Understanding the recommendation on IL-6 receptor blockers

We recommend treatment with IL-6 receptor blockers (tocilizumab or sarilumab) for patients with severe or critical covid-19. (Note: corticosteroids have previously been strongly recommended in patients with severe and critical covid-19, and we recommend patients meeting these severity criteria should now receive both corticosteroids and IL-6 receptor blockers.)

Balance of benefit and harm—There was high certainty evidence for a clinically important reduction in mortality and need for mechanical ventilation. The effects of IL-6 receptor blockers on duration of both hospitalisation and mechanical ventilation are uncertain (low certainty evidence; serious risk of bias due to lack of blinding and serious inconsistency) (box 4).

There was uncertainty about the risk of serious adverse effects (low certainty evidence). The risk of bacterial infections with immunomodulatory IL-6 receptor blocker therapy may be similar to usual care. However, the guideline development panel had some concerns that, given the short term follow-up of most trials and the challenges associated with accurately capturing adverse events such as bacterial or fungal infection, the evidence summary may under-represent the risks of treatment with IL-6 receptor blockers. Furthermore, the trials of IL-6 receptor blockers that inform this recommendation were mostly performed in high income countries where the risk of infectious complications may be less than in some other parts of the world, and so the generalisability of the data on these adverse events is unclear.

Values and preferences—The guideline panel inferred that almost all well informed patients with severe or critical covid-19 infection would want to receive IL-6 receptor blockers given the reduction in mortality and mechanical ventilation, despite the low certainty around serious adverse events. A minority of the panel felt that a significant proportion of patients might decline the intervention due to the uncertainties around harms and taking account of the small reduction in mortality.

Resource implications, feasibility, equity, and human rights—IL-6 receptor blockers require intravenous administration but only require one, or at most two, doses.

Compared with other treatments for covid-19, IL-6 receptor blockers are expensive. The recommendation does not take account of cost effectiveness. Access to these drugs is challenging in many parts of the world, and this recommendation could exacerbate health inequity. However, this strong recommendation should provide a stimulus to improve global access to these treatments.

At a time of drug shortage, many jurisdictions have suggested triaging use of IL-6 receptor blockers. Strategies for this include prioritising patients with the highest baseline risk for mortality (those with critical disease over those with severe disease), in whom the absolute benefit of treatment is therefore greatest. The relative effects (odds ratio 0.87) for reduction in mortality with IL-6 receptor blockers result in 28 fewer deaths per 1000 (95% confidence interval 9 to 47 fewer deaths) in critically ill patients compared with 12 fewer deaths per 1000 (4 to 19 fewer deaths) in the severely ill.

Other suggestions, which lack direct evidence, include prioritising patients who are deteriorating despite corticosteroid treatment and avoiding use in those with established multi-organ failure (in whom the benefit is likely to be smaller). Finally, sarilumab is not indicated to be used in children, and therefore there could be a preference for tocilizumab in this subgroup.

Understanding the recommendation on ivermectin

We recommend not to use ivermectin in patients with covid-19 except in the context of a clinical trial, regardless of disease severity or duration of symptoms.

Balance of benefit and harm—For most important outcomes, the guideline panel considered the evidence to be of very low certainty. A combination of serious risk of bias and very serious imprecision contributed to very low certainty of evidence for mortality, despite a point estimate and confidence interval that seem to suggest benefit with ivermectin. The picture was similar for other important outcomes, including mechanical ventilation, hospital admission, duration of hospitalisation, and viral clearance. The very low certainty of evidence was a critical factor in the recommendation.

Ivermectin may have little or no effect on time to clinical improvement (low certainty evidence) and may increase the risk of adverse effects leading to drug discontinuation (low certainty evidence). A recommendation to only use a drug in the setting of a clinical trials is appropriate when there is very low certainty evidence and future research has a large potential for reducing uncertainty about the effects of the intervention and for doing so at reasonable cost.

Subgroup analyses indicated no effect modification based on dose. We were unable to examine subgroups based on patient age or severity of illness due to insufficient trial data. Therefore, we assumed similar effects in all subgroups.

Values and preferences—The guideline panel inferred that almost all well informed patients would not want to receive ivermectin, given the evidence left a very high degree of uncertainty in effect on critical outcomes and there was a possibility of harms, such as adverse events associated with treatment (box 2). The panel did not expect there would be much variation among patients in values and preferences when it came to this intervention.

Resource implications, feasibility, equity, and human rights—Although the cost of ivermectin may be low per patient, the panel raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe covid-19 and other supportive care interventions. Also, use of ivermectin for covid-19 would divert supply away from pathologies for which it is clearly indicated, potentially contributing to drug shortages, especially for helminth control and elimination programmes. If corticosteroids are used in the treatment of covid-19, empiric treatment with ivermectin may still be considered in strongyloidiasis-endemic areas, albeit not for treatment of covid-19 itself.

