key: cord-0756183-f8cpklab
authors: Chalmers, James D.; Crichton, Megan L.; Goeminne, Pieter C.; Cao, Bin; Humbert, Marc; Shteinberg, Michal; Antoniou, Katerina M.; Ulrik, Charlotte Suppli; Parks, Helen; Wang, Chen; Vandendriessche, Thomas; Qu, Jieming; Stolz, Daiana; Brightling, Christopher; Welte, Tobias; Aliberti, Stefano; Simonds, Anita K.; Tonia, Thomy; Roche, Nicolas
title: Management of hospitalised adults with coronavirus disease-19 (COVID-19): A European Respiratory Society living guideline
date: 2021-03-11
journal: Eur Respir J
DOI: 10.1183/13993003.00048-2021
sha: 44ac19ff8ca580cb7c83b912a4a8f483657cd0e8
doc_id: 756183
cord_uid: f8cpklab

INTRODUCTION: Hospitalised patients with coronavirus disease 19 (COVID-19) as a result of SARS-CoV-2 infection have a high mortality rate and frequently require non-invasive respiratory support or invasive ventilation. Optimising and standardising management through evidence-based guidelines may improve quality of care and therefore patient outcomes. METHODS: A task force from the European Respiratory Society and endorsed by the Chinese Thoracic Society identified priority interventions (pharmacological and non-pharmacological) for the initial version of this “living guideline” using the PICO (population, intervention, comparator, outcome) format. The GRADE approach was used for assessing the quality of evidence and strength of recommendations. Systematic literature reviews were performed, and data pooled by meta-analysis where possible. Evidence tables were presented and evidence to decision frameworks were used to formulate recommendations. RESULTS: Based on the available evidence at the time of guideline development (February 20th, 2021) the panel makes a strong recommendation in favour of the use of systemic corticosteroids in patients requiring supplementary oxygen or ventilatory support, and for the use of anticoagulation in hospitalised patients. The panel makes a conditional recommendation for IL-6 receptor antagonist monoclonal antibody treatment and high flow nasal oxygen or continuous positive airway pressure in patients with hypoxaemic respiratory failure. The panel make strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir. Conditional recommendations are made against the use of azithromycin, hydroxychloroquine and azithromycin, colchicine, and remdesivir, in the latter case specifically in patients requiring invasive mechanical ventilation. No recommendation was made for remdesivir in patients requiring supplemental oxygen. Further recommendations for research are made. CONCLUSION: The evidence base for management of COVID-19 now supports strong recommendations in favour and against specific interventions. These guidelines will be regularly updated as further evidence becomes available.

First identified in Wuhan, China in November 2019, the disease rapidly developed into a global pandemic with over 62.2 million infections and more than 1.4 million deaths recorded worldwide as of the end of November 2020. [1] [2] [3] The onset of symptoms occurs around 3-5 days from initial infection, with fever, new continuous cough, dyspnoea, anosmia, ageusia and fatigue being amongst the most frequently experienced symptoms. [3] [4] [5] Pre-symptomatic transmission has been suggested as one of the features that promote the widespread transmission of the virus. 1, 6 The spectrum of disease is remarkably broad, ranging from true asymptomatic or paucisymptomatic infection to fatal acute respiratory distress syndrome. 4, [7] [8] [9] The case fatality rate of COVID-19 is debated but appears to be lower than MERS and SARS, with an estimated 5% of those experiencing symptoms requiring hospitalisation. The mortality rate in those requiring hospitalisation ranges from 5-25%. 2, 10, 11 Risk factors for hospitalisation and mortality have been defined. [12] [13] [14] [15] In hospitalised patients, the ISARIC risk prediction tool incorporates increased age, male sex, number of co-morbidities, increased respiratory rate, oxygen saturations, Glasgow coma scale, urea and C-reactive protein as risk factors for mortality. 12 Risk of hospitalisation and mortality is most strongly associated with age, and therefore SARS-CoV-2 infection rarely results in hospitalisation or mortality in children. 16 COVID-19 is often described as a biphasic illness with distinct stages. 17 The initial stage of infection with fever, cough and other symptoms is associated with the highest viral loads which peak in the first seven days of illness. 18 Live virus remains detectable in the respiratory tract for up to 9 days and in the majority of individuals symptoms start to improve after the first week of symptoms. 18 In a proportion of patients, however, a second phase characterized by a dysfunctional host inflammatory response and the development of lung inflammation and lung injury follows. [19] [20] [21] [22] [23] The inflammatory response in moderate and severe COVID-19 has been variously described as a pro-inflammatory cytokine storm or a manifestation of profound immunosuppression. [22] [23] [24] There is, nevertheless, clear evidence of increased systemic inflammatory markers including IL-6, IL-8, IL-1β, activation of coagulation pathways with increased markers such as D-dimer, neutrophil recruitment, activation and extracellular trap formation, deficient production in some patients of antiviral defence mediators such as IFN-α and -β, autoimmunity and T-cell activation among multiple other mechanisms. 4, 19, [25] [26] [27] [28] In view of the involvement of both the viral load and host inflammatory response in the disease, repurposing and development of new therapies in COVID-19 has focussed primarily on anti-viral, immunosuppressive and immunomodulatory treatments. 18,29-32 Randomized clinical trials have been conducted at an unprecedented rate to generate evidence for specific interventions. 33 During the early stages of the pandemic in particular, empirical use of antiviral and anti-inflammatory drugs such as hydroxychloroquine, lopinavir-ritonavir, remdesivir and monoclonal antibodies was widespread globally in the absence of formal guidelines or randomized trial evidence. [34] [35] [36] [37] It is therefore important to have both recommendations in favour of successful interventions but also evidence to avoid certain therapies if their benefit-risk balance is unfavourable. 34

The objective of these guidelines is to provide evidence-based recommendations primarily related to the management of hospitalised adults with COVID-19. This guideline does not address in detail the management of COVID-19 in the community, as the majority of evidence obtained relates to hospitalised patients. In addition, management in children is not addressed. A guideline cannot address the full complexity of a disease; hence all recommendations should be interpreted considering the clinical circumstances and patients' perceptions, values and preferences.

The evidence for the management of COVID-19 is accumulating at an unprecedented rate with new trials published every day. The formal literature review and evidence synthesis process of these guidelines, and the lag to publication, mean that all guidelines will be "out of date" at the point that they are published. Consequently, the present document represents the first European Respiratory Society Guideline on this topic and is therefore the starting point. It is intended to be continuously updated as a "living guideline" with rapid literature searches and updated grading and recommendations as new evidence emerges published as rapid guideline updates on specific topics in the ERS journals.

The target audience for this guideline comprises all stakeholders involved in the care of patients with COVID-19 in hospital. This includes specialists in respiratory medicine, infectious diseases, general internal medicine and multiple other medical and surgical specialities in view of the high prevalence of COVID-19. Allied health professionals, including but not limited to, pharmacists and nurses; regulatory authorities; pharmaceutical companies, policy makers, patients and their families. 

