3
The panel agreed that a standard prophylactic dose of a low molecular weight heparin (LMWH) should be offered as soon as possible to manage the risk of VTE based on current standard practice. Following standard prophylactic dose administration on admission, a more detailed assessment should be done to see whether people should be offered a treatment dose or not.
The panel also noted that people who are discharged early (before 7 days) could be at risk of clots. They emphasised the importance of continuing treatment after discharge until 7 days has passed to ensure people have had a full dose of a LMWH. The treatment duration comes from NICE's guideline on VTE in over 16s. The panel also made a recommendation for research on the effectiveness and safety of extended VTE prophylaxis after discharge from hospital.
Recommendation 5.3.4 and 5.3.5
The panel agreed that some young people and adults with COVID-19 who need low-flow oxygen supplementation may benefit from a treatment dose of an LMWH. The evidence suggests that a treatment dose of an LMWH for adults with COVID-19 who are in hospital and needing low-flow oxygen supplementation may reduce the risk of death and need for organ support compared with a standard prophylactic dose. It also suggests an increased risk in major bleeding compared with a standard prophylactic dose. Because of the fine balance of benefits and harms, the panel agreed that this decision should be carefully considered, and that this choice should be guided by bleeding risk, clinical judgement and local protocols.
The treatment duration in the largest included trial was 14 days or until discharge, whichever was sooner. The panel thought that the timeframe for treatment should reflect the trial evidence.
The panel noted an absence of evidence for anticoagulation in children. They recognised that younger children have different haematological physiology, meaning that VTE is less likely. However, their clinical experience suggested that, after puberty, people under 18 years are also at risk of VTE if admitted to hospital with COVID-19. For that reason, the panel included young people in the recommendations as well as adults and made a recommendation for research for this population.
Based on the lack of clear benefit with intermediate- or treatment-dose anticoagulation, the panel concluded that young people and adults with severe COVID-19 should be offered standard prophylactic-dose anticoagulation. They also concluded that intermediate- or treatment-dose VTE prophylaxis should only be used as part of a clinical trial.
The panel were aware of ongoing trials of LMWHs that use intermediate or treatment doses in this group of people, including REMAP-CAP. They agreed that intermediate- or treatment- dose LMWHs should only be used for VTE prophylaxis in this group as part of a clinical trial to support recruitment into these trials.
The panel agreed that D-dimer levels do not influence peoples' response to anticoagulation.
This recommendation was adapted from the original NICE rapid guideline on reducing the risk of VTE in over 16s with COVID-19 (now withdrawn) that considered intermediate doses in this population. In its development, the panel indicated that dose adjustments may be needed for people at extremes of body weight and those with renal impairment. To ensure that everyone gets an appropriate dose, the panel included dose adjustment in their recommendation. They added that summary of product characteristics and local protocols should be used to guide decisions on dose adjustment.
Acute care in the community
There was no evidence to inform recommendations on reducing the risk of VTE in people with COVID-19 pneumonia managed in hospital-led acute care in the community settings with input from hospital clinicians, such as 'hospital-at-home' services or COVID-19 'virtual wards'. People whose condition is managed in these settings have an increased risk of VTE that is similar to that of people having management in hospital. The panel therefore included a recommendation to consider pharmacological VTE prophylaxis for these people to ensure that they have the same care as those admitted to hospital.
The panel also made a recommendation for research on extending pharmacological VTE prophylaxis after discharge in people who have had treatment for COVID-19 pneumonia.
Additional risk factors
Recommendations 5.3.15 and 5.3.16
The panel noted the lack of evidence on pharmacological VTE prophylaxis for people with COVID-19 and additional risk factors. They agreed that VTE risk in women with COVID-19 who are pregnant or have given birth in the past 6 weeks should be managed in line with advice on COVID-19 in pregnancy published by the Royal College of Obstetricians and Gynaecologists.
