PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T17	0-12	Sentence	denotes	Introduction
T18	13-225	Sentence	denotes	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries [[1], [2], [3]].
T19	226-521	Sentence	denotes	The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure, with the true proportion of severe cases still remaining partly unclear as a result of an incomplete denominator and a possible lack of adjustment for relevant confounding factors [4,5].
T20	522-836	Sentence	denotes	Nonetheless, of particular clinical concern at the present time is not the relative frequency of severe cases in patients requiring ventilation support, but rather their absolute number, which is reaching or even surpassing the intensive care unit (ICU) bed capacity in the most affected regions and countries [6].
T21	837-1189	Sentence	denotes	From this perspective, in addition to the important prevention and restrictive measures implemented for reducing transmission [7], it remains crucial to optimize the therapeutic management of symptomatic patients requiring noninvasive oxygen therapy in order both to improve the absolute cure rates and to reduce and prevent the need for ICU admission.
T22	1190-1485	Sentence	denotes	However, the lack of high-level evidence, inherent to the novelty and rapid spread of COVID-19, has led to the adoption of heterogeneous approaches worldwide, often without a clear distinction between the relative weight of available evidence and expert opinion in informing therapeutic choices.
T23	1486-1766	Sentence	denotes	In this narrative review, we sought to summarize the available evidence on important therapeutic questions we are continuously facing as clinicians caring for COVID-19 patients in Italy, trying to find a balance between current evidence, frontline experiences and expert opinions.
T24	1768-1775	Sentence	denotes	Methods
T25	1776-2002	Sentence	denotes	Members of a panel of 17 experts from the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP) were selected; they developed a list of 8 practical therapeutic questions to be addressed.
T26	2003-2302	Sentence	denotes	The members of the panel (which included infectious diseases specialists and pneumonologists) were divided into small groups and asked to summarize the available literature and their frontline-based opinion in brief (500 words maximum) narrative answers, plus a conclusive statement for each answer.
T27	2303-2423	Sentence	denotes	All the answers and statements were ultimately reviewed and discussed by the entire panel until a consensus was reached.
T28	2424-2504	Sentence	denotes	A brief summary of questions and conclusive statements is available in Table 1 .
T29	2505-2680	Sentence	denotes	Table 2 summarizes available or ongoing randomized controlled trial (RCT) information for off-label/compassionate-use drugs mostly used for the treatment of COVID-19 patients.
T30	2681-2911	Sentence	denotes	Of note, we focused on pneumologic and anti-infective/anti-inflammatory treatments; the discussion of the therapeutic approach to COVID-19–related cardiovascular/coagulative disorders is outside the scope of this narrative review.
T31	2912-2955	Sentence	denotes	Table 1 Summary of questions and statements
T32	2956-2974	Sentence	denotes	Question Statement
T33	2975-2986	Sentence	denotes	Question 1.
T34	2987-3086	Sentence	denotes	How to use at best oxygen therapy and noninvasive mechanical ventilation for preventing intubation?
T35	3087-3281	Sentence	denotes	Supplementary oxygen should be administered to patients with hypoxic respiratory failure for avoiding values of Spo2 lower than 90% and it should be aimed at reaching values not higher than 96%.
T36	3282-3586	Sentence	denotes	Although still without firm evidence, we currently support the use of CPAP helmet (with gentle ventilation and a PEEP of no more than 10–12 cm of water) if the patient does not respond to standard/HFNC oxygen supplementation and there is no urgent indication for endotracheal intubation (expert opinion).
T37	3587-3669	Sentence	denotes	However, no clear indications/criteria can be provided pending further experience.
T38	3670-3905	Sentence	denotes	Finally, it should be kept in mind that patients with COVID-19 can get worse in a few hours, so they should be carefully monitored for worsening respiratory function for rapidly prompting tracheal intubation and mechanical ventilation.
T39	3906-3917	Sentence	denotes	Question 2.
T40	3918-3958	Sentence	denotes	Should antiviral agents be administered?
T41	3959-4089	Sentence	denotes	At the present time, evidence from the first published RCT does not support off-label treatment with LPV/RTV in COVID-19 patients.
T42	4090-4234	Sentence	denotes	This result should also discourage the use of other protease inhibitors (e.g. darunavir), at least until results of dedicated RCT are available.
T43	4235-4457	Sentence	denotes	Although promising in preclinical studies, remdesivir should be currently provided to COVID-19 patients only within RCT (preferentially) or compassionate-use/expanded-access programmes, owing to its investigational nature.
T44	4458-4642	Sentence	denotes	Pending high-level supporting evidence, favipiravir and umifenovir should not be provided an outside RCT, at least in those countries where they are not approved for other indications.
T45	4643-4750	Sentence	denotes	Oseltamivir or zanamivir should be provided only in the presence of suspected/proven concomitant influenza.
T46	4751-4762	Sentence	denotes	Question 3.
T47	4763-4817	Sentence	denotes	Should chloroquine/hydroxychloroquine be administered?
T48	4818-5067	Sentence	denotes	Pending results of RCT, the use of hydroxychloroquine may be considered for treating worsening patients with COVID-19 only if no important drug interactions can be anticipated and with close monitoring of hepatic, renal function and QT prolongation.
T49	5068-5277	Sentence	denotes	This is based on its activity in vitro against SARS-CoV-2 (although weak) and on the availability of low-level clinical evidence of anticipation of virus clearance from a small controlled, nonrandomized study.
T50	5278-5450	Sentence	denotes	However, it should also be kept in mind that the study was highly susceptible to bias and there are still no data regarding hard clinical endpoints such as crude mortality.
T51	5451-5575	Sentence	denotes	For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies.
T52	5576-5685	Sentence	denotes	When this is unfeasible, off-label use may be considered according to local protocols and consent procedures.
T53	5686-5882	Sentence	denotes	In view of the absence of evidence, we are currently unable to support the use of hydroxychloroquine in asymptomatic or mildly symptomatic nonhospitalized patients outside investigational studies.
T54	5883-5920	Sentence	denotes	The same applies to prophylactic use.
T55	5921-5932	Sentence	denotes	Question 4.
T56	5933-5968	Sentence	denotes	Should antibiotics be administered?
T57	5969-6151	Sentence	denotes	In our opinion, it might be prudent to consider empiric antibiotic treatment in critically ill patients with pneumonia due to COVID-19 in whom bacterial infection cannot be excluded.
T58	6152-6389	Sentence	denotes	This suggestion is based on the fact that bacterial coinfection (a) is common in patients with viral pneumonia and (b) can be associated with a substantial risk of delaying appropriate treatment, thereby potentially increasing mortality.
T59	6390-6637	Sentence	denotes	Because of the limited available data on both the microbiologic epidemiology (and the prevalence of antimicrobial resistance) of bacterial superinfections in COVID-19 patients, it is difficult to provide specific pathogen-oriented recommendations.
T60	6638-7052	Sentence	denotes	Therefore, pending further studies, we suggest to empirically treat COVID-19 patients according to their clinical syndrome (e.g. community-acquired pneumonia, hospital-acquired pneumonia), choosing the best antimicrobial agent or agents on the basis of local guidelines and local antibiotic susceptibility patterns, with early de-escalation or discontinuation according to microbiology results, whenever available.
T61	7053-7064	Sentence	denotes	Question 5.
T62	7065-7097	Sentence	denotes	Should steroids be administered?
T63	7098-7251	Sentence	denotes	So far, no definitive efficacy or effectiveness data are available on the benefit of corticosteroid administration in patients with SARS-CoV-2 infection.
T64	7252-7395	Sentence	denotes	As the WHO underlines, there is an important need for efficacy data from RCT for supporting corticosteroid therapy in patients with SARS-Cov-2.
T65	7396-7842	Sentence	denotes	However, considering that overwhelming inflammation and cytokine-related lung injury might be responsible for rapidly progressive pneumonia and clinical deterioration in COVID-19 patients, we suggest (expert opinion only) to consider administration of corticosteroids in critically ill COVID-19 patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections (independent of ICU admission).
T66	7843-8075	Sentence	denotes	Yet in the absence of convincing evidence, the following cannot currently be supported: (1) steroid administration stratified according to inflammatory markers; and (b) steroid administration in non–critically ill COVID-19 patients.
T67	8076-8087	Sentence	denotes	Question 6.
T68	8088-8169	Sentence	denotes	Should other immunosuppressive and/or immunomodulatory therapies be administered?
T69	8170-8324	Sentence	denotes	Owing to the lack of high-level evidence, administration of tocilizumab to patients with COVID-19 should preferentially occur within the framework of RCT.
T70	8325-8651	Sentence	denotes	Off-label use according to local protocols and consent procedures may be considered only in those COVID-19 patients excluded from RCT (or hospitalized where RCT are not available or still to be implemented) and who are worsening while receiving standard supportive care (in the absence of concomitant/superimposed infections).
T71	8652-9121	Sentence	denotes	In our opinion, this could be a reasonable off-label use of tocilizumab in these early phases of the COVID-19 pandemic, although patients and physicians should be aware that currently there is only a non–peer-reviewed, noncomparative, observational experience (very low evidence from an unreviewed cases series) and that it only supports a potential favourable effect on inflammatory signs and symptoms, while there is no information on any possible effect on survival.
T72	9122-9327	Sentence	denotes	In the absence of clinical studies, we suggest to preferentially administer also other immunosuppressive and/or immunomodulatory therapies (e.g. anakinra, Janus kinase family enzyme inhibitors) within RCT.
T73	9328-9646	Sentence	denotes	This also applies to modifications of the immune response through high-dose intravenous immunoglobulins or plasma from convalescent patients, which, although promising in small case series, both deserve dedicated RCT investigation to clearly understand their role in impacting COVID-19 outcomes and their tolerability.
T74	9647-9658	Sentence	denotes	Question 7.
T75	9659-9710	Sentence	denotes	What is the optimal timing of treatment initiation?
T76	9711-10006	Sentence	denotes	Supportive therapy (symptomatic therapy, rehydration and oxygen supplementation, if necessary), should be initiated as soon as the patient manifests respiratory or systemic symptoms, including severe asthenia, high fever, persistent cough and/or clinical or radiologic signs of lung involvement.
T77	10007-10277	Sentence	denotes	Pending further evidence, in our opinion, antiviral treatments should not be provided to patients with SARS-CoV-2 infection outside RCT or compassionate-use programmes (with the exception of early oseltamivir initiation in patients with suspected concomitant influenza).
T78	10278-10549	Sentence	denotes	Corticosteroids should be provided early in well-defined categories of patients (patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections), while their role in other COVID-19 patients still remains uncertain.
T79	10550-10936	Sentence	denotes	Although based on low-level evidence and pending RCT results, in our opinion, early hydroxychloroquine administration may be considered in COVID-19 patients manifesting moderate to severe symptoms, whereas further data are needed to better delineate the true balance between possible favourable effects and toxicity of hydroxychloroquine in mildly symptomatic and asymptomatic patients.
T80	10937-10948	Sentence	denotes	Question 8.
T81	10949-10988	Sentence	denotes	What is the optimal treatment duration?
T82	10989-11288	Sentence	denotes	Chloroquine/hydroxychloroquine treatment should be continued for at least 5 days, and possibly up to 20 days, according to some expert opinions, although it should be noted that data regarding the relative safety of different lengths of administration in COVID-19 patients are currently unavailable.
T83	11289-11416	Sentence	denotes	Early discontinuation should be considered in the presence of adverse effects (e.g. QT prolongation or hepatic/renal toxicity).
T84	11417-11694	Sentence	denotes	If the administration of remdesivir is approved within compassionate-use/expanded-access programmes, treatment duration should follow compassionate or expanded access protocols (e.g. up to 10 days according to the most recent compassionate protocol at the time of this review).
T85	11695-11812	Sentence	denotes	If corticosteroids are provided, we suggest a total treatment duration of 7–10 days, with progressive dose reduction.
T86	11813-12083	Sentence	denotes	If the patient's condition deteriorates with worsening lung physiology after withdrawal of steroid treatment in the absence of bacterial or fungal superinfection, a second course of corticosteroid treatment may be considered, followed by slow tapering after improvement.
T87	12084-12459	Sentence	denotes	ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; CPAP, continuous positive airway pressure; HFNC, high-flow nasal cannula; ICU, intensive care unit; LPV/RTV, lopinavir/ritonavir; PEEP, positive end expiratory pressure; RCT, randomized controlled trial; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health Organization.
T88	12460-12635	Sentence	denotes	Table 2 Available and ongoing RCT on anti-infective and anti-inflammatory drugs most provided as off-label/compassionate treatments in the first phase of the COVID-19 pandemic
T89	12636-12787	Sentence	denotes	Drug Class/mechanism Published RCT Ongoing RCT for treatment/prevention of COVID-19 (recruiting or not yet recruiting) registered at ClinicalTrials.gov
T90	12788-12854	Sentence	denotes	Lopinavir/ritonavir Lopinavir is an HIV type 1 protease inhibitor.
T91	12855-13047	Sentence	denotes	Ritonavir is a CYP3A4 inhibitor that boosts lopinavir concentrations • Open-label RCT comparing lopinavir/ritonavir (99 patients) vs. standard of care (100) in patients with COVID-19 in China.
T92	13048-13125	Sentence	denotes	Lopinavir/ritonavir was administered at the dosage of 400/100 mg for 14 days.
T93	13126-13205	Sentence	denotes	The primary time-to-event endpoint was clinical improvement from randomization.
T94	13206-13594	Sentence	denotes	In the primary study population (ITT), no statistically significant differences were observed with regard to the primary endpoint of clinical improvement (HR 1.24 with standard of care as reference, 95% CI 0.90 to 1.72) and the secondary endpoint of 28-day mortality (19.2% vs. 25.0% in investigational and comparator arms, respectively; percentage difference −5.8%, 95% CI −17.3 to 5.7).
T95	13595-13748	Sentence	denotes	In the mITT population, lopinavir/ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care.
T96	13749-13921	Sentence	denotes	Median time between symptoms onset and randomization was 13 days (IQR 11–16) [22] • Comparison of lopinavir/ritonavir vs. hydroxychloroquine in patients with mild COVID-19.
T97	13922-13963	Sentence	denotes	Open-label RCT (NCT04307693, recruiting).
T98	13964-14023	Sentence	denotes	Primary endpoint: virus load at day 3, 5, 7, 10, 14 and 18.
T99	14024-14127	Sentence	denotes	• Comparison of ASC09/ritonavir vs. lopinavir/ritonavir in patients with confirmed COVID-19 pneumoniae.
T100	14128-14177	Sentence	denotes	Open-label RCT (NCT04261907, not yet recruiting).
T101	14178-14347	Sentence	denotes	Primary endpoint: adverse outcome at day 14 (composite of Spo 2 ≤ 93% without oxygen supplementation, PaO2/FiO2 ≤ 300 mm Hg or respiratory rate ≥ 30 breaths per minute).
T102	14348-14450	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus umifenovir in patients with COVID-19.
T103	14451-14492	Sentence	denotes	Open-label RCT (NCT04252885, recruiting).
T104	14493-14569	Sentence	denotes	Primary endpoint: rate of virus inhibition at day 0, 2, 4, 7, 10, 14 and 21.
T105	14570-14695	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus ribavirin plus interferon beta 1b in patients with COVID-19.
T106	14696-14737	Sentence	denotes	Open-label RCT (NCT04276688, recruiting).
T107	14738-14820	Sentence	denotes	Primary endpoint: time to negative nasopharyngeal swab RT-PCR (follow-up 30 days).
T108	14821-14964	Sentence	denotes	• Comparison of only supportive treatment vs. lopinavir/ritonavir vs. oseltamivir vs. umifenovir in patients with confirmed COVID-19 pneumonia.
T109	14965-15006	Sentence	denotes	Open-label RCT (NCT04255017, recruiting).
T110	15007-15282	Sentence	denotes	Primary endpoints: (a) rate of disease remission (mild disease: fever, cough and other symptoms relieved with improved lung CT; severe disease: fever, cough and other symptoms relieved with improved lung CT, Spo 2 > 93% or Pao 2/Fio 2 > 300 mm Hg); (b) time to lung recovery.
T111	15283-15395	Sentence	denotes	• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19.
T112	15396-15447	Sentence	denotes	Double-blind RCT (NCT04328285, not yet recruiting).
T113	15448-15542	Sentence	denotes	Primary endpoint: occurrence of a symptomatic or asymptomatic COVID-19 (follow-up 2.5 months).
T114	15543-15659	Sentence	denotes	• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia.
T115	15660-15709	Sentence	denotes	Open-label RCT (NCT04286503, not yet recruiting).
T116	15710-15892	Sentence	denotes	Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.
T117	15893-16075	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus xiyanping (injectable component derived from a plant used in traditional Chinese medicine) in patients with COVID-19.
T118	16076-16125	Sentence	denotes	Open-label RCT (NCT04295551, not yet recruiting).
T119	16126-16187	Sentence	denotes	Primary endpoint: clinical recovery time (follow-up 28 days).
T120	16188-16357	Sentence	denotes	• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus xiyanping injection in patients with COVID-19.
T121	16358-16407	Sentence	denotes	Open-label RCT (NCT04275388, not yet recruiting).
T122	16408-16469	Sentence	denotes	Primary endpoint: clinical recovery time (follow-up 14 days).
T123	16470-16649	Sentence	denotes	• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus traditional Chinese medicines in patients with COVID-19.
T124	16650-16691	Sentence	denotes	Open-label RCT (NCT04251871, recruiting).
T125	16692-16769	Sentence	denotes	Primary endpoint: time to complete remission of symptoms (follow-up 28 days).
T126	16770-16985	Sentence	denotes	• Comparison of lopinavir/ritonavir plus hydroxychloroquine vs. lopinavir/ritonavir plus hydroxychloroquine plus levamisole pill plus budesonide plus formoterol inhaler in patients with nonsevere COVID-19 pneumonia.
T127	16986-17039	Sentence	denotes	Partly blinded RCT (NCT04331470, not yet recruiting).
T128	17040-17121	Sentence	denotes	Primary endpoint: (a) clear CT scan at 3–7 days; (b) negative RT-PCR at 3–7 days.
T129	17122-17233	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19.
T130	17234-17295	Sentence	denotes	Double-blind, adaptive RCT (NCT04328012, not yet recruiting).
T131	17296-17372	Sentence	denotes	Primary endpoint: NIAID COVID-19 ordinal severity scale (follow-up 60 days).
T132	17373-17542	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19.
T133	17543-17596	Sentence	denotes	Double-blind, adaptive RCT (NCT04315948, recruiting).
T134	17597-17668	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 15.
T135	17669-17968	Sentence	denotes	• Comparison of lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) vs. natural honey plus lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) in patients with COVID-19.
T136	17969-18020	Sentence	denotes	Single-blind RCT (NCT04323345, not yet recruiting).
