PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T1	0-207	Sentence	denotes	Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP)
T2	209-217	Sentence	denotes	Abstract
T3	218-228	Sentence	denotes	Background
T4	229-425	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.
T5	426-534	Sentence	denotes	The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure.
T6	535-731	Sentence	denotes	At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries.
T7	733-743	Sentence	denotes	Objectives
T8	744-947	Sentence	denotes	To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions.
T9	949-956	Sentence	denotes	Sources
T10	957-1020	Sentence	denotes	Inductive PubMed search for publications relevant to the topic.
T11	1022-1029	Sentence	denotes	Content
T12	1030-1223	Sentence	denotes	The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer.
T13	1225-1237	Sentence	denotes	Implications
T14	1238-1350	Sentence	denotes	Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19.
T15	1351-1623	Sentence	denotes	Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials.
T16	1624-1809	Sentence	denotes	Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.
T17	1811-1823	Sentence	denotes	Introduction
T18	1824-2036	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	2037-2332	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	2333-2647	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	2648-3000	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	3001-3296	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	3297-3577	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	3579-3586	Sentence	denotes	Methods
T25	3587-3813	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	3814-4113	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	4114-4234	Sentence	denotes	All the answers and statements were ultimately reviewed and discussed by the entire panel until a consensus was reached.
T28	4235-4315	Sentence	denotes	A brief summary of questions and conclusive statements is available in Table 1 .
T29	4316-4491	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	4492-4722	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	4723-4766	Sentence	denotes	Table 1 Summary of questions and statements
T32	4767-4785	Sentence	denotes	Question Statement
T33	4786-4797	Sentence	denotes	Question 1.
T34	4798-4897	Sentence	denotes	How to use at best oxygen therapy and noninvasive mechanical ventilation for preventing intubation?
T35	4898-5092	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	5093-5397	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	5398-5480	Sentence	denotes	However, no clear indications/criteria can be provided pending further experience.
T38	5481-5716	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	5717-5728	Sentence	denotes	Question 2.
T40	5729-5769	Sentence	denotes	Should antiviral agents be administered?
T41	5770-5900	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	5901-6045	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	6046-6268	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	6269-6453	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	6454-6561	Sentence	denotes	Oseltamivir or zanamivir should be provided only in the presence of suspected/proven concomitant influenza.
T46	6562-6573	Sentence	denotes	Question 3.
T47	6574-6628	Sentence	denotes	Should chloroquine/hydroxychloroquine be administered?
T48	6629-6878	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	6879-7088	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	7089-7261	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	7262-7386	Sentence	denotes	For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies.
T52	7387-7496	Sentence	denotes	When this is unfeasible, off-label use may be considered according to local protocols and consent procedures.
T53	7497-7693	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	7694-7731	Sentence	denotes	The same applies to prophylactic use.
T55	7732-7743	Sentence	denotes	Question 4.
T56	7744-7779	Sentence	denotes	Should antibiotics be administered?
T57	7780-7962	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	7963-8200	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	8201-8448	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	8449-8863	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	8864-8875	Sentence	denotes	Question 5.
T62	8876-8908	Sentence	denotes	Should steroids be administered?
T63	8909-9062	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	9063-9206	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	9207-9653	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	9654-9886	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	9887-9898	Sentence	denotes	Question 6.
T68	9899-9980	Sentence	denotes	Should other immunosuppressive and/or immunomodulatory therapies be administered?
T69	9981-10135	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	10136-10462	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	10463-10932	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	10933-11138	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	11139-11457	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	11458-11469	Sentence	denotes	Question 7.
T75	11470-11521	Sentence	denotes	What is the optimal timing of treatment initiation?
T76	11522-11817	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	11818-12088	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	12089-12360	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	12361-12747	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	12748-12759	Sentence	denotes	Question 8.
T81	12760-12799	Sentence	denotes	What is the optimal treatment duration?
T82	12800-13099	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	13100-13227	Sentence	denotes	Early discontinuation should be considered in the presence of adverse effects (e.g. QT prolongation or hepatic/renal toxicity).