There was no evidence on pharmacological VTE prophylaxis for specific groups with additional risk factors for VTE, including people who are having treatment with sex hormones, have or have previously had cancer, are having renal replacement therapy or extracorporeal membrane oxygenation, have a clotting condition or history of VTE, or have obesity (body mass index 30 kg/m² or higher). The panel made a recommendation for research on standard-dose compared with intermediate-dose pharmacological VTE prophylaxis in people with COVID-19 who have additional risk factors for VTE.
Diagnosing and treating COVID-19-associated pulmonary aspergillosis (CAPA)
Diagnosing CAPA
The panel agreed that the evidence was not strong enough to recommend specific factors that increase the risk of CAPA so the panel made a recommendation for research to identify risk factors associated with developing CAPA. They noted the importance of multidisciplinary decision making and using local protocols when deciding whether to suspect CAPA.
Because the incidence of CAPA is low, there is a lack of evidence on how to diagnose the condition. Also, there are no specific combinations of signs and symptoms for diagnosing it. The panel concluded that the likelihood of CAPA should be considered when deciding whether to do diagnostic tests.
There is a lack of evidence on diagnosing CAPA, including on what diagnostic tests to use, how frequently to test and the diagnostic value of the different investigations so the panel made a recommendation for research to identify the most accurate testing for CAPA. The panel noted that using a range of tests, including bronchoalveolar lavage (BAL), follows current best practice recommended in a taskforce report by Verweij et al. (2021) on diagnosing and managing CAPA.
Because BAL is an invasive procedure, it is important that any benefits or harms are considered before using it to investigate CAPA. The panel noted that BAL may not always be suitable or feasible and made a recommendation for research on people's views and experiences on available testing for CAPA. They agreed that other tests could be used instead of BAL, such as serological assays, non-bronchoscopic lavage or endotracheal aspirates.
In clinical practice, microbiological investigations can be used to assess antifungal resistance of isolates cultured from test samples. The panel noted the importance of testing for azole resistance to support clinical management decisions and ensure that suitable antifungal treatments are used. They agreed that treatment can be started before test results are confirmed, but should be reviewed when test results are available.
See the British Society for Medical Mycology's guidance on therapeutic drug monitoring of antifungal agents.
The panel noted that results of laboratory tests, in particular fungal antigen tests, are needed to diagnose CAPA. They also noted that if test results are not timely, there could be a delay in treatment, or people could have treatments that they do not need. They highlighted the importance of having test results available in an appropriate timeframe to support clinical decision making and to improve people's outcomes.
There is a lack of evidence on the tests used to diagnose CAPA and on treatments for CAPA in people who are critically ill and have, or have had, COVID-19 as part of their acute illness. So, the panel agreed that local protocols should be developed to collect more information on the current prevalence of CAPA and practices for diagnosing and managing the condition.
Treating CAPA
The panel noted that there are risks with antifungal treatments for CAPA, including antifungal resistance and adverse effects. They agreed that treatment should only be started if investigations support a diagnosis of CAPA, or a multidisciplinary team agrees to start treatment.
The panel noted the lack of evidence on treatments for CAPA and decided to make a recommendation for research on antifungal treatments for CAPA. They agreed that treatment decisions, including on when to start treatment, should be guided by advice from infection specialists, and in line with local protocols and best practice guidelines. The panel noted that the evidence provided limited insights on the benefits or harms of antifungals so made a recommendation for research on the outcomes for people with CAPA. The panel also made a recommendation for research on people's views and experiences on treatments for CAPA.
For information on monitoring antifungal treatments, see the British Society for Medical Mycology's guidance on therapeutic drug monitoring of antifungal agents.
The panel noted the importance of national antifungal stewardship guidance, such as NICE's guideline on antimicrobial stewardship
The panel noted the importance of good antifungal stewardship for reducing the risk of adverse effects and antifungal resistance, particularly when treatment is started before diagnosis is confirmed. They wanted to ensure that antifungal treatment would be stopped when investigations do not support a diagnosis of CAPA. However, the panel were aware that interpreting diagnostic test results and confirming a diagnosis of CAPA can be challenging. So, they recommended a multidisciplinary approach when deciding whether to stop treatment.