T137	18021-18214	Sentence	denotes	Primary endpoints: (a) positive to negative swabs at day 14; (b) fever to normal temperature in days (follow-up 14 days); (c) resolution of lung inflammation in CT or X-ray (follow-up 30 days).
T138	18215-18352	Sentence	denotes	• Comparison of colchicine (with or without lopinavir/ritonavir) vs. local standard of care in patients with moderate to severe COVID-19.
T139	18353-18402	Sentence	denotes	Open-label RCT (NCT04328480, not yet recruiting).
T140	18403-18461	Sentence	denotes	Primary endpoint: all-cause mortality (follow-up 30 days).
T141	18462-18866	Sentence	denotes	• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19.
T142	18867-18916	Sentence	denotes	Open-label RCT (NCT04303299, not yet recruiting).
T143	18917-18984	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).
T144	18985-19015	Sentence	denotes	Remdesivir Adenosine analogue.
T145	19016-19181	Sentence	denotes	It binds to RNA-dependent RNA polymerase and acts as an RNA-chain terminator • Not available • Comparison of remdesivir vs. placebo in patients with severe COVID-19.
T146	19182-19225	Sentence	denotes	Double-blind RCT (NCT04257656, recruiting).
T147	19226-19315	Sentence	denotes	Primary endpoint: clinical status, assessed by an ordinal scale at days 7, 14, 21 and 28.
T148	19316-19398	Sentence	denotes	• Comparison of remdesivir vs. placebo in patients with mild to moderate COVID-19.
T149	19399-19442	Sentence	denotes	Double-blind RCT (NCT04252664, recruiting).
T150	19443-19516	Sentence	denotes	Primary endpoint: time to clinical recovery in hours (follow-up 28 days).
T151	19517-19604	Sentence	denotes	• Comparison of remdesivir vs. local standard of care in patients with severe COVID-19.
T152	19605-19646	Sentence	denotes	Open-label RCT (NCT04252664, recruiting).
T153	19647-19754	Sentence	denotes	Primary endpoint: composite of fever normalization and oxygen saturation normalization (follow-up 14 days).
T154	19755-19844	Sentence	denotes	• Comparison of remdesivir vs. local standard of care in patients with moderate COVID-19.
T155	19845-19886	Sentence	denotes	Open-label RCT (NCT04292730, recruiting).
T156	19887-19933	Sentence	denotes	Primary endpoint: discharged status at day 14.
T157	19934-19999	Sentence	denotes	• Comparison of remdesivir vs. placebo in patients with COVID-19.
T158	20000-20043	Sentence	denotes	Double-blind RCT (NCT04280705, recruiting).
T159	20044-20115	Sentence	denotes	Primary endpoint: severity rating on a 8-point ordinal scale at day 15.
T160	20116-20231	Sentence	denotes	• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19.
T161	20232-20290	Sentence	denotes	Open-label adaptive RCT (NCT04321616, not yet recruiting).
T162	20291-20361	Sentence	denotes	Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).
T163	20362-20531	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19.
T164	20532-20585	Sentence	denotes	Double-blind, adaptive RCT (NCT04315948, recruiting).
T165	20586-20657	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 15.
T166	20658-20725	Sentence	denotes	Darunavir/cobicistat Darunavir is an HIV type 1 protease inhibitor.
T167	20726-20906	Sentence	denotes	Cobicistat is a CYP3A4 inhibitor that boosts darunavir concentrations • Not available • Comparison of darunavir/cobicistat vs. standard of care in patients with COVID-19 pneumonia.
T168	20907-20948	Sentence	denotes	Open-label RCT (NCT04252274, recruiting).
T169	20949-21063	Sentence	denotes	Primary endpoint: virologic clearance rate of throat swabs, sputum or lower respiratory tract secretions at day 7.
T170	21064-21370	Sentence	denotes	Favipiravir Anti-influenza RNA-dependent RNA polymerase inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir.
T171	21371-21546	Sentence	denotes	The manuscript is publicly available but still to be peer reviewed [30] • Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19.
T172	21547-21588	Sentence	denotes	Open-label RCT (NCT04310228, recruiting).
T173	21589-21642	Sentence	denotes	Primary endpoint: clinical cure (follow-up 3 months).
T174	21643-22047	Sentence	denotes	• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19.
T175	22048-22097	Sentence	denotes	Open-label RCT (NCT04303299, not yet recruiting).
T176	22098-22165	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).
T177	22166-22274	Sentence	denotes	• Comparison of hydroxychloroquine plus darunavir/cobicistat vs. standard of care in patients with COVID-19.
T178	22275-22316	Sentence	denotes	Open-label RCT (NCT04304053, recruiting).
T179	22317-22434	Sentence	denotes	Primary endpoint: incidence of secondary cases among contacts of a case and contacts of contacts (follow-up 14 days).
T180	22435-22534	Sentence	denotes	• Comparison of chloroquine plus favipiravir vs. favipiravir vs. placebo in patients with COVID-19.
T181	22535-22578	Sentence	denotes	Double-blind RCT (NCT04319900, recruiting).
T182	22579-22750	Sentence	denotes	Primary endpoints: (a) time to improvement/recovery and frequency of improvement/recovery (follow-up 10 days); (b) time to negative swab/sputum RT-PCR (follow-up 10 days).
T183	22751-22826	Sentence	denotes	• Comparison of favipiravir vs. standard of care in patients with COVID-19.
T184	22827-22876	Sentence	denotes	Open-label RCT (NCT04333589, not yet recruiting).
T185	22877-22989	Sentence	denotes	Primary endpoint: viral nucleic acid test negative conversion rate in nasopharyngeal swabs (follow-up 5 months).
T186	22990-23394	Sentence	denotes	• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19.
T187	23395-23444	Sentence	denotes	Open-label RCT (NCT04303299, not yet recruiting).
T188	23445-23512	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).
T189	23513-23805	Sentence	denotes	Umifenovir Anti-influenza membrane fusion inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir.
T190	23806-23962	Sentence	denotes	The manuscript is publicly available but still to be peer reviewed [30] • Comparison of umifenovir vs. standard of care in patients with COVID-19 pneumonia.
T191	23963-24012	Sentence	denotes	Open-label RCT (NCT04260594, not yet recruiting).
T192	24013-24081	Sentence	denotes	Primary endpoint: virus negative conversion rate (follow-up 7 days).
T193	24082-24461	Sentence	denotes	Chloroquine, hydroxychloroquine Some proposed mechanisms are the following: increase in the endosomal Ph necessary for the virus/host cell fusion; interference with the glycosylation of cell receptors; immunomodulatory activity • Not available • Comparison of different hydroxychloroquine dosages vs. placebo in three cohorts (outpatients, inpatients, healthcare workers a risk).
T194	24462-24586	Sentence	denotes	Double-blind RCT for outpatients and healthcare workers and open-label RCT for inpatients (NCT04329923, not yet recruiting).
T195	24587-24784	Sentence	denotes	Primary endpoints: (a) release from quarantine (outpatients, follow-up 14 days); (b) discharge (inpatients, follow-up 14 days); (c) development of COVID-19 (healthcare workers, follow-up 2 months).
T196	24785-24871	Sentence	denotes	• Comparison of hydroxychloroquine vs. ascorbic acid in contacts of COVID-19 patients.
T197	24872-24923	Sentence	denotes	Double-blind RCT (NCT04328961, not yet recruiting).
T198	24924-24992	Sentence	denotes	Primary endpoint: laboratory-confirmed COVID-19 (follow-up 14 days).
T199	24993-25129	Sentence	denotes	• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19.
T200	25130-25179	Sentence	denotes	Open-label RCT (NCT04332094, not yet recruiting).
T201	25180-25407	Sentence	denotes	Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).• Comparison of ciclesonide plus hydroxychloroquine vs. ciclesonide in patients with COVID-19.
T202	25408-25457	Sentence	denotes	Open-label RCT (NCT04330586, not yet recruiting).
T203	25458-25531	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication (based on virus load) at day 14.
T204	25532-25658	Sentence	denotes	• Comparison of hydroxychloroquine vs. placebo in patients with COVID-19 and under biological treatment and/or JAK inhibitors.
T205	25659-25710	Sentence	denotes	Double-blind RCT (NCT04330495, not yet recruiting).
T206	25711-25921	Sentence	denotes	Primary endpoints: (a) incidence rate of COVID-19 (follow-up 27 weeks); (b) prevalence of COVID-19 (follow-up 27 weeks); (c) case fatality rate (follow-up 27 weeks); (d) ICU admission rate (follow-up 27 weeks).
T207	25922-26030	Sentence	denotes	• Comparison of hydroxychloroquine vs. placebo for the prevention of COVID-19 in healthcare workers at risk.
T208	26031-26082	Sentence	denotes	Double-blind RCT (NCT04328467, not yet recruiting).
T209	26083-26145	Sentence	denotes	Primary endpoint: prevalence of COVID-19 (follow-up 12 weeks).
T210	26146-26258	Sentence	denotes	• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19.
T211	26259-26310	Sentence	denotes	Double-blind RCT (NCT04328285, not yet recruiting).
T212	26311-26328	Sentence	denotes	Primary endpoint:
T213	26329-26417	Sentence	denotes	Occurrence of a symptomatic or asymptomatic SARS-CoV-2 infection (follow-up 2.5 months).
T214	26418-26539	Sentence	denotes	• Comparison of hydroxychloroquine vs. placebo in symptomatic COVID-19 patients or exposed healthcare workers/households.
T215	26540-26583	Sentence	denotes	Double-blind RCT (NCT04308668, recruiting).
T216	26584-26731	Sentence	denotes	Primary endpoints: (a) incidence of symptomatic COVID-19 among asymptomatic participants; (b) severity rating on a 3-point ordinal scale at day 14.
T217	26732-26847	Sentence	denotes	• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19.
T218	26848-26906	Sentence	denotes	Open-label adaptive RCT (NCT04321616, not yet recruiting).
T219	26907-26977	Sentence	denotes	Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).
T220	26978-27089	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19.
T221	27090-27151	Sentence	denotes	Double-blind, adaptive RCT (NCT04328012, not yet recruiting).
T222	27152-27228	Sentence	denotes	Primary endpoint: NIAID COVID-19 Ordinal Severity Scale (follow-up 60 days).
T223	27229-27387	Sentence	denotes	• Comparison of convalescent plasma plus hydroxychloroquine plus azithromycin vs. hydroxychloroquine plus azithromycin in hospitalized patients with COVID-19.
T224	27388-27437	Sentence	denotes	Open-label RCT (NCT04332835, not yet recruiting).
T225	27438-27617	Sentence	denotes	Primary endpoints: (a) change in virus load at days 0, 4, 7, 14 and 28; (b) change in IgM COVID-19 titers at days 0, 4, 7, 14 and 28; (c) change in IgG at days 0, 4, 7, 14 and 28.
T226	27618-27787	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta-1a vs. remdesivir vs. standard of care in patients with COVID-19.
T227	27788-27841	Sentence	denotes	Double-blind, adaptive RCT (NCT04315948, recruiting).
T228	27842-27913	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 15.
T229	27914-28276	Sentence	denotes	Methylprednisolone A subgroup of patients with severe COVID-19 might develop a cytokine storm syndrome which causes rapidly progressive pneumonia, ARDS and clinical deterioration and corticosteroids administration may halt the dysregulated cytokine release • Not available • Comparison of methylprednisolone vs. standard of care in patients with severe COVID-19.
T230	28277-28318	Sentence	denotes	Open-label RCT (NCT04244591, recruiting).
T231	28319-28385	Sentence	denotes	Primary endpoint: lower Murray lung injury score at days 7 and 14.
T232	28386-28468	Sentence	denotes	• Comparison of methylprednisolone vs. standard of care in patients with COVID-19.
T233	28469-28510	Sentence	denotes	Open-label RCT (NCT04273321, recruiting).
T234	28511-28567	Sentence	denotes	Primary endpoint: treatment failure (follow-up 14 days).
T235	28568-28768	Sentence	denotes	• Comparison of inhaled alpha interferon plus methylprednisolone plus umifenovir vs. thalidomide plus inhaled alpha interferon plus methylprednisolone plus umifenovir in patients with severe COVID-19.
T236	28769-28820	Sentence	denotes	Double-blind RCT (NCT04273581, not yet recruiting).
T237	28821-28888	Sentence	denotes	Primary endpoint: time to clinical improvement (follow-up 28 days).
T238	28889-28971	Sentence	denotes	• Comparison of different dosages of methylprednisolone in patients with COVID-19.
T239	28972-29013	Sentence	denotes	Open-label RCT (NCT04263402, recruiting).
T240	29014-29095	Sentence	denotes	Primary endpoints: (a) disease readmission at day 7; (b) critical stage at day 7.
T241	29096-29204	Sentence	denotes	• Comparison of siltuximab (anti–IL-6 monoclonal antibody) vs. methylprednisolone in patients with COVID-19.
T242	29205-29254	Sentence	denotes	Open-label RCT (NCT04329650, not yet recruiting).
T243	29255-29306	Sentence	denotes	Primary endpoint: ICU admission (follow-up 29 days)
T244	29307-29423	Sentence	denotes	Tocilizumab Humanized monoclonal IgG1 antibody, tocilizumab inhibits both membrane-bound and soluble IL-6 receptors.
T245	29424-29674	Sentence	denotes	IL-6, is one of the main drivers of immunologic response and symptoms in patients with dysregulated cytokine release that has been observed in severe COVID-19 • Not available • Comparison of tocilizumab vs. standard of care in patients with COVID-19.
T246	29675-29724	Sentence	denotes	Open-label RCT (NCT04331808, not yet recruiting).
T247	29725-29827	Sentence	denotes	Primary endpoint: WHO progression scale at day 7 and 14 (severity rating on a 10-point ordinal scale).
T248	29828-29931	Sentence	denotes	• Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19.
T249	29932-29973	Sentence	denotes	Open-label RCT (NCT04310228, recruiting).
T250	29974-30027	Sentence	denotes	Primary endpoint: clinical cure (follow-up 3 months).
T251	30028-30107	Sentence	denotes	• Comparison of tocilizumab vs. placebo in hospitalized patients with COVID-19.
T252	30108-30159	Sentence	denotes	Double-blind RCT (NCT04320615, not yet recruiting).
T253	30160-30231	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 28.
T254	30232-30368	Sentence	denotes	• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19.
T255	30369-30418	Sentence	denotes	Open-label RCT (NCT04332094, not yet recruiting).
T256	30419-30552	Sentence	denotes	Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).
T257	30553-30708	Sentence	denotes	• Comparison of chloroquine analog (GNS651) vs. tocilizumab vs. nivolumab vs. standard of care in patients with advanced or metastatic cancer and COVID-19.
T258	30709-30758	Sentence	denotes	Open-label RCT (NCT04333914, not yet recruiting).
T259	30759-30776	Sentence	denotes	Primary endpoint:
T260	30777-30793	Sentence	denotes	28-day survival.
T261	30794-30995	Sentence	denotes	• Comparison of tocilizumab intravenously vs. tocilizumab subcutaneously vs. sarilumab (anti-interleukin 6 receptor α monoclonal antibody) subcutaneously vs. standard of care in patients with COVID-19.
T262	30996-31045	Sentence	denotes	Open-label RCT (NCT04322773, not yet recruiting).
T263	31046-31139	Sentence	denotes	Primary endpoint: time to independence from supplementary oxygen therapy (follow-up 28 days).
T264	31140-31341	Sentence	denotes	• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19.
T265	31342-31391	Sentence	denotes	Open-label RCT (NCT04330638, not yet recruiting).
T266	31392-31459	Sentence	denotes	Primary endpoint: time to clinical improvement (follow-up 15 days).
T267	31460-31576	Sentence	denotes	• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia.
T268	31577-31626	Sentence	denotes	Open-label RCT (NCT04286503, not yet recruiting).
T269	31627-31809	Sentence	denotes	Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.
T270	31810-31847	Sentence	denotes	Anakinra Antagonist of IL-1 receptor.
T271	31848-32104	Sentence	denotes	IL-1 is one of the main drivers of immunologic response and symptoms in patients with cytokine-release syndrome. • Not available • Comparison of anakinra vs. emapalumab (anti–interferon γ monoclonal antibody) vs. standard of care in patients with COVID-19.
T272	32105-32154	Sentence	denotes	Open-label RCT (NCT04324021, not yet recruiting).
T273	32155-32201	Sentence	denotes	Primary endpoint: treatment success at day 15.
T274	32202-32403	Sentence	denotes	• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19.
T275	32404-32453	Sentence	denotes	Open-label RCT (NCT04330638, not yet recruiting).
T276	32454-32521	Sentence	denotes	Primary endpoint: time to clinical improvement (follow-up 15 days).
T277	32522-32655	Sentence	denotes	Off-label drugs mostly provided in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience.
T278	32656-32839	Sentence	denotes	Of note, there are also registered RCT for other drugs to be investigated in patients with COVID-19 (e.g. the Janus kinase family inhibitors ruxolitinib, baricitinib and tofacitinib).
T279	32840-33359	Sentence	denotes	ARDS = acute respiratory distress syndrome; CI, confidence interval; COVID-19, coronavirus disease 2019; CT, computed tomography; EOT, end of treatment; HR, hazard ratio; Ig, immunoglobulin; IL-1, interleukin 1; IQR, interquartile range; ITT, intent to treat; mITT, modified intent to treat; Pao2/Fio2, of arterial oxygen partial pressure to fractional inspired oxygen; RCT, randomized controlled trial; RT-PCR, real-time PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health Organization.
T280	33361-33472	Sentence	denotes	Question 1. how to use at best oxygen therapy and noninvasive mechanical ventilation for preventing intubation?
T281	33473-33676	Sentence	denotes	In moderate to severe cases, COVID-19 usually presents as a lung disease (mostly in the form of bilateral interstitial pneumonia) causing hypoxic respiratory failure and requiring passive oxygen therapy.
T282	33677-33775	Sentence	denotes	The prevalence of hypoxic respiratory failure in patients with COVID-19 may be as high as 19% [8].
T283	33776-33978	Sentence	denotes	In observational studies conducted in China, 4% to 13% of COVID-19 patients received noninvasive positive pressure ventilation, and 2.3% to 12% required invasive mechanical ventilation [[8], [9], [10]].
T284	33979-34267	Sentence	denotes	In general, oxygen treatment should be provided to patients with shortness of breath or hypoxaemia, or those in shock, which is aimed at maintaining an appropriate level of peripheral capillary oxygen saturation (Spo 2), avoiding values of Spo 2 lower than 90% (92–95% in pregnant women).
T285	34268-34333	Sentence	denotes	During oxygen supplementation, Spo 2 should not surpass 96% [11].
T286	34334-34446	Sentence	denotes	An alternative to conventional oxygen supplementation is supplementation through high-flow nasal cannula (HFNC).
T287	34447-34548	Sentence	denotes	HFNC is an oxygen supply system that provides a mixture of air and oxygen with a known concentration.
T288	34549-34830	Sentence	denotes	HFNC provides high concentrations of humidified oxygen and low levels of positive end-expiratory pressure; it can also facilitate the elimination of carbon dioxide, thereby potentially reducing the need for intubation compared to standard oxygen supplementation [[12], [13], [14]].
T289	34831-35145	Sentence	denotes	However, it should also be considered that there are no standard evidence-based guidelines for the use of HFNC and that the experience in patients with COVID-19 is still limited (and without adjusted comparison to standard oxygen supplement) to provide universal recommendations, at least pending further data [9].
T290	35146-35528	Sentence	denotes	Other relevant things to be considered are: (a) HFNC should be used in settings with rapid availability of endotracheal intubation in the case of rapid deterioration [15]; and (b) the possible increased risk of contracting the infection for healthcare personnel as a result of aerosol generation should be appropriately managed (HFNC should be used in negative-pressure rooms) [16].
T291	35529-35991	Sentence	denotes	These two considerations also apply to continuous positive airway pressure (CPAP) with helmet (the most frequent system of noninvasive mechanical ventilation used in real life), which can be considered if the patient does not respond to standard or HFNC oxygen supplementation (i.e. if the ratio of arterial oxygen partial pressure to fractional inspired oxygen (Pao 2/Fio 2) has a decreasing trend) and there is no urgent indication for endotracheal intubation.
T292	35992-36141	Sentence	denotes	As for HFNC, also in the case of CPAP with helmet, close monitoring and short interval assessment for worsening of respiratory failure are mandatory.
T293	36142-36529	Sentence	denotes	In addition, it should be necessarily noted that although CPAP with helmet has become an established procedure for primary hypoxemic lung failure in the last few years, some experts do not support its use for COVID-19 [15], arguing that success rates in critically ill COVID-19 patients may be limited and there could be a risk of delayed intubation unfavourably influencing the outcome.