T84	13228-13505	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	13506-13623	Sentence	denotes	If corticosteroids are provided, we suggest a total treatment duration of 7–10 days, with progressive dose reduction.
T86	13624-13894	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	13895-14270	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	14271-14446	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	14447-14598	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	14599-14665	Sentence	denotes	Lopinavir/ritonavir Lopinavir is an HIV type 1 protease inhibitor.
T91	14666-14858	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	14859-14936	Sentence	denotes	Lopinavir/ritonavir was administered at the dosage of 400/100 mg for 14 days.
T93	14937-15016	Sentence	denotes	The primary time-to-event endpoint was clinical improvement from randomization.
T94	15017-15405	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	15406-15559	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	15560-15732	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	15733-15774	Sentence	denotes	Open-label RCT (NCT04307693, recruiting).
T98	15775-15834	Sentence	denotes	Primary endpoint: virus load at day 3, 5, 7, 10, 14 and 18.
T99	15835-15938	Sentence	denotes	• Comparison of ASC09/ritonavir vs. lopinavir/ritonavir in patients with confirmed COVID-19 pneumoniae.
T100	15939-15988	Sentence	denotes	Open-label RCT (NCT04261907, not yet recruiting).
T101	15989-16158	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	16159-16261	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus umifenovir in patients with COVID-19.
T103	16262-16303	Sentence	denotes	Open-label RCT (NCT04252885, recruiting).
T104	16304-16380	Sentence	denotes	Primary endpoint: rate of virus inhibition at day 0, 2, 4, 7, 10, 14 and 21.
T105	16381-16506	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus ribavirin plus interferon beta 1b in patients with COVID-19.
T106	16507-16548	Sentence	denotes	Open-label RCT (NCT04276688, recruiting).
T107	16549-16631	Sentence	denotes	Primary endpoint: time to negative nasopharyngeal swab RT-PCR (follow-up 30 days).
T108	16632-16775	Sentence	denotes	• Comparison of only supportive treatment vs. lopinavir/ritonavir vs. oseltamivir vs. umifenovir in patients with confirmed COVID-19 pneumonia.
T109	16776-16817	Sentence	denotes	Open-label RCT (NCT04255017, recruiting).
T110	16818-17093	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	17094-17206	Sentence	denotes	• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19.
T112	17207-17258	Sentence	denotes	Double-blind RCT (NCT04328285, not yet recruiting).
T113	17259-17353	Sentence	denotes	Primary endpoint: occurrence of a symptomatic or asymptomatic COVID-19 (follow-up 2.5 months).
T114	17354-17470	Sentence	denotes	• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia.
T115	17471-17520	Sentence	denotes	Open-label RCT (NCT04286503, not yet recruiting).
T116	17521-17703	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	17704-17886	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	17887-17936	Sentence	denotes	Open-label RCT (NCT04295551, not yet recruiting).
T119	17937-17998	Sentence	denotes	Primary endpoint: clinical recovery time (follow-up 28 days).
T120	17999-18168	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	18169-18218	Sentence	denotes	Open-label RCT (NCT04275388, not yet recruiting).
T122	18219-18280	Sentence	denotes	Primary endpoint: clinical recovery time (follow-up 14 days).
T123	18281-18460	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	18461-18502	Sentence	denotes	Open-label RCT (NCT04251871, recruiting).
T125	18503-18580	Sentence	denotes	Primary endpoint: time to complete remission of symptoms (follow-up 28 days).
T126	18581-18796	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	18797-18850	Sentence	denotes	Partly blinded RCT (NCT04331470, not yet recruiting).
T128	18851-18932	Sentence	denotes	Primary endpoint: (a) clear CT scan at 3–7 days; (b) negative RT-PCR at 3–7 days.
T129	18933-19044	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19.
T130	19045-19106	Sentence	denotes	Double-blind, adaptive RCT (NCT04328012, not yet recruiting).
T131	19107-19183	Sentence	denotes	Primary endpoint: NIAID COVID-19 ordinal severity scale (follow-up 60 days).
T132	19184-19353	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	19354-19407	Sentence	denotes	Double-blind, adaptive RCT (NCT04315948, recruiting).
T134	19408-19479	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 15.
T135	19480-19779	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	19780-19831	Sentence	denotes	Single-blind RCT (NCT04323345, not yet recruiting).
T137	19832-20025	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	20026-20163	Sentence	denotes	• Comparison of colchicine (with or without lopinavir/ritonavir) vs. local standard of care in patients with moderate to severe COVID-19.
T139	20164-20213	Sentence	denotes	Open-label RCT (NCT04328480, not yet recruiting).
T140	20214-20272	Sentence	denotes	Primary endpoint: all-cause mortality (follow-up 30 days).
T141	20273-20677	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	20678-20727	Sentence	denotes	Open-label RCT (NCT04303299, not yet recruiting).
T143	20728-20795	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).
T144	20796-20826	Sentence	denotes	Remdesivir Adenosine analogue.
T145	20827-20992	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	20993-21036	Sentence	denotes	Double-blind RCT (NCT04257656, recruiting).
T147	21037-21126	Sentence	denotes	Primary endpoint: clinical status, assessed by an ordinal scale at days 7, 14, 21 and 28.
T148	21127-21209	Sentence	denotes	• Comparison of remdesivir vs. placebo in patients with mild to moderate COVID-19.
T149	21210-21253	Sentence	denotes	Double-blind RCT (NCT04252664, recruiting).
T150	21254-21327	Sentence	denotes	Primary endpoint: time to clinical recovery in hours (follow-up 28 days).
