key: cord-0688886-mva5mu5d authors: Bartoletti, Michele; Azap, Ozlem; Barac, Aleksandra; Bussini, Linda; Ergonul, Onder; Krause, Robert; Paño-Pardo, José Ramón; Power, Nicholas R.; Sibani, Marcella; Szabo, Balint Gergely; Tsiodras, Sotirios; Verweij, Paul E.; Zollner-Schwetz, Ines; Rodríguez-Baño, Jesús title: ESCMID COVID-19 Living guidelines: drug treatment and clinical management date: 2021-11-22 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2021.11.007 sha: 050cc1fb3c8325412364915a5571a40e3b1a5236 doc_id: 688886 cord_uid: mva5mu5d SCOPE: In January 2021, the ESCMID Executive Committee (EC) decided to launch a new initiative to develop ESCMID guidelines on several COVID19-related issues, including treatment of COVID-19. METHODS: An ESCMID COVID-19 guidelines task force was established by the ESCMID Executive Committee. A small group was established, half appointed by the chair, and the remaining selected with an open call. Each panel met virtually once a week. For all decisions, a simple majority vote was used. A long list of clinical questions using the PICO (population, intervention, comparison, outcome) format was developed at the beginning of the process. For each PICO, two panel members performed a literature search with a third panelist involved in case of inconsistent results. Voting was based on the GRADE approach. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: A synthesis of the available evidence and recommendations are provided for each of the 15 PICOs, which cover use of hydroxychloroquine, bamlanivimab alone or in combination with etesevimab, casirivimab combined with imdevimab, ivermectin, azithromycin and empirical antibiotics, colchicine, corticosteroids, convalescent plasma, favipiravir, remdesivir, tocilizumab, and interferon β-1a, as well as the utility of antifungal prophylaxis and enoxaparin. In general, the panel recommended against the use of hydroxychloroquine, ivermectin, azithromycin, colchicine, and interferon β-1a. Conditional recommendations were given for the use of monoclonal antibodies in high-risk outpatients with mild-moderate COVID-19, and remdesivir. There was insufficient evidence to make a recommendation for use of favipiravir and antifungal prophylaxis, and it was recommended that antibiotics should not be routinely prescribed in patients with COVID-19 unless bacterial coinfection or secondary infection is suspected or confirmed. Tocilizumab and corticosteroids was recommended for treatment of severe COVID-19 but not in outpatients with non-severe COVID-19. inconsistent results. The results of the searches were presented to the panel during weekly meetings for discussion and voting (quality of evidence, evidence-to-decision criteria, need for update, etc.) based on the GRADE approach. Definitions WHO severity criteria for COVID-19 were used [9] . Data from the European Center for Disease Prevention and Control (ECDC) was used to define risk factors and groups for severe COVID-19 [10] . For each PICO question, the motivations for use, patient preferences and additional comments are presented in Supplementary Appendix 1. A summary of all recommendations is presented in Table 2 . Twenty-three randomized trials in >10,000 patients have assessed the effect of hydroxychloroquine (HCQ) on COVID-19 compared with standard of care (SOC). For the present assessment, 19 trials were included ( Overall, in high-risk outpatients bamlanivimab alone (RR 0.26; 95% CI 0.09-0.75; Table 4 ) or combined with etesevimab (RR 0.30; 95% CI 0.16-0.59; Table 5 ) is associated with reduced hospitalization. Bamlanivimab plus etesevimab is also associated with reduction in 29-day mortality (RR 0.05; 95%CI 0.00-0.80) in the same population (Table 5) . Bamlanivimab was effective in preventing severe disease among residents and staff of long-term care facilities (BLAZE-2 trial) [33], but not in recovery of hospitalized patients [34] . In vitro studies suggest that bamlanivimab plus etesevimab retains in vitro susceptibility to the B.1.1.7 (Alpha -UK variant), but has markedly reduced activity against the P1 (Gamma, Brazilian) and B.1.351 (Beta, South African) variants. Lastly, the SARS-CoV-2 variant B.1.617 (Delta, Indian) seems to be resistant to bamlanivimab, but its activity may be restored when combined with etesevimab. 48]. The committee was thus uncertain whether ivermectin increased or decreased the chance of need for mechanical ventilation or death. While no serious adverse events were recorded (Table 7) , there was uncertainty with regards to adverse events and gastrointestinal effects were frequently reported in some studies. Common side effects associated with ivermectin included diarrhea, nausea, and dizziness. Strong recommendation against use of ivermectin to treat COVID-19 (QoE: low). Azithromycin was assessed in four randomized trials (1 in outpatients and 3 in hospitalized patients). In our analysis, it had no effect on 28-day mortality [RR 1.01; 95% CI 0.92-1.10), risk of disease progression (RR 0.94; 95% CI 0.79-1.14 for mechanical ventilation or ECMO; [20, 50] . Azithromycin was not associated with better outcomes in hospitalized patients [51] or outpatients [52] . Rates of adverse events and severe adverse events were similar in patients receiving azithromycin or SOC [49, 50, 52] . In the only study that assessed azithromycin and HCQ, adverse events and prolongation of the QTc interval were more frequent in patients receiving HCQ or HCQ plus azithromycin compared to controls [20] . [53] . Colchicine showed promising results in small preliminary RCTs [54, 55] . However, recent unrefereed results of RECOVERY comparing 28-day mortality in patients receiving colchicine (n=5160) or SOC (n=5730) showed no benefit (RR 1.01; 95% CI 0.93-1.10; p=0.77); this finding was similar in all pre-specified subgroups and in those with SARS-CoV-2 infection confirmed by molecular analysis [56] . Colchicine has known bone marrow toxicity and several dose-dependent gastrointestinal adverse effects [57] . In