Understanding the recommendation on hydroxychloroquine

We recommend against using hydroxychloroquine or chloroquine in addition to usual care for the treatment of patients with covid-19, regardless of disease severity or duration of symptoms (strong recommendation).

Balance of benefit and harm—Hydroxychloroquine and chloroquine probably do not reduce mortality or mechanical ventilation and may not reduce duration of hospitalisation. The evidence does not exclude the potential for a small increased risk of death and mechanical ventilation with hydroxychloroquine. The effect on other less important outcomes—including time to symptom resolution, admission to hospital, and duration of mechanical ventilation—remains uncertain.

Hydroxychloroquine may increase the risk of diarrhoea and nausea or vomiting, a finding consistent with evidence from its use in other conditions. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension, and acute kidney injury, especially in settings where healthcare resources are limited. Whether and to what degree hydroxychloroquine increases the risk of cardiac toxicity, including life-threatening arrhythmias, when used in patients with covid-19 is uncertain.

Subgroup analyses indicated no effect modification based on severity of illness (comparing either critical versus severe/non-severe or non-severe versus critical/severe) or age (comparing those aged <70 years versus those ≥70 years). Further, the cumulative dose and predicted day 3 serum trough concentrations (lowest predicted blood concentration on day 3) did not modify the effect for any outcome. Therefore, we assumed similar effects in all subgroups.

We also reviewed evidence comparing the use of hydroxychloroquine plus azithromycin versus hydroxychloroquine alone. There was no evidence that the addition of azithromycin modified the effect of hydroxychloroquine for any outcome (very low certainty).

Values and preferences—Applying the agreed values and preferences (box 2), the guideline +6panel inferred that almost all well informed patients would not want to receive hydroxychloroquine given the evidence suggesting there was probably no effect on mortality or need for mechanical ventilation and that there was a risk of adverse events including diarrhoea and nausea/vomiting. The panel did not expect there would be much variation in values and preferences among patients when it came to this intervention.

Resource implications, feasibility, equity, and human rights—Hydroxychloroquine and chloroquine are relatively inexpensive compared with other drugs used for covid-19 and are already widely available, including in low income settings. Despite this, the panel felt that almost all patients would choose not to use hydroxychloroquine or chloroquine because the harms outweigh the benefits. Although the cost may be low per patient, the panel raised concerns about diverting attention and resources away from care likely to provide a benefit such as corticosteroids in patients with severe covid-19 and other supportive care interventions.

Understanding the recommendation on lopinavir-ritonavir

We recommend against using lopinavir-ritonavir in addition to usual care for the treatment of patients with covid-19, regardless of disease severity and duration of symptoms (strong recommendation).

Balance of benefit and harm—The guideline panel found a lack of evidence that lopinavir-ritonavir improved patient-important outcomes such as reduced mortality, need for mechanical ventilation, time to clinical improvement, and others. For mortality and need for mechanical ventilation, this was based on moderate certainty evidence; for the other outcomes, this was based on low or very low certainty evidence.

There was low certainty evidence that lopinavir-ritonavir may increase the risk of diarrhoea and nausea or vomiting, a finding consistent with the indirect evidence evaluating its use in patients with HIV infection. Diarrhoea and vomiting may increase the risk of hypovolaemia, hypotension, and acute kidney injury, especially in settings where healthcare resources are limited. There was an uncertain effect on viral clearance and acute kidney injury.

Subgroup analysis indicated no effect modification based on severity of illness (comparing either critical versus severe/non-severe or non-severe versus critical/severe) or age (comparing those aged <70 years versus those ≥70 years). As there was no evidence of a statistical subgroup effect, we did not formally evaluate credibility. Although the trials did not report subgroup effects by time from symptom onset, many of the trials enrolled patients early in the disease course. The guideline panel therefore felt that the evidence applies to all patients with covid-19.

Values and preferences—Applying the agreed values and preferences (box 2), the guideline panel inferred that almost all well informed patients would not want to receive lopinavir-ritonavir given that the evidence suggested there was probably no effect on mortality or need for mechanical ventilation and there was a risk of adverse events including diarrhoea and nausea or vomiting. The panel did not expect there would be much variation in values and preferences between patients for this intervention.

Resource implications, feasibility, equity, and human rights—Although the cost of lopinavir-ritonavir is not as high as some other investigational drugs for covid-19 and the drug is generally available in most healthcare settings, the panel raised concerns about opportunity costs and the importance of not drawing attention and resources away from best supportive care or the use of corticosteroids in severe covid-19.