T151	21328-21415	Sentence	denotes	• Comparison of remdesivir vs. local standard of care in patients with severe COVID-19.
T152	21416-21457	Sentence	denotes	Open-label RCT (NCT04252664, recruiting).
T153	21458-21565	Sentence	denotes	Primary endpoint: composite of fever normalization and oxygen saturation normalization (follow-up 14 days).
T154	21566-21655	Sentence	denotes	• Comparison of remdesivir vs. local standard of care in patients with moderate COVID-19.
T155	21656-21697	Sentence	denotes	Open-label RCT (NCT04292730, recruiting).
T156	21698-21744	Sentence	denotes	Primary endpoint: discharged status at day 14.
T157	21745-21810	Sentence	denotes	• Comparison of remdesivir vs. placebo in patients with COVID-19.
T158	21811-21854	Sentence	denotes	Double-blind RCT (NCT04280705, recruiting).
T159	21855-21926	Sentence	denotes	Primary endpoint: severity rating on a 8-point ordinal scale at day 15.
T160	21927-22042	Sentence	denotes	• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19.
T161	22043-22101	Sentence	denotes	Open-label adaptive RCT (NCT04321616, not yet recruiting).
T162	22102-22172	Sentence	denotes	Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).
T163	22173-22342	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	22343-22396	Sentence	denotes	Double-blind, adaptive RCT (NCT04315948, recruiting).
T165	22397-22468	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 15.
T166	22469-22536	Sentence	denotes	Darunavir/cobicistat Darunavir is an HIV type 1 protease inhibitor.
T167	22537-22717	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	22718-22759	Sentence	denotes	Open-label RCT (NCT04252274, recruiting).
T169	22760-22874	Sentence	denotes	Primary endpoint: virologic clearance rate of throat swabs, sputum or lower respiratory tract secretions at day 7.
T170	22875-23181	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	23182-23357	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	23358-23399	Sentence	denotes	Open-label RCT (NCT04310228, recruiting).
T173	23400-23453	Sentence	denotes	Primary endpoint: clinical cure (follow-up 3 months).
T174	23454-23858	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	23859-23908	Sentence	denotes	Open-label RCT (NCT04303299, not yet recruiting).
T176	23909-23976	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).
T177	23977-24085	Sentence	denotes	• Comparison of hydroxychloroquine plus darunavir/cobicistat vs. standard of care in patients with COVID-19.
T178	24086-24127	Sentence	denotes	Open-label RCT (NCT04304053, recruiting).
T179	24128-24245	Sentence	denotes	Primary endpoint: incidence of secondary cases among contacts of a case and contacts of contacts (follow-up 14 days).
T180	24246-24345	Sentence	denotes	• Comparison of chloroquine plus favipiravir vs. favipiravir vs. placebo in patients with COVID-19.
T181	24346-24389	Sentence	denotes	Double-blind RCT (NCT04319900, recruiting).
T182	24390-24561	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	24562-24637	Sentence	denotes	• Comparison of favipiravir vs. standard of care in patients with COVID-19.
T184	24638-24687	Sentence	denotes	Open-label RCT (NCT04333589, not yet recruiting).
T185	24688-24800	Sentence	denotes	Primary endpoint: viral nucleic acid test negative conversion rate in nasopharyngeal swabs (follow-up 5 months).
T186	24801-25205	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	25206-25255	Sentence	denotes	Open-label RCT (NCT04303299, not yet recruiting).
T188	25256-25323	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).
T189	25324-25616	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	25617-25773	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	25774-25823	Sentence	denotes	Open-label RCT (NCT04260594, not yet recruiting).
T192	25824-25892	Sentence	denotes	Primary endpoint: virus negative conversion rate (follow-up 7 days).
T193	25893-26272	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	26273-26397	Sentence	denotes	Double-blind RCT for outpatients and healthcare workers and open-label RCT for inpatients (NCT04329923, not yet recruiting).
T195	26398-26595	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	26596-26682	Sentence	denotes	• Comparison of hydroxychloroquine vs. ascorbic acid in contacts of COVID-19 patients.
T197	26683-26734	Sentence	denotes	Double-blind RCT (NCT04328961, not yet recruiting).
T198	26735-26803	Sentence	denotes	Primary endpoint: laboratory-confirmed COVID-19 (follow-up 14 days).
T199	26804-26940	Sentence	denotes	• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19.
T200	26941-26990	Sentence	denotes	Open-label RCT (NCT04332094, not yet recruiting).
T201	26991-27218	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	27219-27268	Sentence	denotes	Open-label RCT (NCT04330586, not yet recruiting).
T203	27269-27342	Sentence	denotes	Primary endpoint: SARS-CoV-2 eradication (based on virus load) at day 14.
T204	27343-27469	Sentence	denotes	• Comparison of hydroxychloroquine vs. placebo in patients with COVID-19 and under biological treatment and/or JAK inhibitors.
T205	27470-27521	Sentence	denotes	Double-blind RCT (NCT04330495, not yet recruiting).
T206	27522-27732	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	27733-27841	Sentence	denotes	• Comparison of hydroxychloroquine vs. placebo for the prevention of COVID-19 in healthcare workers at risk.
T208	27842-27893	Sentence	denotes	Double-blind RCT (NCT04328467, not yet recruiting).
T209	27894-27956	Sentence	denotes	Primary endpoint: prevalence of COVID-19 (follow-up 12 weeks).
T210	27957-28069	Sentence	denotes	• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19.
T211	28070-28121	Sentence	denotes	Double-blind RCT (NCT04328285, not yet recruiting).
T212	28122-28139	Sentence	denotes	Primary endpoint:
T213	28140-28228	Sentence	denotes	Occurrence of a symptomatic or asymptomatic SARS-CoV-2 infection (follow-up 2.5 months).