T294	36530-36868	Sentence	denotes	However, considering the atypical physiopathology of acute lung injury in patients with COVID-19 [17], gentle ventilation with a positive end expiratory pressure (PEEP) not higher than 10 to 12 cm of water may represent a reasonable approach for avoiding excessive damage during CPAP with helmet and possibly also the need for intubation.
T295	36869-37003	Sentence	denotes	Large studies, possibly RCT, are urgently needed to definitely clarify the precise role of CPAP with helmet in patients with COVID-19.
T296	37004-37304	Sentence	denotes	Finally, borrowing from what is already known and used in intensive care, pronation, although certainly more difficult to implement during noninvasive than invasive mechanical ventilation, may allow improved gas exchange and decreased respiratory distress, and may also promote lung recruitment [18].
T297	37306-37326	Sentence	denotes	Question 1 statement
T298	37327-37523	Sentence	denotes	Supplementary oxygen should be administered to patients with hypoxic respiratory failure for avoiding values of Spo 2 lower than 90%, and it should be aimed at reaching values not higher than 96%.
T299	37524-37828	Sentence	denotes	Although still without firm evidence, we currently support the use of CPAP helmet (with gentle ventilation and a PEEP of no more than 10–12 cm of water) if the patient does not respond to standard/HFNC oxygen supplementation and there is no urgent indication for endotracheal intubation (expert opinion).
T300	37829-37911	Sentence	denotes	However, no clear indications/criteria can be provided pending further experience.
T301	37912-38166	Sentence	denotes	Finally, it should be kept in mind that patients with COVID-19 can get worse in a few hours, so they should be closely monitored for worsening respiratory function so that tracheal intubation and mechanical ventilation can be quickly performed if needed.
T302	38168-38220	Sentence	denotes	Question 2. should antiviral agents be administered?
T303	38221-38502	Sentence	denotes	Several antiviral agents have demonstrated in vitro activity against SARS-CoV-2 or other coronaviruses, but currently there are no approved antiviral agents for coronavirus-related diseases, and there are still no favourable efficacy results from RCT available at the present time.
T304	38503-38651	Sentence	denotes	Lopinavir is a protease inhibitor used for the treatment of HIV patients, administered in combination with ritonavir to improve its serum half-life.
T305	38652-38953	Sentence	denotes	On the basis of its activity against SARS-CoV-1 and/or Middle East respiratory syndrome (MERS)-CoV observed in in vitro and animal studies [[19], [20], [21]], lopinavir/ritonavir (LPV/RTV) was compared to supportive care alone for the treatment of COVID-19 patients in an open-label RCT in China [22].
T306	38954-39202	Sentence	denotes	The primary time-to-event endpoint was clinical improvement from randomization (defined as a composite of discharge from the hospital or improvement of two points on a seven-category ordinal scale, ranging from no need of hospitalization to death).
T307	39203-39306	Sentence	denotes	Overall, 199 patients were enrolled (99 and 100 in the LPV/RTV and supportive care arms, respectively).
T308	39307-39504	Sentence	denotes	No differences were observed in the intent-to-treat population with regard to clinical improvement (hazard ratio 1.24 with standard of care as reference, 95% confidence interval (CI) 0.90 to 1.72).
T309	39505-39773	Sentence	denotes	In addition, no associations were observed with regard to 28-day mortality, although a smaller number of deaths were registered in the LPV/RTV arm (19.2% vs. 25.0% in investigational and comparator arms, respectively; percentage difference −5.8%, 95% CI −17.3 to 5.7).
T310	39774-40420	Sentence	denotes	Although some important considerations preclude a definite judgement on the possible efficacy of LPV/RTV (e.g. some major limitations are the open-label nature of the trial and the fact that LPV/RTV was initiated late with respect to the onset of symptoms; see question 7), especially in the case of early therapy initiation, the results of this RCT provide evidence currently discouraging the use of LPV/RTV (or of other protease inhibitors such as darunavir) in COVID-19 patients (also considering the potential side effects; Table 3 ), unless favourable results from other ongoing RCT in specific subgroups of patients are available (Table 2).
T311	40421-40635	Sentence	denotes	Furthermore, harmful drug interactions of antivirals with other drugs (such as hydroxychloroquine) cannot be excluded a priori because there are currently no large clinical data about the use of these combinations.
T312	40636-40803	Sentence	denotes	Table 3 Known adverse events of marketed anti-infective and anti-inflammatory drugs mostly provided as off-label treatments in the first phase of the COVID-19 pandemic
T313	40804-40823	Sentence	denotes	Drug Adverse events
T314	40824-40909	Sentence	denotes	Lopinavir/ritonavir • Hypercholesterolaemia and increased serum triglycerides (3–39%)
T315	40910-40953	Sentence	denotes	• Increased γ-glutamyl transferase (10–29%)
T316	40954-41005	Sentence	denotes	• Diarrhoea (7–28%; greater with once-daily dosing)
T317	41006-41039	Sentence	denotes	• Increased serum ALT (grade 3/4:
T318	41040-41046	Sentence	denotes	1–11%)
T319	41047-41063	Sentence	denotes	• Nausea (5–16%)
T320	41064-41105	Sentence	denotes	• Upper respiratory tract infection (14%)
T321	41106-41130	Sentence	denotes	• Abdominal pain (1–11%)
T322	41131-41148	Sentence	denotes	• Vomiting (2–7%)
T323	41149-41163	Sentence	denotes	• Fatigue (8%)
T324	41164-41210	Sentence	denotes	• Increased serum amylase and/or lipase (3–8%)
T325	41211-41228	Sentence	denotes	• Headache (2–6%)
T326	41229-41246	Sentence	denotes	• Skin rash (≤5%)
T327	41247-41272	Sentence	denotes	• Neutropenia (grade 3/4:
T328	41273-41278	Sentence	denotes	1–5%)
T329	41279-41293	Sentence	denotes	• Anxiety (4%)
T330	41294-41310	Sentence	denotes	• Insomnia (≤4%)
T331	41311-41381	Sentence	denotes	Chloroquine/hydroxychloroquine • Retinopathy (4% of treated patients)a
T332	41382-41633	Sentence	denotes	• Other adverse effects with unknown frequency included Stevens-Johnson syndrome, abdominal pain, diarrhoea, nausea, vomiting, agranulocytosis, leukopenia, thrombocytopenia, abnormal hepatic function tests, acute hepatic ailure, myopathy, bronchospasm
T333	41634-41740	Sentence	denotes	• Risk of prolonged QT interval, further increased when administered with fluoroquinolones or azithromycin
T334	41741-41796	Sentence	denotes	Tocilizumab • Increased serum ALT (≤36%) and AST (≤22%)
T335	41797-41832	Sentence	denotes	• Increased LDL cholesterol (9–10%)
T336	41833-41866	Sentence	denotes	• Injection site reaction (4–10%)
T337	41867-41890	Sentence	denotes	• Neutropenia (grade 3:
T338	41891-41918	Sentence	denotes	2–7% of all adult patients)
T339	41919-41936	Sentence	denotes	• Headache (1–7%)
T340	41937-41958	Sentence	denotes	• Hypertension (1–6%)
T341	41959-41975	Sentence	denotes	• Dizziness (3%)
T342	41976-41998	Sentence	denotes	• Hypothyroidism (<2%)
T343	41999-42020	Sentence	denotes	• Abdominal pain (2%)
T344	42021-42057	Sentence	denotes	• Oral mucosa or gastric ulcers (2%)
T345	42058-42231	Sentence	denotes	• Infections due to Pneumocystis, Mycobacterium tuberculosis and varicella zoster have been reported after tocilizumab, but their prevalence has not been clearly established
T346	42232-42276	Sentence	denotes	Anakinra • Injection site reactionb (24–71%)
T347	42277-42390	Sentence	denotes	• Antibody development (up to 50% of the patients but no correlation of antibody development and adverse effects)
T348	42391-42423	Sentence	denotes	• Headache and vomiting (12–14%)
T349	42424-42445	Sentence	denotes	• Arthralgia (10–12%)
T350	42446-42462	Sentence	denotes	• Fever (10–12%)
T351	42463-42557	Sentence	denotes	• Haematologic disorder including eosinophilia, leukopenia and change in platelet count (2–9%)
T352	42558-42587	Sentence	denotes	• Nausea and diarrhoea (7–8%)
T353	42588-42615	Sentence	denotes	• Serious infectionc (2–3%)
T354	42616-42749	Sentence	denotes	Off-label drugs mostly provided in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience.
T355	42750-42879	Sentence	denotes	ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; LDL, low-density lipoprotein.
T356	42880-43020	Sentence	denotes	a Serum concentration dependent adverse effect; early changes are generally reversible but may progress despite discontinuation if advanced.
T357	43021-43089	Sentence	denotes	b Injection site reactions were considered serious in 2–3% of cases.
T358	43090-43173	Sentence	denotes	c Serious infections included cellulitis, pneumonia, and bone and joint infections.
T359	43174-43429	Sentence	denotes	Remdesivir is an investigational nucleotide analogue undergoing clinical development for Ebola and showing in vitro activity against coronaviruses (SARS-CoV-2, SARS-CoV-1 and MERS-CoV) and favourable effects in animal MERS models [[23], [24], [25], [26]].
T360	43430-43533	Sentence	denotes	Following these promising preclinical findings, RCT in COVID-19 patients have been initiated (Table 2).
T361	43534-43765	Sentence	denotes	However, pending their results, and considering the investigational nature of the drug, access to remdesivir outside RCT is currently provided only within strictly regulated and limited compassionate-use/expanded-access frameworks.
T362	43766-43925	Sentence	denotes	Oseltamivir and zanamivir are neuraminidase inhibitors used for treating influenza which are also being tested in RCT for treating COVID-19 patients (Table 2).
T363	43926-44235	Sentence	denotes	However, no apparent activity of oseltamivir and zanamivir has previously been observed against SARS-CoV-1 in vitro [27], and the fact that up to 76% of the first critically ill patients with COVID-19 received oseltamivir may also be related to the suspicion of infection (or coinfection) with influenza [28].
T364	44236-44413	Sentence	denotes	Overall, this information is currently insufficient for supporting the use of these agents in COVID-19 patients unless in the presence of suspected/proven concomitant influenza.
T365	44414-44667	Sentence	denotes	Other antiviral agents currently being investigated in RCT for the treatment of COVID-19 patients are favipiravir, an RNA-dependent RNA polymerase inhibitor with anti-influenza activity, and umifenovir, and anti-influenza membrane fusion inhibitor [29].
T366	44668-45030	Sentence	denotes	Even though these two agents attracted important media attention in the last few months, and even though there were some favourable preliminary results, especially for favipiravir, released as preprints, we advocate caution in using these agents outside investigational studies until completion of the standard peer-review processes of the first released trials.
T367	45031-45496	Sentence	denotes	For example, in a recent RCT comparing 120 COVID-19 patients treated with favipiravir versus 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir, but it is of note that the all-cause mortality was 0 in the entire study population, making it uncertain whether, if confirmed, these favourable results may be extrapolated to relevant survival endpoints in critically ill COVID-19 patients [30].
T368	45497-45637	Sentence	denotes	Finally, antiviral activity against SARS-CoV-2 in vitro has been recently reported for ivermectin, but clinical data are still lacking [31].
T369	45639-45659	Sentence	denotes	Question 2 statement
T370	45660-45790	Sentence	denotes	At the present time, evidence from the first published RCT does not support off-label treatment with LPV/RTV in COVID-19 patients.
T371	45791-45935	Sentence	denotes	This result should also discourage the use of other protease inhibitors (e.g. darunavir), at least until results of dedicated RCT are available.
T372	45936-46168	Sentence	denotes	Although promising in preclinical studies, remdesivir should be currently provided for treating COVID-19 patients only within RCT (preferentially) or compassionate-use/expanded-access programmes, owing to its investigational nature.
T373	46169-46350	Sentence	denotes	Pending high-level supporting evidence, favipiravir and umifenovir should not be provided outside RCT, at least in those countries where they are not approved for other indications.
T374	46351-46458	Sentence	denotes	Oseltamivir or zanamivir should be provided only in the presence of suspected/proven concomitant influenza.
T375	46460-46526	Sentence	denotes	Question 3. should chloroquine/hydroxychloroquine be administered?
T376	46527-46706	Sentence	denotes	The rationale of using chloroquine for treating COVID-19 patients is based on two potential and non–mutually exclusive mechanisms: antiviral activity and immunomodulatory effects.
T377	46707-47040	Sentence	denotes	With regard to antiviral activity, chloroquine has been shown to inhibit various viruses in cell cultures, including SARS-CoV-1 and SARS-CoV-2, possibly via pH-dependent inhibition of virus–endosome fusion and/or posttranslational modifications of CoV proteins, although other mechanisms may also contribute [[32], [33], [34], [35]].
T378	47041-47389	Sentence	denotes	With regard to the immunomodulatory effects, the attenuated production of tumor necrosis factor alpha, interleukin (IL)-6 and interferons that follows the administration of chloroquine might help counteract an exaggerated proinflammatory response, which is thought to contribute to the organ damage observed in SARS-CoV-2–infected patients [36,37].
T379	47390-47545	Sentence	denotes	However, some authors have pointed out that an unfavourable immunomodulatory effect cannot be excluded, based on a reduced T helper 2 differentiation [38].
T380	47546-47768	Sentence	denotes	In our opinion, hydroxychloroquine should be preferred over chloroquine because of its less toxic profile (reduced ocular toxicity and fewer drug interactions) and its more potent in vitro activity against SARS-CoV-2 [39].
T381	47769-48028	Sentence	denotes	Recently, Cortegiani et al. [40] reviewed the available information on ongoing case series, comparative observational studies and RCT evaluating the use of chloroquine or hydroxychloroquine in patients with COVID-19 and registered in Chinese or US registries.
T382	48029-48081	Sentence	denotes	They found 23 studies, all being conducted in China.
T383	48082-48271	Sentence	denotes	However, in the few weeks after the paper was made available online (10 March 2020), the number of registered studies being conducted in countries other than China has multiplied (Table 2).
T384	48272-48552	Sentence	denotes	In particular, results of registered RCT are necessary to guide (or discourage) the use of chloroquine/hydroxychloroquine in two different settings: prophylaxis of exposed individuals and treatment of proven cases, stratified for the severity of clinical presentation/progression.
T385	48553-48695	Sentence	denotes	In the meantime, a small controlled nonrandomized study of COVID-19 patients treated with hydroxychloroquine has been recently published [41].
T386	48696-48949	Sentence	denotes	In this study, Gautret et al. enrolled 26 COVID-19 patients to receive 200 mg of hydroxychloroquine every 8 hours for 10 days, whereas a total of 16 patients who denied consent as well as untreated patients from another centre were included as controls.
T387	48950-49031	Sentence	denotes	Of note, six patients treated with hydroxychloroquine also received azithromycin.
T388	49032-49166	Sentence	denotes	The primary endpoint was virologic clearance (based on results of real-time PCR on nasopharyngeal specimens) at day 6 after inclusion.
T389	49167-49522	Sentence	denotes	At day 6, 70% (14/20) of hydroxychloroquine-treated patients were virologically cured versus 12.5% (2/16) in the control group (p 0.001), although it cannot be excluded that selection bias and baseline virus load played a role in influencing results, thereby biasing results towards observing a favourable effect of hydroxychloroquine administration [42].
T390	49523-49754	Sentence	denotes	Furthermore, the opposite results (apparent absence of reduction of virus clearance) were recently described by another French group (albeit in a tiny sample size of 11 patients receiving hydroxychloroquine plus azithromycin) [43].
T391	49755-50103	Sentence	denotes	Uncertainty also surrounds the more marked positive effect observed in patients receiving azithromycin in addition to hydroxychloroquine in the study by Gautret et al., especially because of the very small number of patients in the combined treatment subgroup and the possible increased risk of QT prolongation by combining the two drugs (Table 3).
T392	50105-50125	Sentence	denotes	Question 3 statement
T393	50126-50384	Sentence	denotes	Pending results of RCT, the use of hydroxychloroquine may be considered for treating worsening patients with COVID-19 only if no important drug interactions can be anticipated and with close monitoring of hepatic function, renal function and QT prolongation.
T394	50385-50593	Sentence	denotes	This is based on its activity in vitro against SARS-CoV-2 (although weak) and on the availability of low-level clinical evidence of anticipation of virus clearance from a small controlled nonrandomized study.
T395	50594-50766	Sentence	denotes	However, it should also be kept in mind that the study was highly susceptible to bias and there are still no data regarding hard clinical endpoints such as crude mortality.
T396	50767-50891	Sentence	denotes	For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies.
T397	50892-51001	Sentence	denotes	When this is unfeasible, off-label use may be considered according to local protocols and consent procedures.
T398	51002-51198	Sentence	denotes	In view of the absence of evidence, we are currently unable to support the use of hydroxychloroquine in asymptomatic or mildly symptomatic nonhospitalized patients outside investigational studies.
T399	51199-51236	Sentence	denotes	The same applies to prophylactic use.
T400	51238-51285	Sentence	denotes	Question 4. should antibiotics be administered?
T401	51286-51488	Sentence	denotes	Bacterial infections can present simultaneously with COVID-19 or occur later during the course of the disease, worsening clinical conditions of patients who were recovering from primary viral pneumonia.
T402	51489-51589	Sentence	denotes	Information regarding the prevalence of bacterial coinfection or superinfection is scant [28,44,45].
T403	51590-51724	Sentence	denotes	According to the available reports, prevalence of bacterial infections in patients with COVID-19 ranges between 1% and 10% [28,44,46].
T404	51725-51857	Sentence	denotes	In these reports, bacterial infections were due to Gram-negative bacteria including Enterobacterales and nonfermenting rods [28,44].
T405	51858-52156	Sentence	denotes	It is of note that up to 98% of COVID-19 patients in available experiences received intravenous broad-spectrum empirical antibiotics [28,44,45,47], probably reflecting the frequent inability to exclude the presence of bacterial coinfection at the onset of severe clinical presentations of COVID-19.
T406	52157-52242	Sentence	denotes	This could have possibly lowered the overall prevalence of bacterial superinfections.
T407	52243-52485	Sentence	denotes	Extrapolating data from experiences on bacterial superinfection in pneumonia due to other viruses in a retrospective case series of critically ill patients with MERS in Saudi Arabia, bacterial infection was registered in 18% of patients [48].
T408	52486-52624	Sentence	denotes	With similar prevalence, bacterial pneumonia occurred in about 20% of patients hospitalized for primary influenza virus infection [49,50].
T409	52625-52730	Sentence	denotes	In these studies, mortality related to influenza was mostly due to secondary bacterial pneumonia [49,50].
T410	52731-52917	Sentence	denotes	Common bacteria implicated were Staphylococcus aureus, including methicillin-resistant strains [51], Streptococcus pneumoniae, Haemophilus influenzae and group A streptococci [49,52,53].
T411	52918-53089	Sentence	denotes	There are currently no large data regarding any possible favourable effects in COVID-19 patients related to possible anti-inflammatory or antiviral effect of azithromycin.
T412	53090-53218	Sentence	denotes	Furthermore, the small experiences of the administration of azithromycin in COVID-19 patients have provided conflicting results.
T413	53220-53240	Sentence	denotes	Question 4 statement