The recommendation can be adopted as a policy in most situations.

Policy making will require substantial debate and involvement of many stakeholders.

# : strong recommendations based on high quality evidence will apply to most patients for whom these recommendations are made, but they may not apply to all patients in all conditions; no recommendation can take into account all of the unique features of individual patients and clinical circumstances. 38, 39 Methods

This guideline was developed by a European Respiratory Society COVID-19 task force chaired by J.D.

Chalmers (UK) and N. Roche (France) and utilised the GRADE methodology. 38 The task force included specialists in respiratory medicine, infectious diseases, guideline methodology, an allied health professional and a patient representative. The task force recommendations have been endorsed by the Chinese Thoracic Society (CTS) and 3 members of CTS participated as full members of the task force panel.

Due to the COVID-19 pandemic, all panel meetings were held online via teleconference and email, with the initial meeting on 26 th June 2020 to identify and prioritise the key topics with the most important associated endpoints. From this meeting, the steering group were divided into working groups to focus on specific topics including anti-virals, anti-inflammatories, anti-coagulants and ventilation strategies. The patient representative was involved in all discussions with the guideline panel providing input into the final recommendations and will be involved in developing a lay version of the guideline. 40 A total of eleven clinical questions were generated using the PICO format (Patients, Intervention, Comparison, Outcomes) and systematic reviews were conducted to answer these specific questions.

The cut-off date for literature searches was 31 st October 2020, with updates performed to identify key studies in November 2020 and again in February 2021. Further details of the literature review process are described below.

Committee members disclosed all potential conflicts of interest according to ERS policy. Conflicted members were asked to abstain from discussions and voting on recommendations in which they were considered to have potential conflicts. Compliance with the conflict of interest policy was monitored by the chairs. The methodologists were non-voting members of the panel. The ERS methodology approach allows for results of existing systematic review and meta-analyses, when conducted to a high methodological standard, to be used for evidence synthesis and grading. If existing systematic reviews are not identified, then randomized controlled trials were identified and data extracted as described in the online supplement. Observational studies are only considered for inclusion in the evidence tables if randomized controlled trials were not available. The results of randomized trials and observational studies are not pooled together but are considered separately.

The panel selected outcomes of interest for each clinical question a priori, based on their relative importance to adult patients with COVID-19 and to clinical decision making (supplementary material). The importance of outcomes was rated on a 9-point scale (ranging from "not important"

to "critical") and only outcomes rated as important or critical for clinical decision making were included in the evidence tables. We followed the GRADE approach to assess the confidence in the evidence (quality) and the degree of recommendations. The GRADE methodology was used to rate the body of evidence at the outcome level rather than the study level with assessment of risk of bias at study level performed as described. 41 One recommendation (on ventilatory support) was addressed using a narrative format due to the lack of homogeneous literature.

Recommendations are reported as strong or conditional after considering the quality of the evidence, the balance of desirable and undesirable consequences of compared management options, the assumptions about the relative importance of outcomes, the implications for resource use, and the acceptability and feasibility of implementation. The quality of evidence was rated on 4 levels (high, moderate, low or very low) based on the GRADE methodology. 39 The overall quality of evidence is then rated as the lowest of the critical outcomes, except where the evidence for all of the critical outcomes favours the same alternative and where the quality of evidence for outcomes that are considered key to clinical decision takes precedence. 42 Evidence summary of findings tables and evidence to decisions frameworks were generated for each clinical question (supplementary material). Based on these formats, the panel formulated the clinical recommendations and decided on their strength by consensus, or, if required, by voting. Following the GRADE approach, strong recommendations are worded as "we recommend", while conditional recommendations are worded as "we suggest". 43 Guideline Table 2 summarises the 14 formal, graded recommendations made within the guideline. In each of the following sections we include a discussion of the underlying evidence and the rationale for the immediate indication for invasive mechanical ventilation. The review of the data identified limited evidence on adverse events, and in particular the RECOVERY trial did not report detailed information on safety of the intervention. 47 Research Recommendations: Dexamethasone 6mg daily for 10 days was the regimen selected for RECOVERY and is therefore the regimen that is used as standard. 47 Unanswered questions regarding corticosteroids include the optimal molecule, the optimal timing, dose and scheme as well as the optimal duration of treatment, long term side effects and whether other subgroups of patients, such as those not requiring oxygen but with evidence of increased systemic inflammation or radiographic changes, would benefit.

Recommendation: The panel suggests offering IL-6 receptor antagonist monoclonal antibody therapy to hospitalised patients with COVID-19 requiring oxygen or ventilatory support (conditional recommendation, low quality of evidence)

The panel suggests NOT to offer IL-6 receptor antagonist monoclonal antibody therapy to patients not requiring supplementary oxygen (conditional recommendation, low quality of evidence)

Notes:

- All patients eligible for IL-6 receptor antagonist monoclonal antibody treatment should have   already received or should be receiving treatment with corticosteroids, unless contraindicated.

-The patients most likely to benefit are those:

o in the first 24 hours after receiving non-invasive or invasive ventilatory support o patients receiving supplementary oxygen and who are progressing despite corticosteroid treatment or who are considered at high risk of future requirement for ventilatory support.

Observational studies in severe COVID-19 found elevated levels of IL-6 that were associated with increased mortality. 20,25,51 Several uncontrolled trials suggested benefit of treatment with anti IL-6 receptor monoclonal antibodies with tocilizumab being among the most widely used and studied, with improvements in disease severity and recovery of inflammatory markers reported. [52] [53] [54] The panel assessed eight randomized, controlled studies comparing the IL-6 receptor antagonist monoclonal antibody treatment (a total of 3,309 patients), to usual care (UC) (3,038 patients). [55] [56] [57] [58] [59] [60] [61] [62] The vast majority of studies utilized tocilizumab, but sarilumab was also studied. 62 

Anti-IL-6 receptor monoclonal antibody treatment reduces the risk of mechanical ventilation or death in hospitalised COVID-19 patients. No major safety concerns were identified. The panel considers that currently it is hard to identify the optimal patient population to benefit from this treatment, but RECOVERY found a benefit in addition to treatment with corticosteroids. As corticosteroids are also recommended for patients requiring oxygen and ventilatory support, anti-IL-6 monoclonal antibody treatment would be expected to be given to patients also receiving corticosteroids in nearly all cases. Anti-IL-6 receptor therapy is relatively expensive, but it is expected the benefits will outweigh the costs. Patient populations most likely to benefit include those meeting the inclusion criteria for REMAP-CAP (within 24 hours of requirement for non-invasive or invasive ventilatory support) and hospitalised patients requiring oxygen who are considered at high risk of requiring mechanical ventilation or who have progressed despite treatment with corticosteroids, which is consistent with patients enrolled in RECOVERY and other trials included in our analysis.