T214	28229-28350	Sentence	denotes	• Comparison of hydroxychloroquine vs. placebo in symptomatic COVID-19 patients or exposed healthcare workers/households.
T215	28351-28394	Sentence	denotes	Double-blind RCT (NCT04308668, recruiting).
T216	28395-28542	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	28543-28658	Sentence	denotes	• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19.
T218	28659-28717	Sentence	denotes	Open-label adaptive RCT (NCT04321616, not yet recruiting).
T219	28718-28788	Sentence	denotes	Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).
T220	28789-28900	Sentence	denotes	• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19.
T221	28901-28962	Sentence	denotes	Double-blind, adaptive RCT (NCT04328012, not yet recruiting).
T222	28963-29039	Sentence	denotes	Primary endpoint: NIAID COVID-19 Ordinal Severity Scale (follow-up 60 days).
T223	29040-29198	Sentence	denotes	• Comparison of convalescent plasma plus hydroxychloroquine plus azithromycin vs. hydroxychloroquine plus azithromycin in hospitalized patients with COVID-19.
T224	29199-29248	Sentence	denotes	Open-label RCT (NCT04332835, not yet recruiting).
T225	29249-29428	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	29429-29598	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	29599-29652	Sentence	denotes	Double-blind, adaptive RCT (NCT04315948, recruiting).
T228	29653-29724	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 15.
T229	29725-30087	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	30088-30129	Sentence	denotes	Open-label RCT (NCT04244591, recruiting).
T231	30130-30196	Sentence	denotes	Primary endpoint: lower Murray lung injury score at days 7 and 14.
T232	30197-30279	Sentence	denotes	• Comparison of methylprednisolone vs. standard of care in patients with COVID-19.
T233	30280-30321	Sentence	denotes	Open-label RCT (NCT04273321, recruiting).
T234	30322-30378	Sentence	denotes	Primary endpoint: treatment failure (follow-up 14 days).
T235	30379-30579	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	30580-30631	Sentence	denotes	Double-blind RCT (NCT04273581, not yet recruiting).
T237	30632-30699	Sentence	denotes	Primary endpoint: time to clinical improvement (follow-up 28 days).
T238	30700-30782	Sentence	denotes	• Comparison of different dosages of methylprednisolone in patients with COVID-19.
T239	30783-30824	Sentence	denotes	Open-label RCT (NCT04263402, recruiting).
T240	30825-30906	Sentence	denotes	Primary endpoints: (a) disease readmission at day 7; (b) critical stage at day 7.
T241	30907-31015	Sentence	denotes	• Comparison of siltuximab (anti–IL-6 monoclonal antibody) vs. methylprednisolone in patients with COVID-19.
T242	31016-31065	Sentence	denotes	Open-label RCT (NCT04329650, not yet recruiting).
T243	31066-31117	Sentence	denotes	Primary endpoint: ICU admission (follow-up 29 days)
T244	31118-31234	Sentence	denotes	Tocilizumab Humanized monoclonal IgG1 antibody, tocilizumab inhibits both membrane-bound and soluble IL-6 receptors.
T245	31235-31485	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	31486-31535	Sentence	denotes	Open-label RCT (NCT04331808, not yet recruiting).
T247	31536-31638	Sentence	denotes	Primary endpoint: WHO progression scale at day 7 and 14 (severity rating on a 10-point ordinal scale).
T248	31639-31742	Sentence	denotes	• Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19.
T249	31743-31784	Sentence	denotes	Open-label RCT (NCT04310228, recruiting).
T250	31785-31838	Sentence	denotes	Primary endpoint: clinical cure (follow-up 3 months).
T251	31839-31918	Sentence	denotes	• Comparison of tocilizumab vs. placebo in hospitalized patients with COVID-19.
T252	31919-31970	Sentence	denotes	Double-blind RCT (NCT04320615, not yet recruiting).
T253	31971-32042	Sentence	denotes	Primary endpoint: severity rating on a 7-point ordinal scale at day 28.
T254	32043-32179	Sentence	denotes	• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19.
T255	32180-32229	Sentence	denotes	Open-label RCT (NCT04332094, not yet recruiting).
T256	32230-32363	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	32364-32519	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	32520-32569	Sentence	denotes	Open-label RCT (NCT04333914, not yet recruiting).
T259	32570-32587	Sentence	denotes	Primary endpoint:
T260	32588-32604	Sentence	denotes	28-day survival.
T261	32605-32806	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	32807-32856	Sentence	denotes	Open-label RCT (NCT04322773, not yet recruiting).
T263	32857-32950	Sentence	denotes	Primary endpoint: time to independence from supplementary oxygen therapy (follow-up 28 days).
T264	32951-33152	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	33153-33202	Sentence	denotes	Open-label RCT (NCT04330638, not yet recruiting).
T266	33203-33270	Sentence	denotes	Primary endpoint: time to clinical improvement (follow-up 15 days).
T267	33271-33387	Sentence	denotes	• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia.
T268	33388-33437	Sentence	denotes	Open-label RCT (NCT04286503, not yet recruiting).
T269	33438-33620	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	33621-33658	Sentence	denotes	Anakinra Antagonist of IL-1 receptor.
T271	33659-33915	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	33916-33965	Sentence	denotes	Open-label RCT (NCT04324021, not yet recruiting).
T273	33966-34012	Sentence	denotes	Primary endpoint: treatment success at day 15.
T274	34013-34214	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	34215-34264	Sentence	denotes	Open-label RCT (NCT04330638, not yet recruiting).
T276	34265-34332	Sentence	denotes	Primary endpoint: time to clinical improvement (follow-up 15 days).
T277	34333-34466	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	34467-34650	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	34651-35170	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	35172-35283	Sentence	denotes	Question 1. how to use at best oxygen therapy and noninvasive mechanical ventilation for preventing intubation?