T414	53241-53423	Sentence	denotes	In our opinion, it might be prudent to consider empiric antibiotic treatment in critically ill patients with pneumonia due to COVID-19 in whom bacterial infection cannot be excluded.
T415	53424-53662	Sentence	denotes	This suggestion is based on the facts that bacterial coinfection is common in patients with viral pneumonia and that it can be associated with a substantial risk of delaying appropriate treatment, thereby potentially increasing mortality.
T416	53663-53910	Sentence	denotes	Because of the limited available data on both the microbiologic epidemiology (and the prevalence of antimicrobial resistance) of bacterial superinfections in COVID-19 patients, it is difficult to provide specific pathogen-oriented recommendations.
T417	53911-54325	Sentence	denotes	Therefore, pending further studies, we suggest to empirically treat COVID-19 patients according to their clinical syndrome (e.g. community-acquired pneumonia, hospital-acquired pneumonia), choosing the best antimicrobial agent or agents on the basis of local guidelines and local antibiotic susceptibility patterns, with early de-escalation or discontinuation according to microbiology results, whenever available.
T418	54327-54371	Sentence	denotes	Question 5. should steroids be administered?
T419	54372-54614	Sentence	denotes	So far, no RCT has been performed on corticosteroids administration in patients with COVID-19, and there are controversial opinions regarding the extrapolation of inference from previous studies in SARS-CoV-1 and MERS-CoV patients [15,54,55].
T420	54615-55023	Sentence	denotes	In an observational study conducted in 84 COVID-19 patients with acute respiratory distress syndrome (ARDS) in China, administration of methylprednisolone was associated with reduced progression to death (hazard ratio 0.38, 95% confidence interval 0.20–0.72, p 0.003), although the unadjusted analysis and the relatively small sample size preclude firm generalization and call for further investigation [47].
T421	55024-55240	Sentence	denotes	Indirect data on the possible efficacy (RCT) or effectiveness (observational comparative studies) of corticosteroid therapy come from studies performed in patients with MERS-CoV, SARS-CoV-1 or other viral infections.
T422	55241-55429	Sentence	denotes	With regard to patients with mild clinical presentation, a RCT including 16 not critically ill patients with SARS-CoV-1 did not report a beneficial effect of hydrocortisone administration.
T423	55430-55577	Sentence	denotes	Of note, higher viraemia was observed in the second and third weeks after infection in the hydrocortisone group compared to the control group [56].
T424	55578-55899	Sentence	denotes	Moreover, as reported in a systematic review and meta-analysis of observational studies on corticosteroids provided to patients with SARS-CoV-1, only four studies provided conclusive data, reporting no survival benefit and possible harms including avascular necrosis, psychosis, diabetes and delayed virus clearance [57].
T425	55900-56104	Sentence	denotes	In critically ill patients, corticosteroids may be provided to decrease the inflammation–coagulation–fibroproliferation observed during acute respiratory distress syndrome (ARDS) [[58], [59], [60], [61]].
T426	56105-56374	Sentence	denotes	A meta-analysis on corticosteroid use in ARDS including eight controlled studies reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, duration of mechanical ventilation and ICU length of stay [62].
T427	56375-56481	Sentence	denotes	A recent multicentre RCT included 277 patients with ARDS to assess the effects of dexamethasone treatment.
T428	56482-56628	Sentence	denotes	Patients in the study arm received dexamethasone 20 mg once daily from day 1 to day 5, which was reduced to 10 mg once daily from day 6 to day 10.
T429	56629-56908	Sentence	denotes	This study reported a significant reduction in duration of mechanical ventilation in the dexamethasone group than in the control group (between-group difference 4.8 days, p < 0.0001) and a significant reduction in mortality at 60 days (between-group difference −15.3%, p 0.0047).
T430	56909-57030	Sentence	denotes	The proportion of adverse events did not differ significantly between the dexamethasone group and the control group [63].
T431	57031-57179	Sentence	denotes	Data on the use of corticosteroids in critically ill patients with SARS-CoV-1 and MERS-CoV infection are available, albeit with conflicting results.
T432	57180-57428	Sentence	denotes	In a retrospective observational study of 152 SARS-CoV-1–infected, critically ill patients, corticosteroid therapy was found to reduce mortality and shorten the length of hospital stay (odds ratio 0.08, 95% confidence intervals 0.01–0.97, p 0.046).
T433	57429-57548	Sentence	denotes	The study did not report increased secondary infections or other complications with corticosteroid administration [64].
T434	57549-57783	Sentence	denotes	Conversely, in a retrospective observational study on 309 critically ill patients with MERS-CoV, the administration of a median hydrocortisone equivalent dose of 300 mg per day was not associated with a difference in 90-day mortality.
T435	57784-57923	Sentence	denotes	In addition, corticosteroid administration was associated with delayed clearance of MERS-CoV RNA from the patients' respiratory tract [65].
T436	57924-58165	Sentence	denotes	With regard to other viral infections, it is worth noting that a recent meta-analysis on patients with influenza pneumonia (including ten observational studies with a total of 6548 included patients) reported increased mortality (risk ratio:
T437	58166-58245	Sentence	denotes	1.75, 95% CI 1.3–2.4; p 0.0002), increased length of ICU stay (mean difference:
T438	58246-58353	Sentence	denotes	2.1, 95% CI 1.2–3.1; p < 0.0001) and increased rate of secondary bacterial or fungal infection (risk ratio:
T439	58354-58429	Sentence	denotes	2.0, 95% CI 1.0–3.8; p 0.04) in patients who received corticosteroids [66].
T440	58431-58451	Sentence	denotes	Question 5 statement
T441	58452-58605	Sentence	denotes	So far, no definitive efficacy or effectiveness data are available on the benefit of corticosteroid administration in patients with SARS-CoV-2 infection.
T442	58606-58772	Sentence	denotes	As the World Health Organization underlines, there is an important need for efficacy data from RCT for supporting corticosteroids therapy in patients with SARS-CoV-2.
T443	58773-59234	Sentence	denotes	However, considering that overwhelming inflammation and cytokine-related lung injury might be responsible for the rapidly progressive pneumonia and clinical deterioration in COVID-19 patients [44,58,67], we suggest (expert opinion only) to consider administration of corticosteroids in critically ill COVID-19 patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections (independent of ICU admission).
T444	59235-59463	Sentence	denotes	However, in the absence of convincing evidence, the following cannot currently be supported: steroid administration stratified according to inflammatory markers and steroid administration in non–critically ill COVID-19 patients.
T445	59465-59558	Sentence	denotes	Question 6. should other immunosuppressive and/or immunomodulatory therapies be administered?
T446	59559-59844	Sentence	denotes	According to some recent evidence, some patients with COVID-19 may develop secondary haemophagocytic lymphohistiocytosis, an underrecognized hyperinflammatory syndrome characterized by a fulminant and fatal hypercytokinaemia, with development of ARDS and multiorgan failure [46,47,67].
T447	59845-59980	Sentence	denotes	Consequently, immunosuppressive and/or immunomodulatory therapies have been proposed to contrast COVID-19–associated hyperinflammation.
T448	59981-60353	Sentence	denotes	Tocilizumab is a recombinant humanized monoclonal antibody inhibiting membrane-bound and soluble IL-6 receptors [68] and is currently approved for the treatment of patients with rheumatoid arthritis, giant-cell arteritis, juvenile idiopathic arthritis and patients with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome [68,69].
T449	60354-60509	Sentence	denotes	In this regard, tocilizumab may help mitigate the cytokine release syndrome by decreasing cytokine concentrations and acute-phase reactant production [70].
T450	60510-60629	Sentence	denotes	In a recent preprint paper, Xu et al. [71] reported their experience of treating 21 COVID-19 patients with tocilizumab.
T451	60630-61020	Sentence	denotes	In their still-to-be-peer-reviewed case series, the following were observed after tocilizumab administration: (a) reduction in body temperature (21/21, 100%); (b) improved blood oxygenation (15/21, 71.4%); (c) normalization of lymphocyte count (10/17, 58.8%); (d) normalization of C-reactive protein (16/19, 82.4%); and (c) resolution of abnormalities on computed tomography (19/21, 90.5%).
T452	61021-61147	Sentence	denotes	Interestingly, no adverse reactions were observed after tocilizumab administration, but long-term follow-up was not available.
T453	61148-61306	Sentence	denotes	Tocilizumab has been deemed by Chinese National Health Commission to be a possible treatment option for patients with severe COVID-19 with elevated IL-6 [72].
T454	61307-61489	Sentence	denotes	The recommended dose is 4 to 8 mg/kg or 400 mg standard dose provided intravenously once, with the option to repeat a dose after 8 to 12 hours (not to exceed a total dose of 800 mg).
T455	61490-61687	Sentence	denotes	However, it should be noted that the optimal time for administering tocilizumab has not yet been fully elucidated; nor is there a clear IL-6 threshold associated with progression to severe disease.
T456	61688-61830	Sentence	denotes	At the time of writing, there are at least eight ongoing RCT evaluating the efficacy and safety of tocilizumab in COVID-19 patients (Table 2).
T457	61831-62027	Sentence	denotes	Other immune-modulatory drugs including anakinra (interleukin 1 receptor antagonist) or Janus kinase family enzyme inhibitors have been proposed for the management of SARS-CoV-2–infected patients.
T458	62028-62127	Sentence	denotes	Notably, there is currently no supporting clinical evidence, and RCT are ongoing (Table 2) [67,73].
T459	62128-62399	Sentence	denotes	Finally, modifications of the immune response through administration of high-dose intravenous immunoglobulin or convalescent plasma have also been proposed or used in small case series, and they merit further investigation in dedicated RCT [[74], [75], [76], [77], [78]].
T460	62401-62421	Sentence	denotes	Question 6 statement
T461	62422-62576	Sentence	denotes	Owing to the lack of high-level evidence, administration of tocilizumab in patients with COVID-19 should preferentially occur within the framework of RCT.
T462	62577-62903	Sentence	denotes	Off-label use according to local protocols and consent procedures may be considered only in those COVID-19 patients excluded from RCT (or hospitalized where RCT are not available or still to be implemented) and who are worsening while receiving standard supportive care (in the absence of concomitant/superimposed infections).
T463	62904-63380	Sentence	denotes	In our opinion, this could be a reasonable off-label use of tocilizumab in these early phases of the COVID-19 pandemic, although patients and physicians should be fully aware that currently there is only a non–peer-reviewed, noncomparative, observational experience (very low evidence from an unreviewed cases series), and that it only supports a potential favourable effect on inflammatory signs and symptoms, while there is no information on any possible effect on survival.
T464	63381-63600	Sentence	denotes	In the absence of clinical studies, we suggest that also other immunosuppressive and/or immunomodulatory therapies (e.g. anakinra, Janus kinase family enzyme inhibitors) should be preferentially administered within RCT.
T465	63601-63939	Sentence	denotes	This also applies to modifications of the immune response through high-dose intravenous immunoglobulins or plasma from convalescent patients, which, although promising in very small case series, both deserve dedicated RCT investigation to clearly understand their tolerability as well as the role they play in affecting COVID-19 outcomes.
T466	63941-64004	Sentence	denotes	Question 7. what is the optimal timing of treatment initiation?
T467	64005-64205	Sentence	denotes	Most clinical data on the timing of antiviral therapy initiation are derived from studies on viruses other than SARS-CoV-2, and it remains unclear whether these data can be extrapolated to SARS-CoV-2.
T468	64206-64389	Sentence	denotes	Previous studies in SARS-CoV-1 and influenza showed a possible favourable impact on mortality of early initiation of antiviral treatment after symptoms onset [[79], [80], [81], [82]].
T469	64390-64793	Sentence	denotes	With regard to SARS-CoV-2, although the results of the previously cited RCT comparing LPV/RTV versus standard of care eventually does not support the use of LPV/RTV in patients with COVID-19, it is also of note that the median time between symptom onset and randomization was 13 days (interquartile range, 11–16 days), so in most cases, the drug was initiated late during the course of the disease [22].
T470	64794-64922	Sentence	denotes	Consequently, we cannot exclude the possibility that an earlier initiation of LPV/RTV may be associated with improved prognosis.
T471	64923-65142	Sentence	denotes	In this regard, we think the results of this RCT may be hypothesis generating and may help guide the design of further RCT evaluating the efficacy of LPV/RTV (and/or other antivirals) in an earlier phase of the disease.
T472	65143-65390	Sentence	denotes	However, until such RCT will be available, we think the currently available clinical evidence is insufficient to support the use of LPV/RTV and/or other antivirals for treating COVID-19 outside the framework of RCT or compassionate-use programmes.
T473	65391-65495	Sentence	denotes	The optimal time of chloroquine/hydroxychloroquine and corticosteroids initiation still remains unknown.
T474	65496-65992	Sentence	denotes	Although based on low-level evidence, the positive effect of virus clearance observed by Gautret et al. [41] was observed in a mixed group of non-ICU patients with upper respiratory tract symptoms, non-ICU patients with lower respiratory tract symptoms and asymptomatic subjects, which overall may support a positive effect of early hydroxychloroquine initiation in non-ICU settings (although information on the exact time of treatment initiation with respect to symptoms onset was not provided).
T475	65993-66140	Sentence	denotes	With regard to steroid treatment, there is currently no evidence of a positive impact of early initiation in non–critically ill, non-ARDS patients.
T476	66141-66399	Sentence	denotes	Although lack of evidence is not a synonym of lack of effect, in our opinion, steroid treatment, considering also its potential detrimental effects, should currently be limited to ARDS patients or non-ARDS patients with worsening conditions (see question 5).
T477	66401-66421	Sentence	denotes	Question 7 statement
T478	66422-66718	Sentence	denotes	Supportive therapy (symptomatic therapy, rehydration and oxygen supplementation, if necessary) should be provided as soon as the patient presents with respiratory or systemic symptoms including severe asthenia, high fever, persistent cough and/or clinical or radiologic signs of lung involvement.
T479	66719-66990	Sentence	denotes	Pending further evidence, in our opinion, antiviral treatments should not be initiated in patients with SARS-CoV-2 infection outside RCT or compassionate-use programmes (with the exception of early oseltamivir initiation in patients with suspected concomitant influenza).
T480	66991-67263	Sentence	denotes	Corticosteroids should be initiated early in well-defined categories of patients (patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections), while their role in other COVID-19 patients still remains uncertain.
T481	67264-67647	Sentence	denotes	Although based on low-level evidence and pending RCT results, in our opinion, early hydroxychloroquine administration may be considered in COVID-19 patients who have moderate to severe symptoms, whereas further data are needed to better delineate the true balance between possible favourable effects and toxicity of hydroxychloroquine in mildly symptomatic and asymptomatic patients.
T482	67649-67700	Sentence	denotes	Question 8. what is the optimal treatment duration?
T483	67701-68004	Sentence	denotes	In the absence of proven effective treatment, treatment duration also remains unclear; it is currently based on expert opinion which is based on treatment durations in other approved indications for the drugs provided and aimed at a balance between potential activity and risk of undesired side effects.
T484	68005-68052	Sentence	denotes	Nonetheless, suggested durations vary markedly.
T485	68053-68458	Sentence	denotes	For example, a wide range of chloroquine/hydroxychloroquine treatment durations (from 5 to 20 days) have been recommended/provided in different centres/studies, making it impossible to provide an univocal recommendation in the absence of direct comparisons of different lengths of treatment with regard to relevant clinical endpoints (e.g. mortality, ICU admission) and safety [33,40,41,[83], [84], [85]].
T486	68459-68620	Sentence	denotes	There is no standard steroid treatment duration, with different consensus/study groups suggesting steroid administration for no longer than 7 to 10 days [54,85].
T487	68622-68642	Sentence	denotes	Question 8 statement
T488	68643-68950	Sentence	denotes	Chloroquine/hydroxychloroquine treatment should be continued for at least 5 days and possibly prolonged up to 20 days according to some expert opinions, although it should be noted that data regarding the relative safety of different lengths of administration in COVID-19 patients are currently unavailable.
T489	68951-69087	Sentence	denotes	Early discontinuation should be considered in the presence of adverse effects (e.g. QT prolongation or hepatic/renal toxicity; Table 3).
T490	69088-69365	Sentence	denotes	If the administration of remdesivir is approved within compassionate-use/expanded-access programmes, treatment duration should follow compassionate or expanded access protocols (e.g. up to 10 days according to the most recent compassionate protocol at the time of this review).
T491	69366-69490	Sentence	denotes	If corticosteroids are administered, we suggest a total treatment duration of 7 to 10 days, with progressive dose reduction.
T492	69491-69746	Sentence	denotes	If the patient deteriorates with worsening lung physiology after removal of steroid treatment in the absence of bacterial or fungal superinfection, a second course of corticosteroid treatment may be considered, followed by slow tapering after improvement.
T493	69748-69767	Sentence	denotes	Future perspectives
T494	69768-70278	Sentence	denotes	In these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity.
T495	70279-70451	Sentence	denotes	Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment.
T496	70452-70665	Sentence	denotes	For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients.
T497	70666-70981	Sentence	denotes	However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87].
T498	70982-71275	Sentence	denotes	For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.
T499	71276-71473	Sentence	denotes	Against this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible.
T500	71474-71748	Sentence	denotes	Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options.
T501	71749-72039	Sentence	denotes	If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices).
T502	72040-72509	Sentence	denotes	Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients.
T503	72511-72522	Sentence	denotes	Conclusions
T504	72523-72644	Sentence	denotes	Many off-label antiviral and anti-inflammatory drugs are being administered in this first phase of the COVID-19 pandemic.
T505	72645-72906	Sentence	denotes	While we do not discourage their use, physicians must be aware that because of the lack of high-level evidence, they may be ethically justifiable only in those worsening patients unlikely to improve with only supportive care and who cannot be enrolled onto RCT.
T506	72907-73108	Sentence	denotes	Implementation of well-designed RCT should be expanded as much as possible, as RCTs are the most secure way to change for the better our approach to COVID-19 patients, including our frontline opinions.
T507	73110-73134	Sentence	denotes	Transparency Declaration
T508	73135-73204	Sentence	denotes	All authors report no conflicts of interest relevant to this article.