Research recommendations: Further research is needed to identify the optimal patient population for treatment with IL-6 receptor antagonist monoclonal antibody treatment, including whether biomarkers of inflammatory are useful to identify responders. hospitalised with mild-to-moderate COVID-19, prolongation of the QT interval was more frequent in patients receiving hydroxychloroquine (alone or with azithromycin), than in those who were not receiving these drugs. 64 In the RECOVERY study, there was a small absolute excess of cardiac mortality of 0.4 percentage points in the hydroxychloroquine group on the basis of very few events. 10

There is no evidence of significant clinical benefits associated with hydroxychloroquine, as compared to standard of care, while there is an increased risk of adverse events. Where there is no benefit and evidence of potential harm, a strong recommendation against the intervention is justified. 

Recommendation:

The panel suggests NOT to offer azithromycin to hospitalised patients with COVID-19 in the absence of bacterial infection (conditional recommendation, very low quality of evidence).

Azithromycin is a macrolide antibiotic with reported antiviral and immunomodulatory activities, and also a well-documented effect on exacerbation rate in patients with chronic lung diseases, including asthma and bronchiectasis. 73, 74 It is one of the most popular antibiotics used in inpatients and outpatients with acute respiratory infections worldwide. 75 Azithromycin is widely available and has a well-established safety profile.

The literature search identified three randomized studies which investigated azithromycin. One study, from Brazil COALITION 1, examined azithromycin plus hydroxychloroquine vs hydroxychloroquine alone. 64 Since hydroxychloroquine has been shown to have no beneficial effect and was regarded as standard of care in many parts of the world during the early part of the pandemic, the panel judged that this data could be used to infer the efficacy of azithromycin. Two studies were identified that examined the effect of azithromycin alone in hospitalised patients, COALITION 2, also performed in Brazil 76 and an open label trial performed by Sekhavati et al. 77 These individual trials, and the pooled data from these three trials demonstrate no difference in mortality odds ratio 1.02 (0.69-1.49), length of hospital stay, clinical status or deterioration.

Bacterial co-infection is reported infrequently in COVID-19 patients, with a systematic review suggestion <10% of patients isolate a bacterial pathogen 78 but there may still be a role for antibiotics in selected patients with proven or strongly suspected bacterial co-infection. The authors therefore recommend against routine use specifically for COVID-19 but acknowledge use for other indications outside the scope of this guideline. Although adverse events were not increased in COVID-19 patients in these 3 trials, long term concerns such as antimicrobial resistance that may result from widespread use of azithromycin should be considered. 75

The panel is aware at the time of writing that results of the azithromycin treatment arm of RECOVERY have been announced indicating no benefit of azithromycin in COVID-19. 79 These were not included in our meta-analysis but support our recommendation.

The panel recommends studies into the frequency of bacterial co-infection in COVID-19 patients utilising molecular techniques and/or biomarkers in view of the outstanding question over the use of antibiotics in this disease. other side effects. 80 The committee recommends studying other antiviral options in well-designed studies of repurposed or SARS-CoV-2 specific medications.

Recommendation: The panel suggests NOT to offer colchicine to patients hospitalised with COVID-19 (conditional recommendation, very low quality of evidence).

The intense inflammatory response following a SARS-CoV-2 infection prompted the investigation of other possible anti-inflammatory therapies which do not show similar adverse effects as seen with corticosteroid or other non-steroidal anti-inflammatory treatments.

Colchicine is considered to have anti-inflammatory properties through targeting IL-1 and IL-6 in hyperinflammatory syndromes and blocking the inflammasome as well as having in-vitro evidence for blocking the coagulation pathway and thrombosis. 81 85 This was in contrast with a second and earlier analysis on 100 randomized patients, where no difference in hospitalisation length was seen (median: 12 vs 13; p=0.91). 86 Deftereos et al.

did however show a significant improvement in time to clinical deterioration in participants receiving colchicine (cumulative event-free 10-day survival of 83% in the control vs 93% in the colchicine group; p=0.03). The confidence intervals of these effects estimates are wide due to the low number of patients studied to date. 86 The benefit of colchicine is uncertain as both trials had a small sample size. There is no consistency in the reported effect on length of hospital stay. The effect of colchicine in the GRECCO-19 trial on a lower risk of deterioration was also based on a small number of events and is therefore uncertain in nature. Other important endpoints such as ICU admission (OR 1.06 95% CI 0.06-18.45) and mortality (OR 0.21 95% 0.02-1.97) were not significantly reduced with therapy, and the studies were underpowered to address these endpoints. Moreover, a significant increase in adverse events (mainly diarrhea) was noted with the administration of colchicine (OR 3.96 95% CI 1.72-9.12), which may be expected based longstanding experience with this drug.

The lack of clear benefits with an increase in adverse events results in a recommendation against use while awaiting further data.

Research recommendations: Colchicine should be evaluated in large randomized controlled trials and at the time of writing it has been added to the large pragmatic RECOVERY trial. 

The panel recommends NOT to offer Lopinavir-ritonavir to hospitalised patients with COVID-19

(strong recommendation, low quality of evidence).

Lopinavir is a human immunodeficiency virus (HIV) type 1 aspartate protease inhibitor, which is usually combined to ritonavir to increase its plasma half-life through inhibition of cytochrome P450. 87 These drugs are widely available as a drug in clinical use for HIV. The combination was shown to reduce the risk of adverse clinical outcomes and viral load among patients with SARS as compared to historical controls. 88 

Lopinavir-ritonavir has a known adverse event profile and significant drug-drug interactions which present potential for patient harm. 91, 92 Therefore, clear evidence of efficacy would be required to recommend its use. The literature review found no evidence of benefit across 3 randomized controlled trials. As the drug is not effective and may theoretically be harmful, this justifies a strong recommendation against its use even considering the low quality of available evidence.

As two very large trials show no benefit, no further trials of lopinavir-ritonavir in this population are justified.

(defined as no treatment, placebo or background therapy according to local practice)?

The panel makes no recommendation regarding the use of remdesivir in patients hospitalised with COVID-19 and not requiring invasive mechanical ventilation (no recommendation, moderate quality of evidence)

The panel suggests NOT to offer remdesivir to patients hospitalised with COVID-19 who require invasive mechanical ventilation (conditional recommendation, moderate quality of evidence)

Remdesivir is an inhibitor of the viral RNA-dependent RNA polymerase. It has proven effective invitro against SARS-CoV-1, MERS-CoV and SARS-CoV-2. 93, 94 A reduction in time to recovery and length of hospital stay was demonstrated for remdesivir in one trial (ACTT1). 95 This trial randomized 1062 patients (541 to remdesivir and 521 to placebo). 95 The primary outcome of recovery time was reduced from 15 days to 10 days (rate ratio for recovery 1.29 95% CI 1.12-1.48,p<0.001). Length of hospital stay was also reduced from a median of 17 days to 12 days, and other secondary endpoints showed positive benefits. 95 In ACTT1 no benefit on the primary outcome of clinical recovery (Recovery rate ratio 0.98 95% CI 0.70-1.36) was observed in patients who started remdesivir when they were already on mechanical ventilation or extracorporeal membrane oxygenation. 95 If treatment is given it should be given for 5 days based on evidence that this is at least as effective as 10 days administration. 96 to recovery in hospitalised patients in another study (ACTT2). 97 Further data on remdesivir, with or without additional therapies, against standard of care will be required to conclusively demonstrate clinical benefit.