Understanding the recommendation on remdesivir

We suggest against administering remdesivir in addition to usual care for the treatment of patients hospitalised with covid-19, regardless of disease severity (weak or conditional recommendation).

When moving from evidence to the conditional recommendation against the use of remdesivir for patients with covid-19, the panel emphasised the evidence of possibly no effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes, albeit of low certainty; it also noted the anticipated variability in patient values and preferences and other contextual factors, such as resource considerations, accessibility, feasibility and impact on health equity (see below).

Balance of benefit and harm—The guideline panel found a lack of evidence that remdesivir improved outcomes that matter to patients such as reduced mortality, need for mechanical ventilation, time to clinical improvement, and others. However, the low certainty evidence for these outcomes, especially mortality, does not prove that remdesivir is ineffective; rather, there is insufficient evidence to confirm that it does improve patient-important outcomes.

There was no evidence of increased risk of serious adverse events in patients receiving remdesivir, at least from the included trials. Further pharmacovigilance is required, because serious adverse events are commonly underreported and rare events could be missed, even in large RCTs.

Data from the network meta-analysis indicated that a subgroup of people with non-critical disease might benefit from remdesivir. However, the panel judged the credibility in this subgroup analysis to be insufficient to make subgroup recommendations.15 Important factors influencing this decision included a lack of a priori hypothesised direction of subgroup effect by trial investigators, little or no previously existing supportive evidence for the subgroup finding, and relatively arbitrary cut points used to examine the subgroups of interest. The overall low certainty evidence for the benefits and harms of remdesivir, driven by risk of bias and imprecision limitations, also contributed to the judgment (see WHO guidance and MAGICapp linked from box 1 for full details). The panel highlighted that, despite the conditional recommendation against remdesivir, they support further enrolment into RCTs evaluating remdesivir, especially to provide higher certainty of evidence for specific subgroups of patients. The panel had a priori requested analyses of other important subgroups of patients, including children and older people, but there were no data to address these groups specifically.

Values and preferences—Applying the agreed values and preferences (box 2), the guideline panel inferred that most patients would be reluctant to use remdesivir, given the evidence left high uncertainty regarding effects on mortality and the other prioritised outcomes. This was particularly so as any beneficial effects of remdesivir, if they do exist, are likely to be small, and the possibility of important harm remains. The panel acknowledged, however, that values and preferences are likely to vary, and there will be patients and clinicians who choose to use remdesivir given that the evidence has not excluded the possibility of benefit.

Resource implications, feasibility, equity, and human rights—A novel therapy typically requires higher certainty evidence of important benefits than is currently available for remdesivir, preferably supported wherever possible by cost effectiveness analysis. In the absence of this information, the guideline panel raised concerns about opportunity costs and the importance of not drawing attention and resources away from best supportive care or the use of corticosteroids in severe covid-19. It was noted that, currently, remdesivir is administered only by the intravenous route and global availability is limited.

Practical issues—Its use is contraindicated in those with liver dysfunction (ALT >5 times normal at baseline) or renal dysfunction (eGFR <30 mL/minute). To date, it can only be administered intravenously, and it has relatively limited availability.

Understanding the recommendations on corticosteroids

Recommendation 1: We recommend systemic corticosteroids rather than no systemic corticosteroids for the treatment of patients with severe and critical covid-19 (strong recommendation)

Who does it apply to? This recommendation applies to patients with severe and critical covid-19. The panel judged that all or almost all fully informed patients with severe covid-19 would choose to take systemic corticosteroids. The recommendation should apply to patients with severe and critical covid-19 even if they cannot be hospitalised or receive oxygen because of resource limitations.

The applicability of the recommendation is less clear for populations that were under-represented in the considered trials, such as children, patients with tuberculosis, and those who are immunocompromised. In considering potential contraindications to short term systemic corticosteroids in such patients, clinicians must determine if they warrant depriving a patient of a potentially lifesaving therapy. Clinicians should exercise caution in use of corticosteroids in patients with diabetes or underlying immunocompromise. The panel was confident that clinicians using these guidelines would be aware of additional potential side effects and contraindications to systemic corticosteroid therapy, which may vary geographically in function of endemic microbiological flora.