T281	35284-35487	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	35488-35586	Sentence	denotes	The prevalence of hypoxic respiratory failure in patients with COVID-19 may be as high as 19% [8].
T283	35587-35789	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	35790-36078	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	36079-36144	Sentence	denotes	During oxygen supplementation, Spo 2 should not surpass 96% [11].
T286	36145-36257	Sentence	denotes	An alternative to conventional oxygen supplementation is supplementation through high-flow nasal cannula (HFNC).
T287	36258-36359	Sentence	denotes	HFNC is an oxygen supply system that provides a mixture of air and oxygen with a known concentration.
T288	36360-36641	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	36642-36956	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	36957-37339	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	37340-37802	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	37803-37952	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	37953-38340	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	38341-38679	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	38680-38814	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	38815-39115	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	39117-39137	Sentence	denotes	Question 1 statement
T298	39138-39334	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	39335-39639	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	39640-39722	Sentence	denotes	However, no clear indications/criteria can be provided pending further experience.
T301	39723-39977	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	39979-40031	Sentence	denotes	Question 2. should antiviral agents be administered?
T303	40032-40313	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	40314-40462	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	40463-40764	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	40765-41013	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	41014-41117	Sentence	denotes	Overall, 199 patients were enrolled (99 and 100 in the LPV/RTV and supportive care arms, respectively).
T308	41118-41315	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	41316-41584	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	41585-42231	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	42232-42446	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	42447-42614	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	42615-42634	Sentence	denotes	Drug Adverse events
T314	42635-42720	Sentence	denotes	Lopinavir/ritonavir • Hypercholesterolaemia and increased serum triglycerides (3–39%)
T315	42721-42764	Sentence	denotes	• Increased γ-glutamyl transferase (10–29%)
T316	42765-42816	Sentence	denotes	• Diarrhoea (7–28%; greater with once-daily dosing)
T317	42817-42850	Sentence	denotes	• Increased serum ALT (grade 3/4:
T318	42851-42857	Sentence	denotes	1–11%)
T319	42858-42874	Sentence	denotes	• Nausea (5–16%)
T320	42875-42916	Sentence	denotes	• Upper respiratory tract infection (14%)
T321	42917-42941	Sentence	denotes	• Abdominal pain (1–11%)
T322	42942-42959	Sentence	denotes	• Vomiting (2–7%)
T323	42960-42974	Sentence	denotes	• Fatigue (8%)
T324	42975-43021	Sentence	denotes	• Increased serum amylase and/or lipase (3–8%)
T325	43022-43039	Sentence	denotes	• Headache (2–6%)
T326	43040-43057	Sentence	denotes	• Skin rash (≤5%)
T327	43058-43083	Sentence	denotes	• Neutropenia (grade 3/4:
T328	43084-43089	Sentence	denotes	1–5%)
T329	43090-43104	Sentence	denotes	• Anxiety (4%)
T330	43105-43121	Sentence	denotes	• Insomnia (≤4%)
T331	43122-43192	Sentence	denotes	Chloroquine/hydroxychloroquine • Retinopathy (4% of treated patients)a
T332	43193-43444	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	43445-43551	Sentence	denotes	• Risk of prolonged QT interval, further increased when administered with fluoroquinolones or azithromycin
T334	43552-43607	Sentence	denotes	Tocilizumab • Increased serum ALT (≤36%) and AST (≤22%)
T335	43608-43643	Sentence	denotes	• Increased LDL cholesterol (9–10%)
T336	43644-43677	Sentence	denotes	• Injection site reaction (4–10%)
T337	43678-43701	Sentence	denotes	• Neutropenia (grade 3:
T338	43702-43729	Sentence	denotes	2–7% of all adult patients)
T339	43730-43747	Sentence	denotes	• Headache (1–7%)
T340	43748-43769	Sentence	denotes	• Hypertension (1–6%)
T341	43770-43786	Sentence	denotes	• Dizziness (3%)
T342	43787-43809	Sentence	denotes	• Hypothyroidism (<2%)
T343	43810-43831	Sentence	denotes	• Abdominal pain (2%)
T344	43832-43868	Sentence	denotes	• Oral mucosa or gastric ulcers (2%)
T345	43869-44042	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	44043-44087	Sentence	denotes	Anakinra • Injection site reactionb (24–71%)
T347	44088-44201	Sentence	denotes	• Antibody development (up to 50% of the patients but no correlation of antibody development and adverse effects)
T348	44202-44234	Sentence	denotes	• Headache and vomiting (12–14%)
T349	44235-44256	Sentence	denotes	• Arthralgia (10–12%)
T350	44257-44273	Sentence	denotes	• Fever (10–12%)
T351	44274-44368	Sentence	denotes	• Haematologic disorder including eosinophilia, leukopenia and change in platelet count (2–9%)
T352	44369-44398	Sentence	denotes	• Nausea and diarrhoea (7–8%)
T353	44399-44426	Sentence	denotes	• Serious infectionc (2–3%)
T354	44427-44560	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	44561-44690	Sentence	denotes	ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; LDL, low-density lipoprotein.
T356	44691-44831	Sentence	denotes	a Serum concentration dependent adverse effect; early changes are generally reversible but may progress despite discontinuation if advanced.
T357	44832-44900	Sentence	denotes	b Injection site reactions were considered serious in 2–3% of cases.
T358	44901-44984	Sentence	denotes	c Serious infections included cellulitis, pneumonia, and bone and joint infections.