T17

0-12

Sentence

denotes

Introduction

T18

13-225

Sentence

denotes

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries [[1], [2], [3]].

T19

226-521

Sentence

denotes

The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure, with the true proportion of severe cases still remaining partly unclear as a result of an incomplete denominator and a possible lack of adjustment for relevant confounding factors [4,5].

T20

522-836

Sentence

denotes

Nonetheless, of particular clinical concern at the present time is not the relative frequency of severe cases in patients requiring ventilation support, but rather their absolute number, which is reaching or even surpassing the intensive care unit (ICU) bed capacity in the most affected regions and countries [6].

T21

837-1189

Sentence

denotes

From this perspective, in addition to the important prevention and restrictive measures implemented for reducing transmission [7], it remains crucial to optimize the therapeutic management of symptomatic patients requiring noninvasive oxygen therapy in order both to improve the absolute cure rates and to reduce and prevent the need for ICU admission.

T22

1190-1485

Sentence

denotes

However, the lack of high-level evidence, inherent to the novelty and rapid spread of COVID-19, has led to the adoption of heterogeneous approaches worldwide, often without a clear distinction between the relative weight of available evidence and expert opinion in informing therapeutic choices.

T23

1486-1766

Sentence

denotes

In this narrative review, we sought to summarize the available evidence on important therapeutic questions we are continuously facing as clinicians caring for COVID-19 patients in Italy, trying to find a balance between current evidence, frontline experiences and expert opinions.

T24

1768-1775

Sentence

denotes

Methods

T25

1776-2002

Sentence

denotes

Members of a panel of 17 experts from the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP) were selected; they developed a list of 8 practical therapeutic questions to be addressed.

T26

2003-2302

Sentence

denotes

The members of the panel (which included infectious diseases specialists and pneumonologists) were divided into small groups and asked to summarize the available literature and their frontline-based opinion in brief (500 words maximum) narrative answers, plus a conclusive statement for each answer.

T27

2303-2423

Sentence

denotes

All the answers and statements were ultimately reviewed and discussed by the entire panel until a consensus was reached.

T28

2424-2504

Sentence

denotes

A brief summary of questions and conclusive statements is available in Table 1 .

T29

2505-2680

Sentence

denotes

Table 2 summarizes available or ongoing randomized controlled trial (RCT) information for off-label/compassionate-use drugs mostly used for the treatment of COVID-19 patients.

T30

2681-2911

Sentence

denotes

Of note, we focused on pneumologic and anti-infective/anti-inflammatory treatments; the discussion of the therapeutic approach to COVID-19–related cardiovascular/coagulative disorders is outside the scope of this narrative review.

T31

2912-2955

Sentence

denotes

Table 1 Summary of questions and statements

T32

2956-2974

Sentence

denotes

Question Statement

T33

2975-2986

Sentence

denotes

Question 1.

T34

2987-3086

Sentence

denotes

How to use at best oxygen therapy and noninvasive mechanical ventilation for preventing intubation?

T35

3087-3281

Sentence

denotes

Supplementary oxygen should be administered to patients with hypoxic respiratory failure for avoiding values of Spo2 lower than 90% and it should be aimed at reaching values not higher than 96%.

T36

3282-3586

Sentence

denotes

Although still without firm evidence, we currently support the use of CPAP helmet (with gentle ventilation and a PEEP of no more than 10–12 cm of water) if the patient does not respond to standard/HFNC oxygen supplementation and there is no urgent indication for endotracheal intubation (expert opinion).

T37

3587-3669

Sentence

denotes

However, no clear indications/criteria can be provided pending further experience.

T38

3670-3905

Sentence

denotes

Finally, it should be kept in mind that patients with COVID-19 can get worse in a few hours, so they should be carefully monitored for worsening respiratory function for rapidly prompting tracheal intubation and mechanical ventilation.

T39

3906-3917

Sentence

denotes

Question 2.

T40

3918-3958

Sentence

denotes

Should antiviral agents be administered?

T41

3959-4089

Sentence

denotes

At the present time, evidence from the first published RCT does not support off-label treatment with LPV/RTV in COVID-19 patients.

T42

4090-4234

Sentence

denotes

This result should also discourage the use of other protease inhibitors (e.g. darunavir), at least until results of dedicated RCT are available.

T43

4235-4457

Sentence

denotes

Although promising in preclinical studies, remdesivir should be currently provided to COVID-19 patients only within RCT (preferentially) or compassionate-use/expanded-access programmes, owing to its investigational nature.

T44

4458-4642

Sentence

denotes

Pending high-level supporting evidence, favipiravir and umifenovir should not be provided an outside RCT, at least in those countries where they are not approved for other indications.

T45

4643-4750

Sentence

denotes

Oseltamivir or zanamivir should be provided only in the presence of suspected/proven concomitant influenza.

T46

4751-4762

Sentence

denotes

Question 3.

T47

4763-4817

Sentence

denotes

Should chloroquine/hydroxychloroquine be administered?

T48

4818-5067

Sentence

denotes

Pending results of RCT, the use of hydroxychloroquine may be considered for treating worsening patients with COVID-19 only if no important drug interactions can be anticipated and with close monitoring of hepatic, renal function and QT prolongation.

T49

5068-5277

Sentence

denotes

This is based on its activity in vitro against SARS-CoV-2 (although weak) and on the availability of low-level clinical evidence of anticipation of virus clearance from a small controlled, nonrandomized study.

T50

5278-5450

Sentence

denotes

However, it should also be kept in mind that the study was highly susceptible to bias and there are still no data regarding hard clinical endpoints such as crude mortality.

T51

5451-5575

Sentence

denotes

For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies.

T52

5576-5685

Sentence

denotes

When this is unfeasible, off-label use may be considered according to local protocols and consent procedures.

T53

5686-5882

Sentence

denotes

In view of the absence of evidence, we are currently unable to support the use of hydroxychloroquine in asymptomatic or mildly symptomatic nonhospitalized patients outside investigational studies.

T54

5883-5920

Sentence

denotes

The same applies to prophylactic use.

T55

5921-5932

Sentence

denotes

Question 4.

T56

5933-5968

Sentence

denotes

Should antibiotics be administered?

T57

5969-6151

Sentence

denotes

In our opinion, it might be prudent to consider empiric antibiotic treatment in critically ill patients with pneumonia due to COVID-19 in whom bacterial infection cannot be excluded.

T58

6152-6389

Sentence

denotes

This suggestion is based on the fact that bacterial coinfection (a) is common in patients with viral pneumonia and (b) can be associated with a substantial risk of delaying appropriate treatment, thereby potentially increasing mortality.

T59

6390-6637

Sentence

denotes

Because of the limited available data on both the microbiologic epidemiology (and the prevalence of antimicrobial resistance) of bacterial superinfections in COVID-19 patients, it is difficult to provide specific pathogen-oriented recommendations.

T60

6638-7052

Sentence

denotes

Therefore, pending further studies, we suggest to empirically treat COVID-19 patients according to their clinical syndrome (e.g. community-acquired pneumonia, hospital-acquired pneumonia), choosing the best antimicrobial agent or agents on the basis of local guidelines and local antibiotic susceptibility patterns, with early de-escalation or discontinuation according to microbiology results, whenever available.

T61

7053-7064

Sentence

denotes

Question 5.

T62

7065-7097

Sentence

denotes

Should steroids be administered?

T63

7098-7251

Sentence

denotes

So far, no definitive efficacy or effectiveness data are available on the benefit of corticosteroid administration in patients with SARS-CoV-2 infection.

T64

7252-7395

Sentence

denotes

As the WHO underlines, there is an important need for efficacy data from RCT for supporting corticosteroid therapy in patients with SARS-Cov-2.

T65

7396-7842

Sentence

denotes

However, considering that overwhelming inflammation and cytokine-related lung injury might be responsible for rapidly progressive pneumonia and clinical deterioration in COVID-19 patients, we suggest (expert opinion only) to consider administration of corticosteroids in critically ill COVID-19 patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections (independent of ICU admission).

T66

7843-8075

Sentence

denotes

Yet in the absence of convincing evidence, the following cannot currently be supported: (1) steroid administration stratified according to inflammatory markers; and (b) steroid administration in non–critically ill COVID-19 patients.

T67

8076-8087

Sentence

denotes

Question 6.

T68

8088-8169

Sentence

denotes

Should other immunosuppressive and/or immunomodulatory therapies be administered?

T69

8170-8324

Sentence

denotes

Owing to the lack of high-level evidence, administration of tocilizumab to patients with COVID-19 should preferentially occur within the framework of RCT.

T70

8325-8651

Sentence

denotes

Off-label use according to local protocols and consent procedures may be considered only in those COVID-19 patients excluded from RCT (or hospitalized where RCT are not available or still to be implemented) and who are worsening while receiving standard supportive care (in the absence of concomitant/superimposed infections).

T71

8652-9121

Sentence

denotes

In our opinion, this could be a reasonable off-label use of tocilizumab in these early phases of the COVID-19 pandemic, although patients and physicians should be aware that currently there is only a non–peer-reviewed, noncomparative, observational experience (very low evidence from an unreviewed cases series) and that it only supports a potential favourable effect on inflammatory signs and symptoms, while there is no information on any possible effect on survival.

T72

9122-9327

Sentence

denotes

In the absence of clinical studies, we suggest to preferentially administer also other immunosuppressive and/or immunomodulatory therapies (e.g. anakinra, Janus kinase family enzyme inhibitors) within RCT.

T73

9328-9646

Sentence

denotes

This also applies to modifications of the immune response through high-dose intravenous immunoglobulins or plasma from convalescent patients, which, although promising in small case series, both deserve dedicated RCT investigation to clearly understand their role in impacting COVID-19 outcomes and their tolerability.

T74

9647-9658

Sentence

denotes

Question 7.

T75

9659-9710

Sentence

denotes

What is the optimal timing of treatment initiation?

T76

9711-10006

Sentence

denotes

Supportive therapy (symptomatic therapy, rehydration and oxygen supplementation, if necessary), should be initiated as soon as the patient manifests respiratory or systemic symptoms, including severe asthenia, high fever, persistent cough and/or clinical or radiologic signs of lung involvement.

T77

10007-10277

Sentence

denotes

Pending further evidence, in our opinion, antiviral treatments should not be provided to patients with SARS-CoV-2 infection outside RCT or compassionate-use programmes (with the exception of early oseltamivir initiation in patients with suspected concomitant influenza).

T78

10278-10549

Sentence

denotes

Corticosteroids should be provided early in well-defined categories of patients (patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections), while their role in other COVID-19 patients still remains uncertain.

T79

10550-10936

Sentence

denotes

Although based on low-level evidence and pending RCT results, in our opinion, early hydroxychloroquine administration may be considered in COVID-19 patients manifesting moderate to severe symptoms, whereas further data are needed to better delineate the true balance between possible favourable effects and toxicity of hydroxychloroquine in mildly symptomatic and asymptomatic patients.

T80

10937-10948

Sentence

denotes

Question 8.

T81

10949-10988

Sentence

denotes

What is the optimal treatment duration?

T82

10989-11288

Sentence

denotes

Chloroquine/hydroxychloroquine treatment should be continued for at least 5 days, and possibly up to 20 days, according to some expert opinions, although it should be noted that data regarding the relative safety of different lengths of administration in COVID-19 patients are currently unavailable.

T83

11289-11416

Sentence

denotes

Early discontinuation should be considered in the presence of adverse effects (e.g. QT prolongation or hepatic/renal toxicity).

T84

11417-11694

Sentence

denotes

If the administration of remdesivir is approved within compassionate-use/expanded-access programmes, treatment duration should follow compassionate or expanded access protocols (e.g. up to 10 days according to the most recent compassionate protocol at the time of this review).

T85

11695-11812

Sentence

denotes

If corticosteroids are provided, we suggest a total treatment duration of 7–10 days, with progressive dose reduction.

T86

11813-12083

Sentence

denotes

If the patient's condition deteriorates with worsening lung physiology after withdrawal of steroid treatment in the absence of bacterial or fungal superinfection, a second course of corticosteroid treatment may be considered, followed by slow tapering after improvement.

T87

12084-12459

Sentence

denotes

ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; CPAP, continuous positive airway pressure; HFNC, high-flow nasal cannula; ICU, intensive care unit; LPV/RTV, lopinavir/ritonavir; PEEP, positive end expiratory pressure; RCT, randomized controlled trial; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health Organization.

T88

12460-12635

Sentence

denotes

Table 2 Available and ongoing RCT on anti-infective and anti-inflammatory drugs most provided as off-label/compassionate treatments in the first phase of the COVID-19 pandemic

T89

12636-12787

Sentence

denotes

Drug Class/mechanism Published RCT Ongoing RCT for treatment/prevention of COVID-19 (recruiting or not yet recruiting) registered at ClinicalTrials.gov

T90

12788-12854

Sentence

denotes

Lopinavir/ritonavir Lopinavir is an HIV type 1 protease inhibitor.

T91

12855-13047

Sentence

denotes

Ritonavir is a CYP3A4 inhibitor that boosts lopinavir concentrations • Open-label RCT comparing lopinavir/ritonavir (99 patients) vs. standard of care (100) in patients with COVID-19 in China.

T92

13048-13125

Sentence

denotes

Lopinavir/ritonavir was administered at the dosage of 400/100 mg for 14 days.

T93

13126-13205

Sentence

denotes

The primary time-to-event endpoint was clinical improvement from randomization.

T94

13206-13594

Sentence

denotes

In the primary study population (ITT), no statistically significant differences were observed with regard to the primary endpoint of clinical improvement (HR 1.24 with standard of care as reference, 95% CI 0.90 to 1.72) and the secondary endpoint of 28-day mortality (19.2% vs. 25.0% in investigational and comparator arms, respectively; percentage difference −5.8%, 95% CI −17.3 to 5.7).

T95

13595-13748

Sentence

denotes

In the mITT population, lopinavir/ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care.

T96

13749-13921

Sentence

denotes

Median time between symptoms onset and randomization was 13 days (IQR 11–16) [22] • Comparison of lopinavir/ritonavir vs. hydroxychloroquine in patients with mild COVID-19.

T97

13922-13963

Sentence

denotes

Open-label RCT (NCT04307693, recruiting).

T98

13964-14023

Sentence

denotes

Primary endpoint: virus load at day 3, 5, 7, 10, 14 and 18.

T99

14024-14127

Sentence

denotes

• Comparison of ASC09/ritonavir vs. lopinavir/ritonavir in patients with confirmed COVID-19 pneumoniae.

T100

14128-14177

Sentence

denotes

Open-label RCT (NCT04261907, not yet recruiting).

T101

14178-14347

Sentence

denotes

Primary endpoint: adverse outcome at day 14 (composite of Spo 2 ≤ 93% without oxygen supplementation, PaO2/FiO2 ≤ 300 mm Hg or respiratory rate ≥ 30 breaths per minute).

T102

14348-14450

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus umifenovir in patients with COVID-19.

T103

14451-14492

Sentence

denotes

Open-label RCT (NCT04252885, recruiting).

T104

14493-14569

Sentence

denotes

Primary endpoint: rate of virus inhibition at day 0, 2, 4, 7, 10, 14 and 21.

T105

14570-14695

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus ribavirin plus interferon beta 1b in patients with COVID-19.

T106

14696-14737

Sentence

denotes

Open-label RCT (NCT04276688, recruiting).

T107

14738-14820

Sentence

denotes

Primary endpoint: time to negative nasopharyngeal swab RT-PCR (follow-up 30 days).

T108

14821-14964

Sentence

denotes

• Comparison of only supportive treatment vs. lopinavir/ritonavir vs. oseltamivir vs. umifenovir in patients with confirmed COVID-19 pneumonia.

T109

14965-15006

Sentence

denotes

Open-label RCT (NCT04255017, recruiting).

T110

15007-15282

Sentence

denotes

Primary endpoints: (a) rate of disease remission (mild disease: fever, cough and other symptoms relieved with improved lung CT; severe disease: fever, cough and other symptoms relieved with improved lung CT, Spo 2 > 93% or Pao 2/Fio 2 > 300 mm Hg); (b) time to lung recovery.

T111

15283-15395

Sentence

denotes

• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19.

T112

15396-15447

Sentence

denotes

Double-blind RCT (NCT04328285, not yet recruiting).

T113

15448-15542

Sentence

denotes

Primary endpoint: occurrence of a symptomatic or asymptomatic COVID-19 (follow-up 2.5 months).

T114

15543-15659

Sentence

denotes

• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia.

T115

15660-15709

Sentence

denotes

Open-label RCT (NCT04286503, not yet recruiting).

T116

15710-15892

Sentence

denotes

Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.

T117

15893-16075

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus xiyanping (injectable component derived from a plant used in traditional Chinese medicine) in patients with COVID-19.

T118

16076-16125

Sentence

denotes

Open-label RCT (NCT04295551, not yet recruiting).

T119

16126-16187

Sentence

denotes

Primary endpoint: clinical recovery time (follow-up 28 days).

T120

16188-16357

Sentence

denotes

• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus xiyanping injection in patients with COVID-19.

T121

16358-16407

Sentence

denotes

Open-label RCT (NCT04275388, not yet recruiting).

T122

16408-16469

Sentence

denotes

Primary endpoint: clinical recovery time (follow-up 14 days).

T123

16470-16649

Sentence

denotes

• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus traditional Chinese medicines in patients with COVID-19.

T124

16650-16691

Sentence

denotes

Open-label RCT (NCT04251871, recruiting).

T125

16692-16769

Sentence

denotes

Primary endpoint: time to complete remission of symptoms (follow-up 28 days).

T126

16770-16985

Sentence

denotes

• Comparison of lopinavir/ritonavir plus hydroxychloroquine vs. lopinavir/ritonavir plus hydroxychloroquine plus levamisole pill plus budesonide plus formoterol inhaler in patients with nonsevere COVID-19 pneumonia.

T127

16986-17039

Sentence

denotes

Partly blinded RCT (NCT04331470, not yet recruiting).

T128

17040-17121

Sentence

denotes

Primary endpoint: (a) clear CT scan at 3–7 days; (b) negative RT-PCR at 3–7 days.

T129

17122-17233

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19.

T130

17234-17295

Sentence

denotes

Double-blind, adaptive RCT (NCT04328012, not yet recruiting).

T131

17296-17372

Sentence

denotes

Primary endpoint: NIAID COVID-19 ordinal severity scale (follow-up 60 days).

T132

17373-17542

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19.

T133

17543-17596

Sentence

denotes

Double-blind, adaptive RCT (NCT04315948, recruiting).

T134

17597-17668

Sentence

denotes

Primary endpoint: severity rating on a 7-point ordinal scale at day 15.

T135

17669-17968

Sentence

denotes

• Comparison of lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) vs. natural honey plus lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) in patients with COVID-19.

T136

17969-18020

Sentence

denotes

Single-blind RCT (NCT04323345, not yet recruiting).

T137

18021-18214

Sentence

denotes

Primary endpoints: (a) positive to negative swabs at day 14; (b) fever to normal temperature in days (follow-up 14 days); (c) resolution of lung inflammation in CT or X-ray (follow-up 30 days).

T138

18215-18352

Sentence

denotes

• Comparison of colchicine (with or without lopinavir/ritonavir) vs. local standard of care in patients with moderate to severe COVID-19.

T139

18353-18402

Sentence

denotes

Open-label RCT (NCT04328480, not yet recruiting).

T140

18403-18461

Sentence

denotes

Primary endpoint: all-cause mortality (follow-up 30 days).

T141

18462-18866

Sentence

denotes

• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19.

T142

18867-18916

Sentence

denotes

Open-label RCT (NCT04303299, not yet recruiting).

T143

18917-18984

Sentence

denotes

Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).

T144

18985-19015

Sentence

denotes

Remdesivir Adenosine analogue.

T145

19016-19181

Sentence

denotes

It binds to RNA-dependent RNA polymerase and acts as an RNA-chain terminator • Not available • Comparison of remdesivir vs. placebo in patients with severe COVID-19.

T146

19182-19225

Sentence

denotes

Double-blind RCT (NCT04257656, recruiting).

T147

19226-19315

Sentence

denotes

Primary endpoint: clinical status, assessed by an ordinal scale at days 7, 14, 21 and 28.

T148

19316-19398

Sentence

denotes

• Comparison of remdesivir vs. placebo in patients with mild to moderate COVID-19.

T149

19399-19442

Sentence

denotes

Double-blind RCT (NCT04252664, recruiting).

T150

19443-19516

Sentence

denotes

Primary endpoint: time to clinical recovery in hours (follow-up 28 days).

T151

19517-19604

Sentence

denotes

• Comparison of remdesivir vs. local standard of care in patients with severe COVID-19.

T152

19605-19646

Sentence

denotes

Open-label RCT (NCT04252664, recruiting).