Recommendation: The panel suggests NOT to offer Interferon-β to hospitalised patients with COVID-19 (conditional recommendation, very low quality of evidence).

Interferons are signaling proteins released by host cells as a component of innate immune system in response to viral infections. 7,98 Type 1 interferons have in-vitro activity against coronaviruses 99 , and in-vivo promoted improved symptoms and viral clearance as part of a triple therapy regimen also containing lopinavir-ritonavir and ribavirin compared to lopinavirritonavir alone. 100 There is evidence that SARS-CoV-2 suppresses innate interferon release and the extent of this is linked to disease severity. 98 All of this provides a sound rationale for evaluating interferon as a therapy for COVID-19.

Our literature review identified three trials. 30,101,102 Two small proof of concept trials showed large benefits including reduced mortality 101,102 but a much larger trial (the WHO SOLIDARITY trial)

suggests no evidence of benefit and potential harm (rate ratio 1.16 95% CI 0.96-1.39,p=0.11). Our pooled estimate of these three trials showed no statistically significant mortality benefit or benefit on clinical deterioration. The quality of evidence was rated as very low.

systemic interferon treatment. The largest trial on this drug showed no effect on mortality and a trend towards an increase in mortality. Safety data is incompletely reported across all trials. In the absence of clear benefit or safety, a recommendation for use cannot be made. The conditional recommendation is based on very low quality of evidence. of good and fair quality. Risk reduction was significant with both prophylactic and therapeutic anticoagulation therapy, but these options could be compared in only three studies providing adjusted estimates, which significantly favoured therapeutic doses but needs to be weighed against potential harm (i.e., bleeding events). 107 The panel notes that the high frequency of pulmonary embolism in patients hospitalised with COVID-19 justifies a low threshold for investigation e.g with CT pulmonary angiogram in severe patients or those that experience a deterioration in oxygenation 105 as a diagnosis of VTE will impact on the indicated dose and length of anticoagulation.

Although the quality of evidence is very low, prophylactic anticoagulation is routine practice for hospitalised patients at risk of thromboembolic complications in hospitals in many countries and the existing evidence and existing practice makes this an intervention that can be strongly advocated. The panel are unable to determine whether the benefit-risk balance is superior for prophylactic vs therapeutic dose anticoagulation nor to identify subgroups with different benefit-risk ratios, and therefore rather than recommending one or the other, the panel makes clear that this is a matter for clinical judgement while awaiting randomised clinical trials. COVID-19-induced acute respiratory distress syndrome (ARDS) is a heterogeneous condition and the presence of specific phenotypes defined by physiological and biochemical markers is debated. 7, [132] [133] [134] [135] There is no RCT on timing of intubation in COVID-19 induced ARDS. A review of the evidence around invasive ventilatory strategies is beyond the scope of the present guideline. Low tidal volume ventilation unless contraindicated, prone positioning and corticosteroid therapy as described elsewhere reduces mortality in patients receiving invasive ventilation. 49, 136, 137 Venous-venous extracorporeal membrane oxygenation (ECMO) is used in patients with refractory hypoxemia despite optimal conventional ventilation and adjunctive interventions. 138 Case series

show encouraging results but there has been no RCT. ECMO is both staffing and resource intensive.

There are no RCTs completed yet comparing either HFNC or CPAP or NIV with standard oxygen therapy, or the three interventions in COVID-19 patients with hARF. However, reducing the need for invasive ventilation and pressure on ICU healthcare resources would be highly advantageous. This is a living guideline with the panel continuously reviewing new evidence as it arises.

Recommendations for additional therapies not addressed in this guideline such as convalescent plasma, monoclonal antibodies directed against SARS-CoV-2 and other therapies will be added in future versions, along with updates on the therapies already reviewed once new data are available.

The guidelines published by the European Respiratory Society (ERS) incorporate data obtained from a comprehensive and systematic literature review of the most recent studies available at the time.

Health professionals are encouraged to take the guidelines into account in their clinical practice. However, the recommendations issued by this guideline may not be appropriate for use in all situations. It is the individual responsibility of health professionals to consult other sources of relevant information, to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and the patient's caregiver where appropriate and/or necessary, and to verify rules and regulations applicable to drugs and devices at the time of prescription 

Systematic review Two experienced external librarians (TV, KT) designed and ran a search strategy using MeSH terms and keywords for each clinical question, in collaboration with the methodologists (PCG, MLC, JDC). The PubMed platform was used to search MEDLINE. EMBASE, International Clinical Trials Registry Platform (ICTRP) and CDC were also searched. The search was initially limited to randomised clinical trials published in English language. In the absence of clinical trials, we subsequently searched for observational studies. All searches were performed systematically through October 2020. The search retrieved 11,343 records after removal of duplicates with a further 11,316 citations excluded through title and abstract screening. A search of MedRxiv database identified 10 further preprints. For the anticoagulation data, 1 meta-analysis detailing 3 studies was identified. A total of 40 references were included in the evidence summaries and all were assessed in full text by at least two authors who determined inclusion by consensus; disagreements were resolved by consultation to guideline panel chairs. All authors monitored the literature up to October 2020.

The panel selected outcomes of interest for each clinical question a priori, based on their relative importance to adult patients with COVID-19 and to clinical decision making. Following the GRADE approach, outcomes were rated as "not important", "important" or "critical" for clinical decision making through an online vote of the entire panel. Only outcomes that were considered important or critical were subsequently used to formulate recommendations.

A methodology group composed of one chair (JDC) and two members (PCG and MLC) extracted the data in duplicate from relevant publications reporting important or critical outcomes and pooled them, whenever applicable, using RevMan 5 software version 5.3. The process of literature search, data extraction and reporting were supervised by an experienced ERS methodologist (TT). We followed the GRADE approach to assess the confidence in the evidence (quality) and the degree of recommendations. This approach specifies four categories of quality (high, moderate, low and very low) that are applied to a body of evidence and not on individual studies. The body of evidence was evaluated based primarily on risk of bias, precision, consistency, directness of evidence and risk of publication bias.