T359	44985-45240	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	45241-45344	Sentence	denotes	Following these promising preclinical findings, RCT in COVID-19 patients have been initiated (Table 2).
T361	45345-45576	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	45577-45736	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	45737-46046	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	46047-46224	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	46225-46478	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	46479-46841	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	46842-47307	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	47308-47448	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	47450-47470	Sentence	denotes	Question 2 statement
T370	47471-47601	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	47602-47746	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	47747-47979	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	47980-48161	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	48162-48269	Sentence	denotes	Oseltamivir or zanamivir should be provided only in the presence of suspected/proven concomitant influenza.
T375	48271-48337	Sentence	denotes	Question 3. should chloroquine/hydroxychloroquine be administered?
T376	48338-48517	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	48518-48851	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	48852-49200	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	49201-49356	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	49357-49579	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	49580-49839	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	49840-49892	Sentence	denotes	They found 23 studies, all being conducted in China.
T383	49893-50082	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	50083-50363	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	50364-50506	Sentence	denotes	In the meantime, a small controlled nonrandomized study of COVID-19 patients treated with hydroxychloroquine has been recently published [41].
T386	50507-50760	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	50761-50842	Sentence	denotes	Of note, six patients treated with hydroxychloroquine also received azithromycin.
T388	50843-50977	Sentence	denotes	The primary endpoint was virologic clearance (based on results of real-time PCR on nasopharyngeal specimens) at day 6 after inclusion.
T389	50978-51333	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	51334-51565	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	51566-51914	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	51916-51936	Sentence	denotes	Question 3 statement
T393	51937-52195	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	52196-52404	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	52405-52577	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	52578-52702	Sentence	denotes	For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies.
T397	52703-52812	Sentence	denotes	When this is unfeasible, off-label use may be considered according to local protocols and consent procedures.
T398	52813-53009	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	53010-53047	Sentence	denotes	The same applies to prophylactic use.
T400	53049-53096	Sentence	denotes	Question 4. should antibiotics be administered?
T401	53097-53299	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	53300-53400	Sentence	denotes	Information regarding the prevalence of bacterial coinfection or superinfection is scant [28,44,45].
T403	53401-53535	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	53536-53668	Sentence	denotes	In these reports, bacterial infections were due to Gram-negative bacteria including Enterobacterales and nonfermenting rods [28,44].
T405	53669-53967	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	53968-54053	Sentence	denotes	This could have possibly lowered the overall prevalence of bacterial superinfections.
T407	54054-54296	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	54297-54435	Sentence	denotes	With similar prevalence, bacterial pneumonia occurred in about 20% of patients hospitalized for primary influenza virus infection [49,50].
T409	54436-54541	Sentence	denotes	In these studies, mortality related to influenza was mostly due to secondary bacterial pneumonia [49,50].
T410	54542-54728	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	54729-54900	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	54901-55029	Sentence	denotes	Furthermore, the small experiences of the administration of azithromycin in COVID-19 patients have provided conflicting results.
T413	55031-55051	Sentence	denotes	Question 4 statement
T414	55052-55234	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	55235-55473	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	55474-55721	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	55722-56136	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	56138-56182	Sentence	denotes	Question 5. should steroids be administered?
T419	56183-56425	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	56426-56834	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	56835-57051	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	57052-57240	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	57241-57388	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	57389-57710	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	57711-57915	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	57916-58185	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	58186-58292	Sentence	denotes	A recent multicentre RCT included 277 patients with ARDS to assess the effects of dexamethasone treatment.
T428	58293-58439	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	58440-58719	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	58720-58841	Sentence	denotes	The proportion of adverse events did not differ significantly between the dexamethasone group and the control group [63].