T153

19647-19754

Sentence

denotes

Primary endpoint: composite of fever normalization and oxygen saturation normalization (follow-up 14 days).

T154

19755-19844

Sentence

denotes

• Comparison of remdesivir vs. local standard of care in patients with moderate COVID-19.

T155

19845-19886

Sentence

denotes

Open-label RCT (NCT04292730, recruiting).

T156

19887-19933

Sentence

denotes

Primary endpoint: discharged status at day 14.

T157

19934-19999

Sentence

denotes

• Comparison of remdesivir vs. placebo in patients with COVID-19.

T158

20000-20043

Sentence

denotes

Double-blind RCT (NCT04280705, recruiting).

T159

20044-20115

Sentence

denotes

Primary endpoint: severity rating on a 8-point ordinal scale at day 15.

T160

20116-20231

Sentence

denotes

• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19.

T161

20232-20290

Sentence

denotes

Open-label adaptive RCT (NCT04321616, not yet recruiting).

T162

20291-20361

Sentence

denotes

Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).

T163

20362-20531

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19.

T164

20532-20585

Sentence

denotes

Double-blind, adaptive RCT (NCT04315948, recruiting).

T165

20586-20657

Sentence

denotes

Primary endpoint: severity rating on a 7-point ordinal scale at day 15.

T166

20658-20725

Sentence

denotes

Darunavir/cobicistat Darunavir is an HIV type 1 protease inhibitor.

T167

20726-20906

Sentence

denotes

Cobicistat is a CYP3A4 inhibitor that boosts darunavir concentrations • Not available • Comparison of darunavir/cobicistat vs. standard of care in patients with COVID-19 pneumonia.

T168

20907-20948

Sentence

denotes

Open-label RCT (NCT04252274, recruiting).

T169

20949-21063

Sentence

denotes

Primary endpoint: virologic clearance rate of throat swabs, sputum or lower respiratory tract secretions at day 7.

T170

21064-21370

Sentence

denotes

Favipiravir Anti-influenza RNA-dependent RNA polymerase inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir.

T171

21371-21546

Sentence

denotes

The manuscript is publicly available but still to be peer reviewed [30] • Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19.

T172

21547-21588

Sentence

denotes

Open-label RCT (NCT04310228, recruiting).

T173

21589-21642

Sentence

denotes

Primary endpoint: clinical cure (follow-up 3 months).

T174

21643-22047

Sentence

denotes

• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19.

T175

22048-22097

Sentence

denotes

Open-label RCT (NCT04303299, not yet recruiting).

T176

22098-22165

Sentence

denotes

Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).

T177

22166-22274

Sentence

denotes

• Comparison of hydroxychloroquine plus darunavir/cobicistat vs. standard of care in patients with COVID-19.

T178

22275-22316

Sentence

denotes

Open-label RCT (NCT04304053, recruiting).

T179

22317-22434

Sentence

denotes

Primary endpoint: incidence of secondary cases among contacts of a case and contacts of contacts (follow-up 14 days).

T180

22435-22534

Sentence

denotes

• Comparison of chloroquine plus favipiravir vs. favipiravir vs. placebo in patients with COVID-19.

T181

22535-22578

Sentence

denotes

Double-blind RCT (NCT04319900, recruiting).

T182

22579-22750

Sentence

denotes

Primary endpoints: (a) time to improvement/recovery and frequency of improvement/recovery (follow-up 10 days); (b) time to negative swab/sputum RT-PCR (follow-up 10 days).

T183

22751-22826

Sentence

denotes

• Comparison of favipiravir vs. standard of care in patients with COVID-19.

T184

22827-22876

Sentence

denotes

Open-label RCT (NCT04333589, not yet recruiting).

T185

22877-22989

Sentence

denotes

Primary endpoint: viral nucleic acid test negative conversion rate in nasopharyngeal swabs (follow-up 5 months).

T186

22990-23394

Sentence

denotes

• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19.

T187

23395-23444

Sentence

denotes

Open-label RCT (NCT04303299, not yet recruiting).

T188

23445-23512

Sentence

denotes

Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).

T189

23513-23805

Sentence

denotes

Umifenovir Anti-influenza membrane fusion inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir.

T190

23806-23962

Sentence

denotes

The manuscript is publicly available but still to be peer reviewed [30] • Comparison of umifenovir vs. standard of care in patients with COVID-19 pneumonia.

T191

23963-24012

Sentence

denotes

Open-label RCT (NCT04260594, not yet recruiting).

T192

24013-24081

Sentence

denotes

Primary endpoint: virus negative conversion rate (follow-up 7 days).

T193

24082-24461

Sentence

denotes

Chloroquine, hydroxychloroquine Some proposed mechanisms are the following: increase in the endosomal Ph necessary for the virus/host cell fusion; interference with the glycosylation of cell receptors; immunomodulatory activity • Not available • Comparison of different hydroxychloroquine dosages vs. placebo in three cohorts (outpatients, inpatients, healthcare workers a risk).

T194

24462-24586

Sentence

denotes

Double-blind RCT for outpatients and healthcare workers and open-label RCT for inpatients (NCT04329923, not yet recruiting).

T195

24587-24784

Sentence

denotes

Primary endpoints: (a) release from quarantine (outpatients, follow-up 14 days); (b) discharge (inpatients, follow-up 14 days); (c) development of COVID-19 (healthcare workers, follow-up 2 months).

T196

24785-24871

Sentence

denotes

• Comparison of hydroxychloroquine vs. ascorbic acid in contacts of COVID-19 patients.

T197

24872-24923

Sentence

denotes

Double-blind RCT (NCT04328961, not yet recruiting).

T198

24924-24992

Sentence

denotes

Primary endpoint: laboratory-confirmed COVID-19 (follow-up 14 days).

T199

24993-25129

Sentence

denotes

• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19.

T200

25130-25179

Sentence

denotes

Open-label RCT (NCT04332094, not yet recruiting).

T201

25180-25407

Sentence

denotes

Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).• Comparison of ciclesonide plus hydroxychloroquine vs. ciclesonide in patients with COVID-19.

T202

25408-25457

Sentence

denotes

Open-label RCT (NCT04330586, not yet recruiting).

T203

25458-25531

Sentence

denotes

Primary endpoint: SARS-CoV-2 eradication (based on virus load) at day 14.

T204

25532-25658

Sentence

denotes

• Comparison of hydroxychloroquine vs. placebo in patients with COVID-19 and under biological treatment and/or JAK inhibitors.

T205

25659-25710

Sentence

denotes

Double-blind RCT (NCT04330495, not yet recruiting).

T206

25711-25921

Sentence

denotes

Primary endpoints: (a) incidence rate of COVID-19 (follow-up 27 weeks); (b) prevalence of COVID-19 (follow-up 27 weeks); (c) case fatality rate (follow-up 27 weeks); (d) ICU admission rate (follow-up 27 weeks).

T207

25922-26030

Sentence

denotes

• Comparison of hydroxychloroquine vs. placebo for the prevention of COVID-19 in healthcare workers at risk.

T208

26031-26082

Sentence

denotes

Double-blind RCT (NCT04328467, not yet recruiting).

T209

26083-26145

Sentence

denotes

Primary endpoint: prevalence of COVID-19 (follow-up 12 weeks).

T210

26146-26258

Sentence

denotes

• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19.

T211

26259-26310

Sentence

denotes

Double-blind RCT (NCT04328285, not yet recruiting).

T212

26311-26328

Sentence

denotes

Primary endpoint:

T213

26329-26417

Sentence

denotes

Occurrence of a symptomatic or asymptomatic SARS-CoV-2 infection (follow-up 2.5 months).

T214

26418-26539

Sentence

denotes

• Comparison of hydroxychloroquine vs. placebo in symptomatic COVID-19 patients or exposed healthcare workers/households.

T215

26540-26583

Sentence

denotes

Double-blind RCT (NCT04308668, recruiting).

T216

26584-26731

Sentence

denotes

Primary endpoints: (a) incidence of symptomatic COVID-19 among asymptomatic participants; (b) severity rating on a 3-point ordinal scale at day 14.

T217

26732-26847

Sentence

denotes

• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19.

T218

26848-26906

Sentence

denotes

Open-label adaptive RCT (NCT04321616, not yet recruiting).

T219

26907-26977

Sentence

denotes

Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).

T220

26978-27089

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19.

T221

27090-27151

Sentence

denotes

Double-blind, adaptive RCT (NCT04328012, not yet recruiting).

T222

27152-27228

Sentence

denotes

Primary endpoint: NIAID COVID-19 Ordinal Severity Scale (follow-up 60 days).

T223

27229-27387

Sentence

denotes

• Comparison of convalescent plasma plus hydroxychloroquine plus azithromycin vs. hydroxychloroquine plus azithromycin in hospitalized patients with COVID-19.

T224

27388-27437

Sentence

denotes

Open-label RCT (NCT04332835, not yet recruiting).

T225

27438-27617

Sentence

denotes

Primary endpoints: (a) change in virus load at days 0, 4, 7, 14 and 28; (b) change in IgM COVID-19 titers at days 0, 4, 7, 14 and 28; (c) change in IgG at days 0, 4, 7, 14 and 28.

T226

27618-27787

Sentence

denotes

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta-1a vs. remdesivir vs. standard of care in patients with COVID-19.

T227

27788-27841

Sentence

denotes

Double-blind, adaptive RCT (NCT04315948, recruiting).

T228

27842-27913

Sentence

denotes

Primary endpoint: severity rating on a 7-point ordinal scale at day 15.

T229

27914-28276

Sentence

denotes

Methylprednisolone A subgroup of patients with severe COVID-19 might develop a cytokine storm syndrome which causes rapidly progressive pneumonia, ARDS and clinical deterioration and corticosteroids administration may halt the dysregulated cytokine release • Not available • Comparison of methylprednisolone vs. standard of care in patients with severe COVID-19.

T230

28277-28318

Sentence

denotes

Open-label RCT (NCT04244591, recruiting).

T231

28319-28385

Sentence

denotes

Primary endpoint: lower Murray lung injury score at days 7 and 14.

T232

28386-28468

Sentence

denotes

• Comparison of methylprednisolone vs. standard of care in patients with COVID-19.

T233

28469-28510

Sentence

denotes

Open-label RCT (NCT04273321, recruiting).

T234

28511-28567

Sentence

denotes

Primary endpoint: treatment failure (follow-up 14 days).

T235

28568-28768

Sentence

denotes

• Comparison of inhaled alpha interferon plus methylprednisolone plus umifenovir vs. thalidomide plus inhaled alpha interferon plus methylprednisolone plus umifenovir in patients with severe COVID-19.

T236

28769-28820

Sentence

denotes

Double-blind RCT (NCT04273581, not yet recruiting).

T237

28821-28888

Sentence

denotes

Primary endpoint: time to clinical improvement (follow-up 28 days).

T238

28889-28971

Sentence

denotes

• Comparison of different dosages of methylprednisolone in patients with COVID-19.

T239

28972-29013

Sentence

denotes

Open-label RCT (NCT04263402, recruiting).

T240

29014-29095

Sentence

denotes

Primary endpoints: (a) disease readmission at day 7; (b) critical stage at day 7.

T241

29096-29204

Sentence

denotes

• Comparison of siltuximab (anti–IL-6 monoclonal antibody) vs. methylprednisolone in patients with COVID-19.

T242

29205-29254

Sentence

denotes

Open-label RCT (NCT04329650, not yet recruiting).

T243

29255-29306

Sentence

denotes

Primary endpoint: ICU admission (follow-up 29 days)

T244

29307-29423

Sentence

denotes

Tocilizumab Humanized monoclonal IgG1 antibody, tocilizumab inhibits both membrane-bound and soluble IL-6 receptors.

T245

29424-29674

Sentence

denotes

IL-6, is one of the main drivers of immunologic response and symptoms in patients with dysregulated cytokine release that has been observed in severe COVID-19 • Not available • Comparison of tocilizumab vs. standard of care in patients with COVID-19.

T246

29675-29724

Sentence

denotes

Open-label RCT (NCT04331808, not yet recruiting).

T247

29725-29827

Sentence

denotes

Primary endpoint: WHO progression scale at day 7 and 14 (severity rating on a 10-point ordinal scale).

T248

29828-29931

Sentence

denotes

• Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19.

T249

29932-29973

Sentence

denotes

Open-label RCT (NCT04310228, recruiting).

T250

29974-30027

Sentence

denotes

Primary endpoint: clinical cure (follow-up 3 months).

T251

30028-30107

Sentence

denotes

• Comparison of tocilizumab vs. placebo in hospitalized patients with COVID-19.

T252

30108-30159

Sentence

denotes

Double-blind RCT (NCT04320615, not yet recruiting).

T253

30160-30231

Sentence

denotes

Primary endpoint: severity rating on a 7-point ordinal scale at day 28.

T254

30232-30368

Sentence

denotes

• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19.

T255

30369-30418

Sentence

denotes

Open-label RCT (NCT04332094, not yet recruiting).

T256

30419-30552

Sentence

denotes

Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).

T257

30553-30708

Sentence

denotes

• Comparison of chloroquine analog (GNS651) vs. tocilizumab vs. nivolumab vs. standard of care in patients with advanced or metastatic cancer and COVID-19.

T258

30709-30758

Sentence

denotes

Open-label RCT (NCT04333914, not yet recruiting).

T259

30759-30776

Sentence

denotes

Primary endpoint:

T260

30777-30793

Sentence

denotes

28-day survival.

T261

30794-30995

Sentence

denotes

• Comparison of tocilizumab intravenously vs. tocilizumab subcutaneously vs. sarilumab (anti-interleukin 6 receptor α monoclonal antibody) subcutaneously vs. standard of care in patients with COVID-19.

T262

30996-31045

Sentence

denotes

Open-label RCT (NCT04322773, not yet recruiting).

T263

31046-31139

Sentence

denotes

Primary endpoint: time to independence from supplementary oxygen therapy (follow-up 28 days).

T264

31140-31341

Sentence

denotes

• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19.

T265

31342-31391

Sentence

denotes

Open-label RCT (NCT04330638, not yet recruiting).

T266

31392-31459

Sentence

denotes

Primary endpoint: time to clinical improvement (follow-up 15 days).

T267

31460-31576

Sentence

denotes

• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia.

T268

31577-31626

Sentence

denotes

Open-label RCT (NCT04286503, not yet recruiting).

T269

31627-31809

Sentence

denotes

Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.

T270

31810-31847

Sentence

denotes

Anakinra Antagonist of IL-1 receptor.

T271

31848-32104

Sentence

denotes

IL-1 is one of the main drivers of immunologic response and symptoms in patients with cytokine-release syndrome. • Not available • Comparison of anakinra vs. emapalumab (anti–interferon γ monoclonal antibody) vs. standard of care in patients with COVID-19.

T272

32105-32154

Sentence

denotes

Open-label RCT (NCT04324021, not yet recruiting).

T273

32155-32201

Sentence

denotes

Primary endpoint: treatment success at day 15.

T274

32202-32403

Sentence

denotes

• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19.

T275

32404-32453

Sentence

denotes

Open-label RCT (NCT04330638, not yet recruiting).

T276

32454-32521

Sentence

denotes

Primary endpoint: time to clinical improvement (follow-up 15 days).

T277

32522-32655

Sentence

denotes

Off-label drugs mostly provided in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience.

T278

32656-32839

Sentence

denotes

Of note, there are also registered RCT for other drugs to be investigated in patients with COVID-19 (e.g. the Janus kinase family inhibitors ruxolitinib, baricitinib and tofacitinib).

T279

32840-33359

Sentence

denotes

ARDS = acute respiratory distress syndrome; CI, confidence interval; COVID-19, coronavirus disease 2019; CT, computed tomography; EOT, end of treatment; HR, hazard ratio; Ig, immunoglobulin; IL-1, interleukin 1; IQR, interquartile range; ITT, intent to treat; mITT, modified intent to treat; Pao2/Fio2, of arterial oxygen partial pressure to fractional inspired oxygen; RCT, randomized controlled trial; RT-PCR, real-time PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health Organization.

T280

33361-33472

Sentence

denotes

Question 1. how to use at best oxygen therapy and noninvasive mechanical ventilation for preventing intubation?

T281

33473-33676

Sentence

denotes

In moderate to severe cases, COVID-19 usually presents as a lung disease (mostly in the form of bilateral interstitial pneumonia) causing hypoxic respiratory failure and requiring passive oxygen therapy.

T282

33677-33775

Sentence

denotes

The prevalence of hypoxic respiratory failure in patients with COVID-19 may be as high as 19% [8].

T283

33776-33978

Sentence

denotes

In observational studies conducted in China, 4% to 13% of COVID-19 patients received noninvasive positive pressure ventilation, and 2.3% to 12% required invasive mechanical ventilation [[8], [9], [10]].

T284

33979-34267

Sentence

denotes

In general, oxygen treatment should be provided to patients with shortness of breath or hypoxaemia, or those in shock, which is aimed at maintaining an appropriate level of peripheral capillary oxygen saturation (Spo 2), avoiding values of Spo 2 lower than 90% (92–95% in pregnant women).

T285

34268-34333

Sentence

denotes

During oxygen supplementation, Spo 2 should not surpass 96% [11].

T286

34334-34446

Sentence

denotes

An alternative to conventional oxygen supplementation is supplementation through high-flow nasal cannula (HFNC).

T287

34447-34548

Sentence

denotes

HFNC is an oxygen supply system that provides a mixture of air and oxygen with a known concentration.

T288

34549-34830

Sentence

denotes

HFNC provides high concentrations of humidified oxygen and low levels of positive end-expiratory pressure; it can also facilitate the elimination of carbon dioxide, thereby potentially reducing the need for intubation compared to standard oxygen supplementation [[12], [13], [14]].

T289

34831-35145

Sentence

denotes

However, it should also be considered that there are no standard evidence-based guidelines for the use of HFNC and that the experience in patients with COVID-19 is still limited (and without adjusted comparison to standard oxygen supplement) to provide universal recommendations, at least pending further data [9].

T290

35146-35528

Sentence

denotes

Other relevant things to be considered are: (a) HFNC should be used in settings with rapid availability of endotracheal intubation in the case of rapid deterioration [15]; and (b) the possible increased risk of contracting the infection for healthcare personnel as a result of aerosol generation should be appropriately managed (HFNC should be used in negative-pressure rooms) [16].

T291

35529-35991

Sentence

denotes

These two considerations also apply to continuous positive airway pressure (CPAP) with helmet (the most frequent system of noninvasive mechanical ventilation used in real life), which can be considered if the patient does not respond to standard or HFNC oxygen supplementation (i.e. if the ratio of arterial oxygen partial pressure to fractional inspired oxygen (Pao 2/Fio 2) has a decreasing trend) and there is no urgent indication for endotracheal intubation.

T292

35992-36141

Sentence

denotes

As for HFNC, also in the case of CPAP with helmet, close monitoring and short interval assessment for worsening of respiratory failure are mandatory.

T293

36142-36529

Sentence

denotes

In addition, it should be necessarily noted that although CPAP with helmet has become an established procedure for primary hypoxemic lung failure in the last few years, some experts do not support its use for COVID-19 [15], arguing that success rates in critically ill COVID-19 patients may be limited and there could be a risk of delayed intubation unfavourably influencing the outcome.

T294

36530-36868

Sentence

denotes

However, considering the atypical physiopathology of acute lung injury in patients with COVID-19 [17], gentle ventilation with a positive end expiratory pressure (PEEP) not higher than 10 to 12 cm of water may represent a reasonable approach for avoiding excessive damage during CPAP with helmet and possibly also the need for intubation.