Recommendations are graded as strong or conditional after considering the quality of the evidence, the balance of desirable and undesirable consequences of compared management options, the assumptions about the relative importance of outcomes, the implications for resource use, and the acceptability and feasibility of implementation. Evidence summaries of findings (SoF tables) and Evidence to Decisions (EtD) frameworks were generated by the methodology group for each clinical question using the GRADEpro Guideline Development Tool. Based on these formats, the panel formulated the clinical recommendations and decided on their strength by consensus and, if required, by voting. Following the GRADE approach, strong recommendations are worded as "we recommend", while conditional recommendations are worded as "we suggest".

PICO Additional endpoints not included in the evidence table which were searched for but were either not studied or data was not found in an extractable format were; Requirement for oxygen; Ordinal scale or clinical status at day 28; ICU length of stay; DLCO and HRCT at 28 days and 3 months (and 6months); Hospital length of stay; Severity of symptoms; Improvement in oxygen saturations or arterial blood gases; Relapse; Viral clearance (negative SARS-CoV-2 test) and Duration of fever. 15) , Need for noninvasive ventilation, need for mechanical ventilation, Hospital length of stay and Adverse events were the measurable endpoint found for hydroxychloroquine and azithromycin combination treatment. Additional endpoints not included in the evidence table which were searched for but were either not studied or data was not found in an extractable format were; Need for ICU admission (incorporating mechanical ventilation/shock/ARDS); Clinical resolution or cure (also includes the reverse i.e patients not cured); Requirement for oxygen; Hospital admission; Ordinal scale or clinical status at day 28; ICU length of stay; Deterioration in those not requiring ventilation at start of treatment; DLCO and HRCT at 28 days and 3 months (and 6months); Severity of symptoms; Improvement in oxygen saturations or arterial blood gases; Relapse; Viral clearance (negative SARS-CoV-2 test) and Duration of fever. Additional endpoints not included in the evidence table which were searched for but were either not studied or data was not found in an extractable format were; Clinical resolution or cure (also includes the reverse i.e patients not cured); Time to clinical improvement or resolution on an ordinal scale; Requirement for oxygen; Hospital admission; Ordinal scale or clinical status at day 28; ICU length of stay; Need for non-invasive ventilation; DLCO and HRCT at 28 days and 3 months (and 6months); Hospital length of stay; Severity of symptoms; Improvement in oxygen saturations or arterial blood gases; Relapse; Viral clearance (negative SARS-CoV-2 test) and Duration of fever. Additional endpoints not included in the evidence table which were searched for but were either not studied or data was not found in an extractable format were; Need for ICU admission (incorporating mechanical ventilation/shock/ARDS); Clinical resolution or cure (also includes the reverse i.e patients not cured); Requirement for oxygen; Hospital admission; Hospital length of stay; Need for non-invasive ventilation; Ordinal scale or clinical status at day 28; ICU length of stay; Deterioration in those not requiring ventilation at start of treatment; DLCO and HRCT at 28 days and 3 months (and 6months); Severity of symptoms; Improvement in oxygen saturations or arterial blood gases; Relapse; and Duration of fever. Additional endpoints not included in the evidence table which were searched for but were either not studied or data was not found in an extractable format were; Deterioration in those not requiring ventilation at start of treatment; Requirement for oxygen; Hospital admission; ICU length of stay; Need for non-invasive ventilation; DLCO and HRCT at 28 days and 3 months (and 6months); Hospital length of stay; Severity of symptoms; Improvement in oxygen saturations or arterial blood gases; Relapse and Duration of fever. Explanations a. Clear differences in the propensity to prescribe anticoagulation which are partially but not fully adjusted for.

b. Heterogeneity statistic (I2=87%) and visual inspection of funnel plots shows major inconsistency between studies with some suggesting a beneficial effect and one suggesting a detrimental effect.

N.B. Mortality was the only measurable endpoint found for anti-coagulants. Additional endpoints not included in the evidence table which were searched for but were either not studied or data was not found in an extractable format were; Need for ICU admission (incorporating mechanical ventilation/shock/ARDS); Clinical resolution or cure (also includes the reverse i.e patients not cured); Time to clinical improvement or resolution on an ordinal scale; Adverse events; Requirement for oxygen; Hospital admission; Ordinal scale or clinical status at day 28; ICU length of stay; Need for non-invasive ventilation; Deterioration in those not requiring ventilation at start of treatment; DLCO and HRCT at 28 days and 3 months (and 6months); Hospital length of stay; Severity of symptoms; Improvement in oxygen saturations or arterial blood gases; Relapse; Viral clearance (negative SARS-CoV-2 test) and Duration of fever. Searches for Interferon and Colchicine were conducted using these individual search terms PLUS the COVID-19 concept using PUBMED only. ERS rules allow searches of one database only. As it was expected that searches for hydroxychloroquine and Azithromycin individually would capture trials in which both drugs were used in combination, no repeat searches were performed and trials were selected from the hydroxychloroquine and azithromycin search results for inclusion in the evidence tables. 'glucocorticoid'/exp OR glucocorticoid*:ti,ab,kw OR glucocorticoidsteroid:ti,ab,kw OR glucocorticosteroid:ti,ab,kw OR glucocortoid:ti,ab,kw OR glycocorticoid:ti,ab,kw OR glycocorticosteroid:ti,ab,kw OR corticosteroid*:ti,ab,kw OR corticoid*:ti,ab,kw OR steroid*:ti,ab,kw OR 'prednisolone'/exp OR prednisolone:ti,ab,kw OR adelcort:ti,ab,kw OR antisolon:ti,ab,kw OR antisolone:ti,ab,kw OR aprednislon:ti,ab,kw OR aprednislone:ti,ab,kw OR benisolon:ti,ab,kw OR benisolone:ti,ab,kw OR berisolon:ti,ab,kw OR berisolone:ti,ab,kw OR caberdelta:ti,ab,kw OR capsoid:ti,ab,kw OR 'co hydeltra':ti,ab,kw OR codelcortone:ti,ab,kw OR compresolon:ti,ab,kw OR cortadeltona:ti,ab,kw OR cortadeltone:ti,ab,kw OR cortalone:ti,ab,kw OR cortelinter:ti,ab,kw OR cortisolone:ti,ab,kw OR cotolone:ti,ab,kw OR dacortin:ti,ab,kw OR dacrotin:ti,ab,kw OR decaprednil:ti,ab,kw OR 'decortin h':ti,ab,kw OR decortril:ti,ab,kw OR 'dehydro cortex':ti,ab,kw OR dehydrocortex:ti,ab,kw OR dehydrocortisol:ti,ab,kw OR dehydrocortisole:ti,ab,kw OR dehydrohydrocortison:ti,ab,kw OR dehydrohydrocortisone:ti,ab,kw OR delcortol:ti,ab,kw OR 'delta cortef':ti,ab,kw OR 'delta cortril':ti,ab,kw OR 'delta ef cortelan':ti,ab,kw OR 'delta f':ti,ab,kw OR 'delta hycortol':ti,ab,kw OR 'delta ophticor':ti,ab,kw OR 'delta stab':ti,ab,kw OR 'delta1 dehydrocortisol':ti,ab,kw OR 'delta1 dehydrohydrocortisone':ti,ab,kw OR deltacortef:ti,ab,kw OR deltacortenolo:ti,ab,kw OR deltacortil:ti,ab,kw OR deltacortoil:ti,ab,kw OR deltacortril:ti,ab,kw OR deltaderm:ti,ab,kw OR deltaglycortril:ti,ab,kw OR deltahycortol:ti,ab,kw OR deltahydrocortison:ti,ab,kw OR deltahydrocortisone:ti,ab,kw OR deltaophticor:ti,ab,kw OR deltasolone:ti,ab,kw OR deltastab:ti,ab,kw OR deltidrosol:ti,ab,kw OR deltisilone:ti,ab,kw