COLCORONA, the rate of serious adverse events was 4.9% and 6.3% (p=0.05) and drug-related adverse events were 24.2% and 15.5% (p<0.0001) in the intervention and placebo groups, respectively. Gastrointestinal adverse events were significantly increased with colchicine (23.9% vs 14.8%, p<0.0001) as was diarrhea (13.7% vs 7.3%, p<0.0001) [53] . In the GRECCO trial, no serious adverse events were reported, while adverse events were similar in the two groups with the exception of diarrhea which was mainly seen with colchicine (45.5% vs 18%; p=0.003) [54] . J o u r n a l P r e -p r o o f Strong recommendation against use of colchicine for COVID-19 (QoE: high). (Table 11) . There was no significant difference between corticosteroid and SOC considering severe adverse events and superinfections. However, corticosteroids are associated with an increase in hyperglycemia. Indirect evidence of corticosteroid use in patients with similar indications has shown no difference in the incidence of gastrointestinal bleeding, superinfections, neuromuscular weakness, or neuropsychiatric effects (Table 10) . severe COVID-19 compared to no treatment? [78] . Among patients on oxygen supplementation but who did not require highflow oxygen or ventilatory support (noninvasive or invasive), there was a significant mortality benefit (4.0% vs. 12.7%; HR 0.30; 95% CI 0.14-0.64 ). An open-label trial randomized hospitalized patients with moderate COVID-19 pneumonia to a 10-day (n=197) or 5-day course of remdesivir (n=199) or SOC (n=200). A 5-day course (odds ratio (OR) 1.65; 95% CI, 1.09-2.48; p=0.02) of remdesivir, but not a 10-day course (p=0.18), was associated with better clinical status at day 11 vs. SOC. No difference in all-cause 28-day mortality was seen [79] . Another open-label randomized trial compared 5-day to 10-day remdesivir in patients with severe COVID-19. The primary outcome was clinical status at day 14 and was similar between groups (p=0.18) [80] . A small and likely underpowered RCT in India did not show clinical improvement with remdesivir compared to SOC [81] . Lastly, a large observational trial suggested mortality benefit in patients treated with remdesivir compared to those not treated with remdesivir [82]. Remdesivir was associated with higher rate of adverse events in two studies, especially when administered for 10 days [79, 80] . These included nausea, hypokalemia, headache, and decrease in eGFR. However, a lower rate of serious adverse events was observed in one RCT [77] . Insufficient evidence to make a recommendation. Is antifungal prophylaxis associated with a lower incidence of coronavirusassociated pulmonary aspergillosis (CAPA) in mechanically-ventilated patients with critical COVID-19 compared to no prophylaxis? No antifungal agent is currently approved for prophylaxis in ICU-patients. Recently, posaconazole prophylaxis has been evaluated in ICU patients with severe influenza to prevent influenza-associated pulmonary aspergillosis (IAPA) [87] . Insufficient evidence to make a recommendation. What is the effect of tocilizumab on mortality or mechanical ventilation in patients with moderate or severe COVID-19 compared to no treatment? Tocilizumab has been assessed in 9 RCTs with conflicting results [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] . Most of the smaller trials did not show any mortality benefit [90, 93-95, 100, 101] . Conversely, REMAP-CAP and RECOVERY showed small but significant benefit. REMAP-CAP is an ongoing international, multifactorial, adaptive platform trial including ICU patients randomly assigned to receive tocilizumab, sarilumab, or SOC. The primary outcome was respiratory and cardiovascular organ support-free days. Overall, those with tocilizumab had an in-hospital mortality of 27% compared to 36% for controls, and a median of 10 to 11 organ support-free days compared with 0 days for controls [96] . (Table 14) . One possible explanation for the different results among RCTs is that many were conducted in the early stages of the pandemic before corticosteroids were established as SOC. In a recent systematic review, a clear benefit of combination of IL-6 blockers and corticosteroids was noted [102] . Tocilizumab likely has little impact on adverse or serious adverse events, septic shock, or clinical progression. The effect of tocilizumab on other outcomes is uncertain. We recommend use of tocilizumab for treatment of severe COVID-19 (QoE: moderate for mortality, high for mechanical ventilation). Narrative synthesis of evidence (Table 15 ). In addition, another RCT by the investigators from the REMAP-CAP Platform found clinical benefit from therapeutic dosages of enoxaparin among non-critical COVID-19 patients [104] . However, an analysis restricted to critically-ill patients found no benefit on the primary outcome (ordinal scale combining in-hospital mortality and days free of organ support to day 21) (adjusted OR 0.87, 95% CI 0.70-1.08) [105] . The main safety outcome in the RCT was major bleeding. There were 7 (2.5%) [106] . In addition to these two trials, another two RCTs are available [107, 108] . Interferon β-1a was not associated with clinical improvement in either trial. Some studies documented a higher rate of adverse events in patients treated with interferon β-1a compared with controls [109] , whereas others do not [12, 106] . Historically, use of interferons in other settings has been associated with several side effects including thrombotic microangiopathy, hepatic injury, nephrotic syndrome, and depression with suicidal ideation. Interferon β-1a is also associated with immune reactions that can produce flu-like symptoms. Strong recommendation against use of interferon β-1a in severe COVID-19 patients (QoE: moderate). The project received a grant from ESCMID for medical writing assistance. [5] GIN. Guidelines International Network [Available from: https://g-i-n.net/COVID-19/COVID-19-evidence-resources. [6] UNiversity M. COVID-END. 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