T431	58842-58990	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	58991-59239	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	59240-59359	Sentence	denotes	The study did not report increased secondary infections or other complications with corticosteroid administration [64].
T434	59360-59594	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	59595-59734	Sentence	denotes	In addition, corticosteroid administration was associated with delayed clearance of MERS-CoV RNA from the patients' respiratory tract [65].
T436	59735-59976	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	59977-60056	Sentence	denotes	1.75, 95% CI 1.3–2.4; p 0.0002), increased length of ICU stay (mean difference:
T438	60057-60164	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	60165-60240	Sentence	denotes	2.0, 95% CI 1.0–3.8; p 0.04) in patients who received corticosteroids [66].
T440	60242-60262	Sentence	denotes	Question 5 statement
T441	60263-60416	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	60417-60583	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	60584-61045	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	61046-61274	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	61276-61369	Sentence	denotes	Question 6. should other immunosuppressive and/or immunomodulatory therapies be administered?
T446	61370-61655	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	61656-61791	Sentence	denotes	Consequently, immunosuppressive and/or immunomodulatory therapies have been proposed to contrast COVID-19–associated hyperinflammation.
T448	61792-62164	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	62165-62320	Sentence	denotes	In this regard, tocilizumab may help mitigate the cytokine release syndrome by decreasing cytokine concentrations and acute-phase reactant production [70].
T450	62321-62440	Sentence	denotes	In a recent preprint paper, Xu et al. [71] reported their experience of treating 21 COVID-19 patients with tocilizumab.
T451	62441-62831	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	62832-62958	Sentence	denotes	Interestingly, no adverse reactions were observed after tocilizumab administration, but long-term follow-up was not available.
T453	62959-63117	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	63118-63300	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	63301-63498	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	63499-63641	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	63642-63838	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	63839-63938	Sentence	denotes	Notably, there is currently no supporting clinical evidence, and RCT are ongoing (Table 2) [67,73].
T459	63939-64210	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	64212-64232	Sentence	denotes	Question 6 statement
T461	64233-64387	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	64388-64714	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	64715-65191	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	65192-65411	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	65412-65750	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	65752-65815	Sentence	denotes	Question 7. what is the optimal timing of treatment initiation?
T467	65816-66016	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	66017-66200	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	66201-66604	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	66605-66733	Sentence	denotes	Consequently, we cannot exclude the possibility that an earlier initiation of LPV/RTV may be associated with improved prognosis.
T471	66734-66953	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	66954-67201	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	67202-67306	Sentence	denotes	The optimal time of chloroquine/hydroxychloroquine and corticosteroids initiation still remains unknown.
T474	67307-67803	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	67804-67951	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	67952-68210	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	68212-68232	Sentence	denotes	Question 7 statement
T478	68233-68529	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	68530-68801	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	68802-69074	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	69075-69458	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	69460-69511	Sentence	denotes	Question 8. what is the optimal treatment duration?
T483	69512-69815	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	69816-69863	Sentence	denotes	Nonetheless, suggested durations vary markedly.
T485	69864-70269	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	70270-70431	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	70433-70453	Sentence	denotes	Question 8 statement
T488	70454-70761	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	70762-70898	Sentence	denotes	Early discontinuation should be considered in the presence of adverse effects (e.g. QT prolongation or hepatic/renal toxicity; Table 3).
T490	70899-71176	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	71177-71301	Sentence	denotes	If corticosteroids are administered, we suggest a total treatment duration of 7 to 10 days, with progressive dose reduction.
T492	71302-71557	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	71559-71578	Sentence	denotes	Future perspectives
T494	71579-72089	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	72090-72262	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	72263-72476	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	72477-72792	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	72793-73086	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	73087-73284	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	73285-73559	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.