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Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial

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In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19

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Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial

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Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial

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Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label

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methacort 40':ti,ab,kw OR 'methacort 80':ti,ab,kw OR methylcotol:ti,ab,kw OR methylcotolone:ti,ab,kw OR 'methylpred dp':ti,ab,kw OR methylsterolone:ti,ab,kw OR metidrol:ti,ab,kw OR metrisone:ti,ab,kw OR metycortin:ti,ab,kw OR metypred:ti,ab,kw OR metypresol:ti,ab,kw OR neomedrone:ti,ab,kw OR 'nsc 19987':ti,ab,kw OR 'nsc19987':ti,ab,kw OR prednol:ti,ab,kw OR solomet:ti,ab,kw OR 'solu decortin':ti,ab,kw OR urbason:ti,ab,kw OR 'dexamethasone'/exp OR dexamethasone:ti,ab,kw OR adrecort:ti,ab,kw OR adrenocot:ti,ab,kw OR 'aeroseb dex':ti,ab,kw OR aflucoson:ti,ab,kw OR aflucosone:ti,ab,kw OR alfalyl:ti,ab,kw OR anaflogistico:ti,ab,kw OR arcodexan:ti,ab,kw OR arcodexane:ti,ab,kw OR artrosone:ti,ab,kw OR azium:ti,ab,kw OR bidexol:ti,ab,kw OR calonat:ti,ab,kw OR cebedex:ti,ab,kw OR cetadexon:ti,ab,kw OR colofoam:ti,ab,kw OR corsona:ti,ab,kw OR cortastat:ti,ab,kw OR cortidex:ti,ab,kw OR cortidexason:ti,ab,kw OR cortidrona:ti,ab,kw OR cortidrone:ti,ab,kw OR cortisumman:ti,ab,kw OR 'dacortina fuerte':ti,ab,kw OR 'dacortine fuerte':ti,ab,kw OR dalalone:ti,ab,kw OR danasone:ti,ab,kw OR 'de-sone la':ti,ab,kw OR decacortin:ti,ab,kw OR decadeltosona:ti,ab,kw OR decadeltosone:ti,ab,kw OR decaderm:ti,ab,kw OR decadion:ti,ab,kw OR decadran:ti,ab,kw OR decadron:ti,ab,kw OR decadronal:ti,ab,kw OR decadrone:ti,ab,kw OR decaesadril:ti,ab,kw OR decaject:ti,ab,kw OR decamethasone:ti,ab,kw OR decasone:ti,ab,kw OR decaspray:ti,ab,kw OR decasterolone:ti,ab,kw OR decdan:ti,ab,kw OR decilone:ti,ab,kw OR decofluor:ti,ab,kw OR dectancyl:ti,ab,kw OR dekacort:ti,ab,kw OR delladec:ti,ab,kw OR deltafluoren:ti,ab,kw OR deltafluorene:ti,ab,kw OR dergramin:ti,ab,kw OR deronil:ti,ab,kw OR desacort:ti,ab,kw OR desacortone:ti,ab,kw OR desadrene:ti,ab,kw OR desalark:ti,ab,kw OR desameton:ti,ab,kw OR desametone:ti,ab,kw OR desigdron:ti,ab,kw OR 'dexa cortisyl':ti,ab,kw OR 'dexa dabrosan':ti,ab,kw OR 'dexa korti':ti,ab,kw OR 'dexa scherosan':ti,ab,kw OR 'dexa scherozon':ti,ab,kw OR 'dexa scherozone':ti,ab,kw OR 'dexap':ti,ab,kw OR 'dexacen 4':ti,ab,kw OR dexachel:ti,ab,kw OR dexacort:ti,ab,kw OR dexacortal:ti,ab,kw OR dexacorten:ti,ab,kw OR dexacortin:ti,ab,kw OR dexacortisyl:ti,ab,kw OR dexadabroson:ti,ab,kw OR dexadecadrol:ti,ab,kw OR dexadrol:ti,ab,kw OR dexagel:ti,ab,kw OR dexagen:ti,ab,kw OR dexahelvacort:ti,ab,kw OR dexakorti:ti,ab,kw OR dexalien:ti,ab,kw OR dexalocal:ti,ab,kw OR dexame:ti,ab,kw OR dexamecortin:ti,ab,kw OR dexameson:ti,ab,kw OR dexamesone:ti,ab,kw OR dexametason:ti,ab,kw OR dexametasone:ti,ab,kw OR dexameth:ti,ab,kw OR dexamethason:ti,ab,kw OR dexamethazon:ti,ab,kw OR dexamethazone:ti,ab,kw OR dexamethonium:ti,ab,kw OR dexamonozon:ti,ab,kw OR dexan:ti,ab,kw OR dexane:ti,ab,kw OR dexano:ti,ab,kw OR dexapot:ti,ab,kw OR dexascheroson:ti,ab,kw OR dexascherozon:ti,ab,kw OR dexascherozone:ti,ab,kw OR dexason:ti,ab,kw OR dexasone:ti,ab,kw OR dexinoral:ti,ab,kw OR dexionil:ti,ab,kw OR dexmethsone:ti,ab,kw OR dexona:ti,ab,kw OR dexone:ti,ab,kw OR 'dexpak':ti,ab,kw OR dextelan:ti,ab,kw OR dextenza:ti,ab,kw OR dextrasone:ti,ab,kw OR dexycu:ti,ab,kw OR dezone:ti,ab,kw OR dibasona:ti,ab,kw OR doxamethasone:ti,ab,kw OR esacortene:ti,ab,kw OR 'ex s1':ti,ab,kw OR exadion:ti,ab,kw OR exadione:ti,ab,kw OR firmalone:ti,ab,kw OR fluormethylprednisolon:ti,ab,kw OR fluormethylprednisolone:ti,ab,kw OR fluormone:ti,ab,kw OR fluorocort:ti,ab,kw OR fluorodelta:ti,ab,kw OR fluoromethylprednisolone:ti,ab,kw OR fortecortin:ti,ab,kw OR gammacorten:ti,ab,kw OR gammacortene:ti,ab,kw OR grosodexon:ti,ab,kw OR grosodexone:ti,ab,kw OR hemady:ti,ab,kw OR hexadecadiol:ti,ab,kw OR hexadecadrol:ti,ab,kw OR hexadiol:ti,ab,kw OR hexadrol:ti,ab,kw OR isnacort:ti,ab,kw OR 'isopto dex':ti,ab,kw OR 'isopto maxidex':ti,ab,kw OR isoptodex:ti,ab,kw OR isoptomaxidex:ti,ab,kw