T295

36869-37003

Sentence

denotes

Large studies, possibly RCT, are urgently needed to definitely clarify the precise role of CPAP with helmet in patients with COVID-19.

T296

37004-37304

Sentence

denotes

Finally, borrowing from what is already known and used in intensive care, pronation, although certainly more difficult to implement during noninvasive than invasive mechanical ventilation, may allow improved gas exchange and decreased respiratory distress, and may also promote lung recruitment [18].

T297

37306-37326

Sentence

denotes

Question 1 statement

T298

37327-37523

Sentence

denotes

Supplementary oxygen should be administered to patients with hypoxic respiratory failure for avoiding values of Spo 2 lower than 90%, and it should be aimed at reaching values not higher than 96%.

T299

37524-37828

Sentence

denotes

Although still without firm evidence, we currently support the use of CPAP helmet (with gentle ventilation and a PEEP of no more than 10–12 cm of water) if the patient does not respond to standard/HFNC oxygen supplementation and there is no urgent indication for endotracheal intubation (expert opinion).

T300

37829-37911

Sentence

denotes

However, no clear indications/criteria can be provided pending further experience.

T301

37912-38166

Sentence

denotes

Finally, it should be kept in mind that patients with COVID-19 can get worse in a few hours, so they should be closely monitored for worsening respiratory function so that tracheal intubation and mechanical ventilation can be quickly performed if needed.

T302

38168-38220

Sentence

denotes

Question 2. should antiviral agents be administered?

T303

38221-38502

Sentence

denotes

Several antiviral agents have demonstrated in vitro activity against SARS-CoV-2 or other coronaviruses, but currently there are no approved antiviral agents for coronavirus-related diseases, and there are still no favourable efficacy results from RCT available at the present time.

T304

38503-38651

Sentence

denotes

Lopinavir is a protease inhibitor used for the treatment of HIV patients, administered in combination with ritonavir to improve its serum half-life.

T305

38652-38953

Sentence

denotes

On the basis of its activity against SARS-CoV-1 and/or Middle East respiratory syndrome (MERS)-CoV observed in in vitro and animal studies [[19], [20], [21]], lopinavir/ritonavir (LPV/RTV) was compared to supportive care alone for the treatment of COVID-19 patients in an open-label RCT in China [22].

T306

38954-39202

Sentence

denotes

The primary time-to-event endpoint was clinical improvement from randomization (defined as a composite of discharge from the hospital or improvement of two points on a seven-category ordinal scale, ranging from no need of hospitalization to death).

T307

39203-39306

Sentence

denotes

Overall, 199 patients were enrolled (99 and 100 in the LPV/RTV and supportive care arms, respectively).

T308

39307-39504

Sentence

denotes

No differences were observed in the intent-to-treat population with regard to clinical improvement (hazard ratio 1.24 with standard of care as reference, 95% confidence interval (CI) 0.90 to 1.72).

T309

39505-39773

Sentence

denotes

In addition, no associations were observed with regard to 28-day mortality, although a smaller number of deaths were registered in the LPV/RTV arm (19.2% vs. 25.0% in investigational and comparator arms, respectively; percentage difference −5.8%, 95% CI −17.3 to 5.7).

T310

39774-40420

Sentence

denotes

Although some important considerations preclude a definite judgement on the possible efficacy of LPV/RTV (e.g. some major limitations are the open-label nature of the trial and the fact that LPV/RTV was initiated late with respect to the onset of symptoms; see question 7), especially in the case of early therapy initiation, the results of this RCT provide evidence currently discouraging the use of LPV/RTV (or of other protease inhibitors such as darunavir) in COVID-19 patients (also considering the potential side effects; Table 3 ), unless favourable results from other ongoing RCT in specific subgroups of patients are available (Table 2).

T311

40421-40635

Sentence

denotes

Furthermore, harmful drug interactions of antivirals with other drugs (such as hydroxychloroquine) cannot be excluded a priori because there are currently no large clinical data about the use of these combinations.

T312

40636-40803

Sentence

denotes

Table 3 Known adverse events of marketed anti-infective and anti-inflammatory drugs mostly provided as off-label treatments in the first phase of the COVID-19 pandemic

T313

40804-40823

Sentence

denotes

Drug Adverse events

T314

40824-40909

Sentence

denotes

Lopinavir/ritonavir • Hypercholesterolaemia and increased serum triglycerides (3–39%)

T315

40910-40953

Sentence

denotes

• Increased γ-glutamyl transferase (10–29%)

T316

40954-41005

Sentence

denotes

• Diarrhoea (7–28%; greater with once-daily dosing)

T317

41006-41039

Sentence

denotes

• Increased serum ALT (grade 3/4:

T318

41040-41046

Sentence

denotes

1–11%)

T319

41047-41063

Sentence

denotes

• Nausea (5–16%)

T320

41064-41105

Sentence

denotes

• Upper respiratory tract infection (14%)

T321

41106-41130

Sentence

denotes

• Abdominal pain (1–11%)

T322

41131-41148

Sentence

denotes

• Vomiting (2–7%)

T323

41149-41163

Sentence

denotes

• Fatigue (8%)

T324

41164-41210

Sentence

denotes

• Increased serum amylase and/or lipase (3–8%)

T325

41211-41228

Sentence

denotes

• Headache (2–6%)

T326

41229-41246

Sentence

denotes

• Skin rash (≤5%)

T327

41247-41272

Sentence

denotes

• Neutropenia (grade 3/4:

T328

41273-41278

Sentence

denotes

1–5%)

T329

41279-41293

Sentence

denotes

• Anxiety (4%)

T330

41294-41310

Sentence

denotes

• Insomnia (≤4%)

T331

41311-41381

Sentence

denotes

Chloroquine/hydroxychloroquine • Retinopathy (4% of treated patients)a

T332

41382-41633

Sentence

denotes

• Other adverse effects with unknown frequency included Stevens-Johnson syndrome, abdominal pain, diarrhoea, nausea, vomiting, agranulocytosis, leukopenia, thrombocytopenia, abnormal hepatic function tests, acute hepatic ailure, myopathy, bronchospasm

T333

41634-41740

Sentence

denotes

• Risk of prolonged QT interval, further increased when administered with fluoroquinolones or azithromycin

T334

41741-41796

Sentence

denotes

Tocilizumab • Increased serum ALT (≤36%) and AST (≤22%)

T335

41797-41832

Sentence

denotes

• Increased LDL cholesterol (9–10%)

T336

41833-41866

Sentence

denotes

• Injection site reaction (4–10%)

T337

41867-41890

Sentence

denotes

• Neutropenia (grade 3:

T338

41891-41918

Sentence

denotes

2–7% of all adult patients)

T339

41919-41936

Sentence

denotes

• Headache (1–7%)

T340

41937-41958

Sentence

denotes

• Hypertension (1–6%)

T341

41959-41975

Sentence

denotes

• Dizziness (3%)

T342

41976-41998

Sentence

denotes

• Hypothyroidism (<2%)

T343

41999-42020

Sentence

denotes

• Abdominal pain (2%)

T344

42021-42057

Sentence

denotes

• Oral mucosa or gastric ulcers (2%)

T345

42058-42231

Sentence

denotes

• Infections due to Pneumocystis, Mycobacterium tuberculosis and varicella zoster have been reported after tocilizumab, but their prevalence has not been clearly established

T346

42232-42276

Sentence

denotes

Anakinra • Injection site reactionb (24–71%)

T347

42277-42390

Sentence

denotes

• Antibody development (up to 50% of the patients but no correlation of antibody development and adverse effects)

T348

42391-42423

Sentence

denotes

• Headache and vomiting (12–14%)

T349

42424-42445

Sentence

denotes

• Arthralgia (10–12%)

T350

42446-42462

Sentence

denotes

• Fever (10–12%)

T351

42463-42557

Sentence

denotes

• Haematologic disorder including eosinophilia, leukopenia and change in platelet count (2–9%)

T352

42558-42587

Sentence

denotes

• Nausea and diarrhoea (7–8%)

T353

42588-42615

Sentence

denotes

• Serious infectionc (2–3%)

T354

42616-42749

Sentence

denotes

Off-label drugs mostly provided in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience.

T355

42750-42879

Sentence

denotes

ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; LDL, low-density lipoprotein.

T356

42880-43020

Sentence

denotes

a Serum concentration dependent adverse effect; early changes are generally reversible but may progress despite discontinuation if advanced.

T357

43021-43089

Sentence

denotes

b Injection site reactions were considered serious in 2–3% of cases.

T358

43090-43173

Sentence

denotes

c Serious infections included cellulitis, pneumonia, and bone and joint infections.

T359

43174-43429

Sentence

denotes

Remdesivir is an investigational nucleotide analogue undergoing clinical development for Ebola and showing in vitro activity against coronaviruses (SARS-CoV-2, SARS-CoV-1 and MERS-CoV) and favourable effects in animal MERS models [[23], [24], [25], [26]].

T360

43430-43533

Sentence

denotes

Following these promising preclinical findings, RCT in COVID-19 patients have been initiated (Table 2).

T361

43534-43765

Sentence

denotes

However, pending their results, and considering the investigational nature of the drug, access to remdesivir outside RCT is currently provided only within strictly regulated and limited compassionate-use/expanded-access frameworks.

T362

43766-43925

Sentence

denotes

Oseltamivir and zanamivir are neuraminidase inhibitors used for treating influenza which are also being tested in RCT for treating COVID-19 patients (Table 2).

T363

43926-44235

Sentence

denotes

However, no apparent activity of oseltamivir and zanamivir has previously been observed against SARS-CoV-1 in vitro [27], and the fact that up to 76% of the first critically ill patients with COVID-19 received oseltamivir may also be related to the suspicion of infection (or coinfection) with influenza [28].

T364

44236-44413

Sentence

denotes

Overall, this information is currently insufficient for supporting the use of these agents in COVID-19 patients unless in the presence of suspected/proven concomitant influenza.

T365

44414-44667

Sentence

denotes

Other antiviral agents currently being investigated in RCT for the treatment of COVID-19 patients are favipiravir, an RNA-dependent RNA polymerase inhibitor with anti-influenza activity, and umifenovir, and anti-influenza membrane fusion inhibitor [29].

T366

44668-45030

Sentence

denotes

Even though these two agents attracted important media attention in the last few months, and even though there were some favourable preliminary results, especially for favipiravir, released as preprints, we advocate caution in using these agents outside investigational studies until completion of the standard peer-review processes of the first released trials.

T367

45031-45496

Sentence

denotes

For example, in a recent RCT comparing 120 COVID-19 patients treated with favipiravir versus 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir, but it is of note that the all-cause mortality was 0 in the entire study population, making it uncertain whether, if confirmed, these favourable results may be extrapolated to relevant survival endpoints in critically ill COVID-19 patients [30].

T368

45497-45637

Sentence

denotes

Finally, antiviral activity against SARS-CoV-2 in vitro has been recently reported for ivermectin, but clinical data are still lacking [31].

T369

45639-45659

Sentence

denotes

Question 2 statement

T370

45660-45790

Sentence

denotes

At the present time, evidence from the first published RCT does not support off-label treatment with LPV/RTV in COVID-19 patients.

T371

45791-45935

Sentence

denotes

This result should also discourage the use of other protease inhibitors (e.g. darunavir), at least until results of dedicated RCT are available.

T372

45936-46168

Sentence

denotes

Although promising in preclinical studies, remdesivir should be currently provided for treating COVID-19 patients only within RCT (preferentially) or compassionate-use/expanded-access programmes, owing to its investigational nature.

T373

46169-46350

Sentence

denotes

Pending high-level supporting evidence, favipiravir and umifenovir should not be provided outside RCT, at least in those countries where they are not approved for other indications.

T374

46351-46458

Sentence

denotes

Oseltamivir or zanamivir should be provided only in the presence of suspected/proven concomitant influenza.

T375

46460-46526

Sentence

denotes

Question 3. should chloroquine/hydroxychloroquine be administered?

T376

46527-46706

Sentence

denotes

The rationale of using chloroquine for treating COVID-19 patients is based on two potential and non–mutually exclusive mechanisms: antiviral activity and immunomodulatory effects.

T377

46707-47040

Sentence

denotes

With regard to antiviral activity, chloroquine has been shown to inhibit various viruses in cell cultures, including SARS-CoV-1 and SARS-CoV-2, possibly via pH-dependent inhibition of virus–endosome fusion and/or posttranslational modifications of CoV proteins, although other mechanisms may also contribute [[32], [33], [34], [35]].

T378

47041-47389

Sentence

denotes

With regard to the immunomodulatory effects, the attenuated production of tumor necrosis factor alpha, interleukin (IL)-6 and interferons that follows the administration of chloroquine might help counteract an exaggerated proinflammatory response, which is thought to contribute to the organ damage observed in SARS-CoV-2–infected patients [36,37].

T379

47390-47545

Sentence

denotes

However, some authors have pointed out that an unfavourable immunomodulatory effect cannot be excluded, based on a reduced T helper 2 differentiation [38].

T380

47546-47768

Sentence

denotes

In our opinion, hydroxychloroquine should be preferred over chloroquine because of its less toxic profile (reduced ocular toxicity and fewer drug interactions) and its more potent in vitro activity against SARS-CoV-2 [39].

T381

47769-48028

Sentence

denotes

Recently, Cortegiani et al. [40] reviewed the available information on ongoing case series, comparative observational studies and RCT evaluating the use of chloroquine or hydroxychloroquine in patients with COVID-19 and registered in Chinese or US registries.

T382

48029-48081

Sentence

denotes

They found 23 studies, all being conducted in China.

T383

48082-48271

Sentence

denotes

However, in the few weeks after the paper was made available online (10 March 2020), the number of registered studies being conducted in countries other than China has multiplied (Table 2).

T384

48272-48552

Sentence

denotes

In particular, results of registered RCT are necessary to guide (or discourage) the use of chloroquine/hydroxychloroquine in two different settings: prophylaxis of exposed individuals and treatment of proven cases, stratified for the severity of clinical presentation/progression.

T385

48553-48695

Sentence

denotes

In the meantime, a small controlled nonrandomized study of COVID-19 patients treated with hydroxychloroquine has been recently published [41].

T386

48696-48949

Sentence

denotes

In this study, Gautret et al. enrolled 26 COVID-19 patients to receive 200 mg of hydroxychloroquine every 8 hours for 10 days, whereas a total of 16 patients who denied consent as well as untreated patients from another centre were included as controls.

T387

48950-49031

Sentence

denotes

Of note, six patients treated with hydroxychloroquine also received azithromycin.

T388

49032-49166

Sentence

denotes

The primary endpoint was virologic clearance (based on results of real-time PCR on nasopharyngeal specimens) at day 6 after inclusion.

T389

49167-49522

Sentence

denotes

At day 6, 70% (14/20) of hydroxychloroquine-treated patients were virologically cured versus 12.5% (2/16) in the control group (p 0.001), although it cannot be excluded that selection bias and baseline virus load played a role in influencing results, thereby biasing results towards observing a favourable effect of hydroxychloroquine administration [42].

T390

49523-49754

Sentence

denotes

Furthermore, the opposite results (apparent absence of reduction of virus clearance) were recently described by another French group (albeit in a tiny sample size of 11 patients receiving hydroxychloroquine plus azithromycin) [43].

T391

49755-50103

Sentence

denotes

Uncertainty also surrounds the more marked positive effect observed in patients receiving azithromycin in addition to hydroxychloroquine in the study by Gautret et al., especially because of the very small number of patients in the combined treatment subgroup and the possible increased risk of QT prolongation by combining the two drugs (Table 3).

T392

50105-50125

Sentence

denotes

Question 3 statement

T393

50126-50384

Sentence

denotes

Pending results of RCT, the use of hydroxychloroquine may be considered for treating worsening patients with COVID-19 only if no important drug interactions can be anticipated and with close monitoring of hepatic function, renal function and QT prolongation.

T394

50385-50593

Sentence

denotes

This is based on its activity in vitro against SARS-CoV-2 (although weak) and on the availability of low-level clinical evidence of anticipation of virus clearance from a small controlled nonrandomized study.

T395

50594-50766

Sentence

denotes

However, it should also be kept in mind that the study was highly susceptible to bias and there are still no data regarding hard clinical endpoints such as crude mortality.

T396

50767-50891

Sentence

denotes

For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies.

T397

50892-51001

Sentence

denotes

When this is unfeasible, off-label use may be considered according to local protocols and consent procedures.

T398

51002-51198

Sentence

denotes

In view of the absence of evidence, we are currently unable to support the use of hydroxychloroquine in asymptomatic or mildly symptomatic nonhospitalized patients outside investigational studies.

T399

51199-51236

Sentence

denotes

The same applies to prophylactic use.

T400

51238-51285

Sentence

denotes

Question 4. should antibiotics be administered?

T401

51286-51488

Sentence

denotes

Bacterial infections can present simultaneously with COVID-19 or occur later during the course of the disease, worsening clinical conditions of patients who were recovering from primary viral pneumonia.

T402

51489-51589

Sentence

denotes

Information regarding the prevalence of bacterial coinfection or superinfection is scant [28,44,45].

T403

51590-51724

Sentence

denotes

According to the available reports, prevalence of bacterial infections in patients with COVID-19 ranges between 1% and 10% [28,44,46].

T404

51725-51857

Sentence

denotes

In these reports, bacterial infections were due to Gram-negative bacteria including Enterobacterales and nonfermenting rods [28,44].

T405

51858-52156

Sentence

denotes

It is of note that up to 98% of COVID-19 patients in available experiences received intravenous broad-spectrum empirical antibiotics [28,44,45,47], probably reflecting the frequent inability to exclude the presence of bacterial coinfection at the onset of severe clinical presentations of COVID-19.

T406

52157-52242

Sentence

denotes

This could have possibly lowered the overall prevalence of bacterial superinfections.

T407

52243-52485

Sentence

denotes

Extrapolating data from experiences on bacterial superinfection in pneumonia due to other viruses in a retrospective case series of critically ill patients with MERS in Saudi Arabia, bacterial infection was registered in 18% of patients [48].

T408

52486-52624

Sentence

denotes

With similar prevalence, bacterial pneumonia occurred in about 20% of patients hospitalized for primary influenza virus infection [49,50].

T409

52625-52730

Sentence

denotes

In these studies, mortality related to influenza was mostly due to secondary bacterial pneumonia [49,50].

T410

52731-52917

Sentence

denotes

Common bacteria implicated were Staphylococcus aureus, including methicillin-resistant strains [51], Streptococcus pneumoniae, Haemophilus influenzae and group A streptococci [49,52,53].

T411

52918-53089

Sentence

denotes

There are currently no large data regarding any possible favourable effects in COVID-19 patients related to possible anti-inflammatory or antiviral effect of azithromycin.

T412

53090-53218

Sentence

denotes

Furthermore, the small experiences of the administration of azithromycin in COVID-19 patients have provided conflicting results.

T413

53220-53240

Sentence

denotes

Question 4 statement

T414

53241-53423

Sentence

denotes

In our opinion, it might be prudent to consider empiric antibiotic treatment in critically ill patients with pneumonia due to COVID-19 in whom bacterial infection cannot be excluded.

T415

53424-53662

Sentence

denotes

This suggestion is based on the facts that bacterial coinfection is common in patients with viral pneumonia and that it can be associated with a substantial risk of delaying appropriate treatment, thereby potentially increasing mortality.

T416

53663-53910

Sentence

denotes

Because of the limited available data on both the microbiologic epidemiology (and the prevalence of antimicrobial resistance) of bacterial superinfections in COVID-19 patients, it is difficult to provide specific pathogen-oriented recommendations.