Balance of benefit and harm—Ultimately, the panel made its recommendation on the basis of the moderate certainty evidence of a 28-day mortality reduction of 3.4% in severe and critical covid-19 combined. Systemic corticosteroids compared with no corticosteroid therapy probably reduce the risk of 28-day mortality in these patients (moderate certainty evidence; relative risk 0.79 (95% confidence interval 0.70 to 0.90); absolute effect estimate 34 fewer deaths per 1000 patients (95% CI 48 fewer to 16 fewer)). Therapy also probably reduces the need for mechanical ventilation (moderate certainty evidence, relative risk 0.74 (0.59 to 0.930; absolute effect estimate 30 fewer cases per 1000 patients (48 fewer to 8 fewer)). The effects of systemic corticosteroids on other outcomes are described in the summary of findings.

Overall, the panel has high certainty that the adverse effects when considered together are sufficiently limited in importance and frequency and suggested that corticosteroids administered in these doses for 7-10 days are not associated with an increased risk of adverse events, beyond likely increasing the incidence of hyperglycaemia (moderate certainty evidence; absolute effect estimate 46 more per 1000 patients (23 more to 72 more)) and hypernatraemia (moderate certainty evidence; 26 more per 1000 patients (13 more to 41 more)). In contrast with new agents proposed for covid-19, clinicians have a vast experience of systemic corticosteroids, and the panel was reassured by their overall safety profile.

Values and preferences—The panel took an individual patient perspective to values and preferences but, given the burden of the pandemic for healthcare systems globally, also placed a high value on resource allocation and equity. The benefits of corticosteroids on mortality was deemed of critical importance to patients, with little or no anticipated variability in their preference to be offered treatment if severely ill from covid-19.

Resource implications, feasibility, equity, and human rights—Systemic corticosteroids are low cost, easy to administer, and readily available globally. Dexamethasone and prednisolone are among the most commonly listed medicines in national essential medicines lists; listed by 95% of countries. Accordingly, systemic corticosteroids are among a relatively small number of interventions for covid-19 that have the potential to reduce inequities and improve equity in health. Those considerations influenced the strength of this recommendation.

Acceptability—The ease of administration, the relatively short duration of a course of systemic corticosteroid therapy, and the generally benign safety profile of systemic corticosteroids administered for up to 7-10 days led the panel to conclude that the acceptability of this intervention was high.

Recommendation 2: We suggest not to use corticosteroids in the treatment of patients with non-severe covid-19 (weak or conditional recommendation)

Who does it apply to? This recommendation applies to patients with non-severe disease regardless of their hospitalisation status. The guideline panel noted that patients with non-severe covid-19 would not normally require acute care in hospital or respiratory support, but in some jurisdictions these patients may be hospitalised for isolation purposes only, in which case they should not be treated with systemic corticosteroids. Several specific circumstances were considered.

• Systemic corticosteroids should not be stopped for patients with non-severe covid-19 who are already treated with systemic corticosteroids for other reasons (such as patients with chronic obstructive pulmonary disease or chronic autoimmune disease).

• If the clinical condition of patients with non-severe covid-19 worsens (that is, increase in respiratory rate, signs of respiratory distress or hypoxaemia) they should receive systemic corticosteroids (see recommendation 1).

• Pregnancy: antenatal corticosteroid therapy may be administered for pregnant women at risk of preterm birth from 24 to 34 weeks’ gestation when there is no clinical evidence of maternal infection and adequate childbirth and newborn care are available. In cases where the woman presents with mild or moderate covid-19, the clinical benefits of antenatal corticosteroid might outweigh the risks of potential harm to the mother. In this situation, the balance of benefits and harms for the woman and the preterm newborn should be discussed with the woman to ensure an informed decision, as this assessment may vary depending on the woman’s clinical condition, her wishes and those of her family, and available healthcare resources.

• Endemic infections that may worsen with corticosteroids should be considered. For example, for Strongyloides stercoralis hyperinfection associated with corticosteroid therapy, diagnosis or empiric treatment may be considered in endemic areas if steroids are used.

Balance of benefit and harm—Systemic corticosteroids may increase the risk of 28-day mortality (low certainty evidence; relative risk 1.22 (95% CI 0.93 to 1.61); absolute effect estimate 39 more per 1000 patients (95% CI 12 fewer to 107 more)). The certainty of the evidence for this specific subgroup was downgraded due to serious imprecision (that is, the evidence does not allow to rule out a mortality reduction) and risk of bias due to lack of blinding. The effects of systemic corticosteroids on other outcomes are described in the summary of findings (infographic and links to MAGICapp).

Values and preferences—The weak or conditional recommendation was driven by likely variation in patient values and preferences. The panel judged that most individuals with non-severe illness would decline systemic corticosteroids. However, many may want them after shared decision making with their treating physician.

Resource implications, feasibility, equity, and human rights—To help guarantee access to systemic corticosteroids for patients with severe and critical covid-19, it is reasonable to avoid their administration to patients who, given the current evidence, do not seem to derive any benefit from this intervention