OR 'lokalison f':ti,ab,kw OR loverine:ti,ab,kw OR luxazone:ti,ab,kw OR marvidione:ti,ab,kw OR maxidex:ti,ab,kw OR mediamethasone:ti,ab,kw OR megacortin:ti,ab,kw OR mephameson:ti,ab,kw OR mephamesone:ti,ab,kw OR metasolon:ti,ab,kw OR metasolone:ti,ab,kw OR 'methazon ion':ti,ab,kw OR 'methazone ion':ti,ab,kw OR methazonion:ti,ab,kw OR methazonione:ti,ab,kw OR 'metisone lafi':ti,ab,kw OR mexasone:ti,ab,kw OR millicorten:ti,ab,kw OR millicortenol:ti,ab,kw OR 'mk 125':ti,ab,kw OR mk125:ti,ab,kw OR mymethasone:ti,ab,kw OR neoforderx:ti,ab,kw OR neofordex:ti,ab,kw OR nisomethasona:ti,ab,kw OR novocort:ti,ab,kw OR 'nsc 34521':ti,ab,kw OR nsc34521:ti,ab,kw OR 'oftan-dexa':ti,ab,kw OR opticorten:ti,ab,kw OR opticortinol:ti,ab,kw OR oradexan:ti,ab,kw OR oradexon:ti,ab,kw OR oradexone:ti,ab,kw OR orgadrone:ti,ab,kw OR ozurdex:ti,ab,kw OR pidexon:ti,ab,kw OR policort:ti,ab,kw OR posurdex:ti,ab,kw OR 'predni-f':ti,ab,kw OR prodexona:ti,ab,kw OR prodexone:ti,ab,kw OR sanamethasone:ti,ab,kw OR santenson:ti,ab,kw OR santeson:ti,ab,kw OR sawasone:ti,ab,kw OR solurex:ti,ab,kw OR spoloven:ti,ab,kw OR sterasone:ti,ab,kw OR thilodexine:ti,ab,kw OR triamcimetil:ti,ab,kw OR vexamet:ti,ab,kw OR visumetazone:ti,ab,kw OR visumethazone:ti,ab,kw OR Methylfluorprednisolone:ti,ab,kw OR methylfluorprednisolon:ti,ab,kw OR decameth:ti,ab,kw OR 'hydrocortisone'/exp OR hydrocortisone:ti,ab,kw OR acticort:ti,ab,kw OR 'aeroseb hc':ti,ab,kw OR 'ala-cort':ti,ab,kw OR 'ala-scalp':ti,ab,kw OR alfacort:ti,ab,kw OR algicortis:ti,ab,kw OR alkindi:ti,ab,kw OR 'alpha derm':ti,ab,kw OR alphaderm:ti,ab,kw OR 'anucort-hc':ti,ab,kw OR 'anumed-hc':ti,ab,kw OR 'anutone-hc':ti,ab,kw OR 'aquanil hc':ti,ab,kw OR 'balneol-hc':ti,ab,kw OR 'barseb hc':ti,ab,kw OR 'beta-hc':ti,ab,kw OR biacort:ti,ab,kw OR cetacort:ti,ab,kw OR cobadex:ti,ab,kw OR colocort:ti,ab,kw OR 'compound f':ti,ab,kw OR 'cordicare lotion':ti,ab,kw OR coripen:ti,ab,kw OR 'cort dome':ti,ab,kw OR cortef:ti,ab,kw OR cortenema:ti,ab,kw OR cortibel:ti,ab,kw OR corticorenol:ti,ab,kw OR cortifan:ti,ab,kw OR cortiphate:ti,ab,kw OR cortisol:ti,ab,kw OR cortisole:ti,ab,kw OR cortispray:ti,ab,kw OR cortoderm:ti,ab,kw OR cortril:ti,ab,kw OR cotacort:ti,ab,kw OR covocort:ti,ab,kw OR 'cremicort-h':ti,ab,kw OR cutaderm:ti,ab,kw OR 'derm-aid cream':ti,ab,kw OR 'dermacrin hc lotion':ti,ab,kw OR dermaid:ti,ab,kw OR dermocare:ti,ab,kw OR dermocortal:ti,ab,kw OR dermolate:ti,ab,kw OR dioderm:ti,ab,kw OR eczacort:ti,ab,kw OR 'ef cortelan':ti,ab,kw OR efcortelan:ti,ab,kw OR egocort:ti,ab,kw OR eksalb:ti,ab,kw OR eldecort:ti,ab,kw OR 'emo-cort':ti,ab,kw OR epicort:ti,ab,kw OR ficortril:ti,ab,kw OR filocot:ti,ab,kw OR flexicort:ti,ab,kw OR 'gly-cort':ti,ab,kw OR glycort:ti,ab,kw OR 'h-cort':ti,ab,kw OR hc:ti,ab,kw OR hebcort:ti,ab,kw OR 'hemril-30':ti,ab,kw OR 'hemril-hc uniserts':ti,ab,kw OR 'hi-cor':ti,ab,kw OR hidrotisona:ti,ab,kw OR hycor:ti,ab,kw OR hycort:ti,ab,kw OR hydracort:ti,ab,kw OR hydrasson:ti,ab,kw OR 'hydro ricortex':ti,ab,kw OR 'hydro-rx':ti,ab,kw OR hydrocort:ti,ab,kw OR hydrocorticosteroid:ti,ab,kw OR hydrocortisate:ti,ab,kw OR hydrocortison:ti,ab,kw OR hydrocortisonum:ti,ab,kw OR hydrocortisyl:ti,ab,kw OR hydrocortone:ti,ab,kw OR hydrogalen:ti,ab,kw OR hydrokort:ti,ab,kw OR hydrokortison:ti,ab,kw OR hydrotopic:ti,ab,kw OR hysone:ti,ab,kw OR hytisone:ti,ab,kw OR hytone:ti,ab,kw OR 'incortin h':ti,ab,kw OR 'instacort 10':ti,ab,kw OR kyypakkaus:ti,ab,kw OR 'lacticare-hc':ti,ab,kw OR lenirit:ti,ab,kw OR 'medihaler cort':ti,ab,kw OR 'medihaler duo':ti,ab,kw OR medrocil:ti,ab,kw OR mildison:ti,ab,kw OR 'mildison-fatty':ti,ab,kw OR 'mitocortyl demangeaisons':ti,ab,kw OR munitren:ti,ab,kw OR novohydrocort:ti,ab,kw OR 'nsc 10483':ti,ab,kw OR 'nsc 741':ti,ab,kw OR 'nsc10483':ti,ab,kw OR nutracort:ti,ab,kw OR optef:ti,ab,kw OR 'otosone f':ti,ab,kw OR penecort:ti,ab,kw OR plenadren:ti,ab,kw OR prepcort:ti,ab,kw OR 'pro cort':ti,ab,kw OR procort:ti,ab,kw OR 'procto-kit':ti,ab,kw OR proctocort:ti,ab,kw OR 'proctosol-hc':ti,ab,kw OR proctosone:ti,ab,kw OR procutan:ti,ab,kw OR 'rectasol-hc':ti,ab,kw OR rectocort:ti,ab,kw OR rederm:ti,ab,kw OR sanatison:ti,ab,kw OR 'scalp-aid':ti,ab,kw OR schericur:ti,ab,kw OR 'scherosone f':ti,ab,kw OR 'sistral hydrocort':ti,ab,kw OR skincalm:ti,ab,kw OR 'stie-cort':ti,ab,kw OR 'substance m':ti,ab,kw OR synacort:ti,ab,kw OR texacort:ti,ab,kw OR 'triburon-hc