T417

53911-54325

Sentence

denotes

Therefore, pending further studies, we suggest to empirically treat COVID-19 patients according to their clinical syndrome (e.g. community-acquired pneumonia, hospital-acquired pneumonia), choosing the best antimicrobial agent or agents on the basis of local guidelines and local antibiotic susceptibility patterns, with early de-escalation or discontinuation according to microbiology results, whenever available.

T418

54327-54371

Sentence

denotes

Question 5. should steroids be administered?

T419

54372-54614

Sentence

denotes

So far, no RCT has been performed on corticosteroids administration in patients with COVID-19, and there are controversial opinions regarding the extrapolation of inference from previous studies in SARS-CoV-1 and MERS-CoV patients [15,54,55].

T420

54615-55023

Sentence

denotes

In an observational study conducted in 84 COVID-19 patients with acute respiratory distress syndrome (ARDS) in China, administration of methylprednisolone was associated with reduced progression to death (hazard ratio 0.38, 95% confidence interval 0.20–0.72, p 0.003), although the unadjusted analysis and the relatively small sample size preclude firm generalization and call for further investigation [47].

T421

55024-55240

Sentence

denotes

Indirect data on the possible efficacy (RCT) or effectiveness (observational comparative studies) of corticosteroid therapy come from studies performed in patients with MERS-CoV, SARS-CoV-1 or other viral infections.

T422

55241-55429

Sentence

denotes

With regard to patients with mild clinical presentation, a RCT including 16 not critically ill patients with SARS-CoV-1 did not report a beneficial effect of hydrocortisone administration.

T423

55430-55577

Sentence

denotes

Of note, higher viraemia was observed in the second and third weeks after infection in the hydrocortisone group compared to the control group [56].

T424

55578-55899

Sentence

denotes

Moreover, as reported in a systematic review and meta-analysis of observational studies on corticosteroids provided to patients with SARS-CoV-1, only four studies provided conclusive data, reporting no survival benefit and possible harms including avascular necrosis, psychosis, diabetes and delayed virus clearance [57].

T425

55900-56104

Sentence

denotes

In critically ill patients, corticosteroids may be provided to decrease the inflammation–coagulation–fibroproliferation observed during acute respiratory distress syndrome (ARDS) [[58], [59], [60], [61]].

T426

56105-56374

Sentence

denotes

A meta-analysis on corticosteroid use in ARDS including eight controlled studies reported a significant reduction in markers of systemic inflammation, pulmonary and extrapulmonary organ dysfunction scores, duration of mechanical ventilation and ICU length of stay [62].

T427

56375-56481

Sentence

denotes

A recent multicentre RCT included 277 patients with ARDS to assess the effects of dexamethasone treatment.

T428

56482-56628

Sentence

denotes

Patients in the study arm received dexamethasone 20 mg once daily from day 1 to day 5, which was reduced to 10 mg once daily from day 6 to day 10.

T429

56629-56908

Sentence

denotes

This study reported a significant reduction in duration of mechanical ventilation in the dexamethasone group than in the control group (between-group difference 4.8 days, p < 0.0001) and a significant reduction in mortality at 60 days (between-group difference −15.3%, p 0.0047).

T430

56909-57030

Sentence

denotes

The proportion of adverse events did not differ significantly between the dexamethasone group and the control group [63].

T431

57031-57179

Sentence

denotes

Data on the use of corticosteroids in critically ill patients with SARS-CoV-1 and MERS-CoV infection are available, albeit with conflicting results.

T432

57180-57428

Sentence

denotes

In a retrospective observational study of 152 SARS-CoV-1–infected, critically ill patients, corticosteroid therapy was found to reduce mortality and shorten the length of hospital stay (odds ratio 0.08, 95% confidence intervals 0.01–0.97, p 0.046).

T433

57429-57548

Sentence

denotes

The study did not report increased secondary infections or other complications with corticosteroid administration [64].

T434

57549-57783

Sentence

denotes

Conversely, in a retrospective observational study on 309 critically ill patients with MERS-CoV, the administration of a median hydrocortisone equivalent dose of 300 mg per day was not associated with a difference in 90-day mortality.

T435

57784-57923

Sentence

denotes

In addition, corticosteroid administration was associated with delayed clearance of MERS-CoV RNA from the patients' respiratory tract [65].

T436

57924-58165

Sentence

denotes

With regard to other viral infections, it is worth noting that a recent meta-analysis on patients with influenza pneumonia (including ten observational studies with a total of 6548 included patients) reported increased mortality (risk ratio:

T437

58166-58245

Sentence

denotes

1.75, 95% CI 1.3–2.4; p 0.0002), increased length of ICU stay (mean difference:

T438

58246-58353

Sentence

denotes

2.1, 95% CI 1.2–3.1; p < 0.0001) and increased rate of secondary bacterial or fungal infection (risk ratio:

T439

58354-58429

Sentence

denotes

2.0, 95% CI 1.0–3.8; p 0.04) in patients who received corticosteroids [66].

T440

58431-58451

Sentence

denotes

Question 5 statement

T441

58452-58605

Sentence

denotes

So far, no definitive efficacy or effectiveness data are available on the benefit of corticosteroid administration in patients with SARS-CoV-2 infection.

T442

58606-58772

Sentence

denotes

As the World Health Organization underlines, there is an important need for efficacy data from RCT for supporting corticosteroids therapy in patients with SARS-CoV-2.

T443

58773-59234

Sentence

denotes

However, considering that overwhelming inflammation and cytokine-related lung injury might be responsible for the rapidly progressive pneumonia and clinical deterioration in COVID-19 patients [44,58,67], we suggest (expert opinion only) to consider administration of corticosteroids in critically ill COVID-19 patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections (independent of ICU admission).

T444

59235-59463

Sentence

denotes

However, in the absence of convincing evidence, the following cannot currently be supported: steroid administration stratified according to inflammatory markers and steroid administration in non–critically ill COVID-19 patients.

T445

59465-59558

Sentence

denotes

Question 6. should other immunosuppressive and/or immunomodulatory therapies be administered?

T446

59559-59844

Sentence

denotes

According to some recent evidence, some patients with COVID-19 may develop secondary haemophagocytic lymphohistiocytosis, an underrecognized hyperinflammatory syndrome characterized by a fulminant and fatal hypercytokinaemia, with development of ARDS and multiorgan failure [46,47,67].

T447

59845-59980

Sentence

denotes

Consequently, immunosuppressive and/or immunomodulatory therapies have been proposed to contrast COVID-19–associated hyperinflammation.

T448

59981-60353

Sentence

denotes

Tocilizumab is a recombinant humanized monoclonal antibody inhibiting membrane-bound and soluble IL-6 receptors [68] and is currently approved for the treatment of patients with rheumatoid arthritis, giant-cell arteritis, juvenile idiopathic arthritis and patients with chimeric antigen receptor T-cell–induced severe or life-threatening cytokine release syndrome [68,69].

T449

60354-60509

Sentence

denotes

In this regard, tocilizumab may help mitigate the cytokine release syndrome by decreasing cytokine concentrations and acute-phase reactant production [70].

T450

60510-60629

Sentence

denotes

In a recent preprint paper, Xu et al. [71] reported their experience of treating 21 COVID-19 patients with tocilizumab.

T451

60630-61020

Sentence

denotes

In their still-to-be-peer-reviewed case series, the following were observed after tocilizumab administration: (a) reduction in body temperature (21/21, 100%); (b) improved blood oxygenation (15/21, 71.4%); (c) normalization of lymphocyte count (10/17, 58.8%); (d) normalization of C-reactive protein (16/19, 82.4%); and (c) resolution of abnormalities on computed tomography (19/21, 90.5%).

T452

61021-61147

Sentence

denotes

Interestingly, no adverse reactions were observed after tocilizumab administration, but long-term follow-up was not available.

T453

61148-61306

Sentence

denotes

Tocilizumab has been deemed by Chinese National Health Commission to be a possible treatment option for patients with severe COVID-19 with elevated IL-6 [72].

T454

61307-61489

Sentence

denotes

The recommended dose is 4 to 8 mg/kg or 400 mg standard dose provided intravenously once, with the option to repeat a dose after 8 to 12 hours (not to exceed a total dose of 800 mg).

T455

61490-61687

Sentence

denotes

However, it should be noted that the optimal time for administering tocilizumab has not yet been fully elucidated; nor is there a clear IL-6 threshold associated with progression to severe disease.

T456

61688-61830

Sentence

denotes

At the time of writing, there are at least eight ongoing RCT evaluating the efficacy and safety of tocilizumab in COVID-19 patients (Table 2).

T457

61831-62027

Sentence

denotes

Other immune-modulatory drugs including anakinra (interleukin 1 receptor antagonist) or Janus kinase family enzyme inhibitors have been proposed for the management of SARS-CoV-2–infected patients.

T458

62028-62127

Sentence

denotes

Notably, there is currently no supporting clinical evidence, and RCT are ongoing (Table 2) [67,73].

T459

62128-62399

Sentence

denotes

Finally, modifications of the immune response through administration of high-dose intravenous immunoglobulin or convalescent plasma have also been proposed or used in small case series, and they merit further investigation in dedicated RCT [[74], [75], [76], [77], [78]].

T460

62401-62421

Sentence

denotes

Question 6 statement

T461

62422-62576

Sentence

denotes

Owing to the lack of high-level evidence, administration of tocilizumab in patients with COVID-19 should preferentially occur within the framework of RCT.

T462

62577-62903

Sentence

denotes

Off-label use according to local protocols and consent procedures may be considered only in those COVID-19 patients excluded from RCT (or hospitalized where RCT are not available or still to be implemented) and who are worsening while receiving standard supportive care (in the absence of concomitant/superimposed infections).

T463

62904-63380

Sentence

denotes

In our opinion, this could be a reasonable off-label use of tocilizumab in these early phases of the COVID-19 pandemic, although patients and physicians should be fully aware that currently there is only a non–peer-reviewed, noncomparative, observational experience (very low evidence from an unreviewed cases series), and that it only supports a potential favourable effect on inflammatory signs and symptoms, while there is no information on any possible effect on survival.

T464

63381-63600

Sentence

denotes

In the absence of clinical studies, we suggest that also other immunosuppressive and/or immunomodulatory therapies (e.g. anakinra, Janus kinase family enzyme inhibitors) should be preferentially administered within RCT.

T465

63601-63939

Sentence

denotes

This also applies to modifications of the immune response through high-dose intravenous immunoglobulins or plasma from convalescent patients, which, although promising in very small case series, both deserve dedicated RCT investigation to clearly understand their tolerability as well as the role they play in affecting COVID-19 outcomes.

T466

63941-64004

Sentence

denotes

Question 7. what is the optimal timing of treatment initiation?

T467

64005-64205

Sentence

denotes

Most clinical data on the timing of antiviral therapy initiation are derived from studies on viruses other than SARS-CoV-2, and it remains unclear whether these data can be extrapolated to SARS-CoV-2.

T468

64206-64389

Sentence

denotes

Previous studies in SARS-CoV-1 and influenza showed a possible favourable impact on mortality of early initiation of antiviral treatment after symptoms onset [[79], [80], [81], [82]].

T469

64390-64793

Sentence

denotes

With regard to SARS-CoV-2, although the results of the previously cited RCT comparing LPV/RTV versus standard of care eventually does not support the use of LPV/RTV in patients with COVID-19, it is also of note that the median time between symptom onset and randomization was 13 days (interquartile range, 11–16 days), so in most cases, the drug was initiated late during the course of the disease [22].

T470

64794-64922

Sentence

denotes

Consequently, we cannot exclude the possibility that an earlier initiation of LPV/RTV may be associated with improved prognosis.

T471

64923-65142

Sentence

denotes

In this regard, we think the results of this RCT may be hypothesis generating and may help guide the design of further RCT evaluating the efficacy of LPV/RTV (and/or other antivirals) in an earlier phase of the disease.

T472

65143-65390

Sentence

denotes

However, until such RCT will be available, we think the currently available clinical evidence is insufficient to support the use of LPV/RTV and/or other antivirals for treating COVID-19 outside the framework of RCT or compassionate-use programmes.

T473

65391-65495

Sentence

denotes

The optimal time of chloroquine/hydroxychloroquine and corticosteroids initiation still remains unknown.

T474

65496-65992

Sentence

denotes

Although based on low-level evidence, the positive effect of virus clearance observed by Gautret et al. [41] was observed in a mixed group of non-ICU patients with upper respiratory tract symptoms, non-ICU patients with lower respiratory tract symptoms and asymptomatic subjects, which overall may support a positive effect of early hydroxychloroquine initiation in non-ICU settings (although information on the exact time of treatment initiation with respect to symptoms onset was not provided).

T475

65993-66140

Sentence

denotes

With regard to steroid treatment, there is currently no evidence of a positive impact of early initiation in non–critically ill, non-ARDS patients.

T476

66141-66399

Sentence

denotes

Although lack of evidence is not a synonym of lack of effect, in our opinion, steroid treatment, considering also its potential detrimental effects, should currently be limited to ARDS patients or non-ARDS patients with worsening conditions (see question 5).

T477

66401-66421

Sentence

denotes

Question 7 statement

T478

66422-66718

Sentence

denotes

Supportive therapy (symptomatic therapy, rehydration and oxygen supplementation, if necessary) should be provided as soon as the patient presents with respiratory or systemic symptoms including severe asthenia, high fever, persistent cough and/or clinical or radiologic signs of lung involvement.

T479

66719-66990

Sentence

denotes

Pending further evidence, in our opinion, antiviral treatments should not be initiated in patients with SARS-CoV-2 infection outside RCT or compassionate-use programmes (with the exception of early oseltamivir initiation in patients with suspected concomitant influenza).

T480

66991-67263

Sentence

denotes

Corticosteroids should be initiated early in well-defined categories of patients (patients with ARDS or with worsening of non-ARDS respiratory failure in the absence of bacterial/fungal superinfections), while their role in other COVID-19 patients still remains uncertain.

T481

67264-67647

Sentence

denotes

Although based on low-level evidence and pending RCT results, in our opinion, early hydroxychloroquine administration may be considered in COVID-19 patients who have moderate to severe symptoms, whereas further data are needed to better delineate the true balance between possible favourable effects and toxicity of hydroxychloroquine in mildly symptomatic and asymptomatic patients.

T482

67649-67700

Sentence

denotes

Question 8. what is the optimal treatment duration?

T483

67701-68004

Sentence

denotes

In the absence of proven effective treatment, treatment duration also remains unclear; it is currently based on expert opinion which is based on treatment durations in other approved indications for the drugs provided and aimed at a balance between potential activity and risk of undesired side effects.

T484

68005-68052

Sentence

denotes

Nonetheless, suggested durations vary markedly.

T485

68053-68458

Sentence

denotes

For example, a wide range of chloroquine/hydroxychloroquine treatment durations (from 5 to 20 days) have been recommended/provided in different centres/studies, making it impossible to provide an univocal recommendation in the absence of direct comparisons of different lengths of treatment with regard to relevant clinical endpoints (e.g. mortality, ICU admission) and safety [33,40,41,[83], [84], [85]].

T486

68459-68620

Sentence

denotes

There is no standard steroid treatment duration, with different consensus/study groups suggesting steroid administration for no longer than 7 to 10 days [54,85].

T487

68622-68642

Sentence

denotes

Question 8 statement

T488

68643-68950

Sentence

denotes

Chloroquine/hydroxychloroquine treatment should be continued for at least 5 days and possibly prolonged up to 20 days according to some expert opinions, although it should be noted that data regarding the relative safety of different lengths of administration in COVID-19 patients are currently unavailable.

T489

68951-69087

Sentence

denotes

Early discontinuation should be considered in the presence of adverse effects (e.g. QT prolongation or hepatic/renal toxicity; Table 3).

T490

69088-69365

Sentence

denotes

If the administration of remdesivir is approved within compassionate-use/expanded-access programmes, treatment duration should follow compassionate or expanded access protocols (e.g. up to 10 days according to the most recent compassionate protocol at the time of this review).

T491

69366-69490

Sentence

denotes

If corticosteroids are administered, we suggest a total treatment duration of 7 to 10 days, with progressive dose reduction.

T492

69491-69746

Sentence

denotes

If the patient deteriorates with worsening lung physiology after removal of steroid treatment in the absence of bacterial or fungal superinfection, a second course of corticosteroid treatment may be considered, followed by slow tapering after improvement.

T493

69748-69767

Sentence

denotes

Future perspectives

T494

69768-70278

Sentence

denotes

In these first phases of the COVID-19 pandemic, where there are no clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by preclinical and/or low-level clinical evidence: the willingness to administer potentially active therapies to COVID-19 patients; and the willingness not to harm by administering potentially inactive therapies that may unfavourably influence the outcome because of either expected or unexpected toxicity.

T495

70279-70451

Sentence

denotes

Finding the right balance between these two forces is certainly not simple, but it remains more necessary than ever if we want to rapidly find effective and safe treatment.

T496

70452-70665

Sentence

denotes

For this reason, RCT should always be the first option to be proposed to patients because RCT are the only way to provide high-level efficacy and safety information for optimizing the treatment of future patients.

T497

70666-70981

Sentence

denotes

However, even when rapidly implemented during evolving pandemics, RCT are usually not immediately available (e.g. even if accelerated, local approval still and correctly requires time to guarantee ethical standards), and also many patients are usually excluded from RCT because of strict selection criteria [86,87].

T498

70982-71275

Sentence

denotes

For some of these patients, off-label uses (for drugs approved for other indications) and compassionate-use/expanded-access programmes (for investigational drugs) may represent an ethically justifiable option in the case of worsening conditions and unlikely survival with only supportive care.

T499

71276-71473

Sentence

denotes

Against this background, the role of the attending physician is crucial, by favouring and not discouraging RCT participation (in favour of off-label administration) whenever the former is possible.

T500

71474-71748

Sentence

denotes

Otherwise, scientific data will still be produced, but most information will be burdened by only partially adjustable selection biases and confounding factors, with consequent risks of inconclusive results and low-level supporting evidence for the various treatment options.

T501

71749-72039

Sentence

denotes

If participation in RCT is maximized, high-level evidence will be available for guiding treatment, with lower-level evidence from off-label uses still remaining useful for hypothesis-generating purposes in order to better design further RCT (and not for directly guiding treatment choices).

T502

72040-72509

Sentence

denotes

Notably, this is what, in our opinion, happened with LPV/RTV: (a) preclinical data supported activity against coronaviruses; (b) patients were enrolled onto RCT whenever possible, and otherwise they were offered off-label administration when not spontaneously improving; (c) because many patients were rapidly enrolled onto the first RCT, evidence rapidly become available that in our opinion discouraged a universal off-label provision of LPV/RTV in COVID-19 patients.

T503

72511-72522

Sentence

denotes

Conclusions

T504

72523-72644

Sentence

denotes

Many off-label antiviral and anti-inflammatory drugs are being administered in this first phase of the COVID-19 pandemic.

T505

72645-72906

Sentence

denotes

While we do not discourage their use, physicians must be aware that because of the lack of high-level evidence, they may be ethically justifiable only in those worsening patients unlikely to improve with only supportive care and who cannot be enrolled onto RCT.

T506

72907-73108

Sentence

denotes

Implementation of well-designed RCT should be expanded as much as possible, as RCTs are the most secure way to change for the better our approach to COVID-19 patients, including our frontline opinions.

T507

73110-73134

Sentence

denotes

Transparency Declaration

T508

73135-73204

Sentence

denotes

All authors report no conflicts of interest relevant to this article.

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