The analysis shows a clinically meaningful reduction in mortality.This effect is even greater in the mechanical ventilation subgroup.The effect in the mechanically ventilated subgroup has been confirmed in a meta-analysis of all trials in critically ill patients with a rate ratio of 0.70.The magnitude of benefit may be smaller in those requiring oxygen without mechanical ventilation but remains clinically meaningful.

How substantial are the undesirable anticipated effects?Adverse events were not reported in the largest trial, but smaller trials show few safety concerns. There is a well-known safety profile for corticosteroids with adverse effects including hyperglycaemia, bruising, confusion and secondary infections.What is the overall certainty of the evidence of effects?The certainty of the most critical endpoint, mortality is high, however adverse events are rated as low. As the majority of endpoints that are important for clinical decision making are rated as high to moderate according to GRADE methodology, the overall quality is regarded as moderate. The consistency of benefit in the meta-analysis for critically ill patients increases certainty that the effect seen in the largest trial (RECOVERY) is generalizable. 

The panel recommends treatment with corticosteroids for patients with COVID-19 infection requiring oxygen, non-invasive mechanical ventilation or invasive mechanical ventilation (strong recommendation, moderate quality of overall evidence)The panel recommends NOT to offer corticosteroids to patients with COVID-19 infection requiring hospitalisation but not requiring supplementary oxygen or ventilatory support (strong recommendation, moderate quality of evidence)

The overall risk versus benefit for corticosteroids is favourable with a clear reduction in mortality and improvement in other clinically relevant endpoints. The consistent results across all trials is reassuring that the data from the largest trial is generalizable.

Recommendations based on subgroups are justified as there is no evidence of benefit in the subgroup of patients without requirement for oxygen.

The largest trial used dexamethasone 6mg daily for 10 days and so it is reasonable to suggest this regimen is implemented where possible. The meta-analysis in critically ill patients suggests a similar trend with other corticosteroids and so where dexamethasone is not available it is reasonable to use alternative steroids.

Although not reported in trials, care should be taken with patients at higher risk of steroid related adverse effects such as patients with diabetes mellitus. Steroids can exacerbate delirium in elderly patients who are also the population most at risk of severe COVID-19.

Further data on adverse effects and to identify the optimal patient population and treatment duration would be welcome. A reduction in patients requiring intensive care unit admission or mechanical ventilation was observed in the pooled analysis. No reduction in mortality was demonstrated in the pooled analysis, but the two largest studies showed an overall reduction in mortality in patients in the intensive care unit, and in the RECOVERY trial with requirement for oxygen and raised C-reactive protein.In the RECOVERY trial the effect appears to be greatest when added to corticosteroids. The benefit was otherwise similar across a number of different subgroups of patients.

How substantial are the undesirable anticipated effects?No increase in adverse events or serious adverse events were noted. Anti-IL-6 therapy can increase the risk of infections and it was noted that reporting of adverse effects was incomplete in the largest trials included. This has not been formally assessed. As there is significant uncertainty about the benefits and risks of this treatment, it is hard to estimate any effect on health equity.

○ No ○ Probably no ○ Probably yes X Yes ○ Varies ○ Don't knowThe treatment has been used in rheumatoid arthritis, is relatively easy to administer and is therefore likely to be acceptable.

○ No ○ Probably no X Probably yes ○ Yes ○ VariesYes, the treatment is relatively easy to administer to hospitalised patients. it is hard to identify the optimal patient population to benefit from this treatment, but RECOVERY found a benefit in addition to treatment with corticosteroids. As corticosteroids are also recommended for patients requiring oxygen and ventilatory support, anti-IL-6 monoclonal antibody treatment would be expected to be given to patients also receiving corticosteroids in nearly all cases. Anti-IL-6 receptor therapy is relatively expensive but it is expected the benefits will outweigh the costs. Patient populations most likely to benefit include those meeting the inclusion criteria for REMAP-CAP (within 24 hours of requirement for noninvasive or invasive ventilatory support) and hospitalised patients requiring oxygen who are considered at high risk of requiring mechanical ventilation or who have progressed despite treatment with corticosteroids, which is consistent with patients enrolled in RECOVERY and other trials included in our analysis.

RECOVERY found no difference in the treatment effect between patients requiring oxygen treatment and CONSIDERATIONS those requiring additional ventilatory support. Therefore, the panel decided not to make different recommendations for patients requiring different levels of oxygen or ventilatory support. There is no evidence to support the use of anti-IL-6 receptor monoclonal antibody therapy in patients with COVID-19 infection and not requiring oxygen or ventilatory support.

RECOVERY showed an additive benefit of tocilizumab on top of corticosteroids and no evidence of benefit in the small group of patients who did not receive corticosteroids. Therefore IL-6 receptor monoclonal antibody therapy should be used in addition to corticosteroids unless corticosteroids are contraindicated. The median time from admission to treatment in RECOVERY was 2 days and in REMAP-CAP patients were treated within 24 hours of requirement for ventilatory support. Therefore, the strongest evidence supports administration of treatment as early in the hospital course as possible.

No adverse events or serious adverse events were observed. Nevertheless IL-6 receptor monoclonal antibody therapy carries a risk of increased infections and should be used with caution in patients with known or strongly suspected bacterial infection.

Further research is needed to identify the optimal patient population for treatment with anti-IL-6 receptor monoclonal antibody treatment.

Research evidence