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Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP)

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209-217

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218-228

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Background

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229-425

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.

T5

426-534

Sentence

denotes

The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure.

T6

535-731

Sentence

denotes

At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries.

T7

733-743

Sentence

denotes

Objectives

T8

744-947

Sentence

denotes

To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions.

T9

949-956

Sentence

denotes

Sources

T10

957-1020

Sentence

denotes

Inductive PubMed search for publications relevant to the topic.

T11

1022-1029

Sentence

denotes

Content

T12

1030-1223

Sentence

denotes

The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer.

T13

1225-1237

Sentence

denotes

Implications

T14

1238-1350

Sentence

denotes

Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19.

T15

1351-1623

Sentence

denotes

Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials.

T16

1624-1809

Sentence

denotes

Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.

T17

1811-1823

Sentence

denotes

Introduction

T18

1824-2036

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

2037-2332

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

2333-2647

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

2648-3000

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

3001-3296

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

3297-3577

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

3579-3586

Sentence

denotes

Methods

T25

3587-3813

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

3814-4113

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

4114-4234

Sentence

denotes

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

T28

4235-4315

Sentence

denotes

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

T29

4316-4491

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

4492-4722

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

4723-4766

Sentence

denotes

Table 1 Summary of questions and statements

T32

4767-4785

Sentence

denotes

Question Statement

T33

4786-4797

Sentence

denotes

Question 1.

T34

4798-4897

Sentence

denotes

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

T35

4898-5092

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

5093-5397

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

5398-5480

Sentence

denotes

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

T38

5481-5716

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

5717-5728

Sentence

denotes

Question 2.

T40

5729-5769

Sentence

denotes

Should antiviral agents be administered?

T41

5770-5900

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

5901-6045

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

6046-6268

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

6269-6453

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

6454-6561

Sentence

denotes

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

T46

6562-6573

Sentence

denotes

Question 3.

T47

6574-6628

Sentence

denotes

Should chloroquine/hydroxychloroquine be administered?

T48

6629-6878

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

6879-7088

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

7089-7261

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

7262-7386

Sentence

denotes

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

T52

7387-7496

Sentence

denotes

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

T53

7497-7693

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

7694-7731

Sentence

denotes

The same applies to prophylactic use.

T55

7732-7743

Sentence

denotes

Question 4.

T56

7744-7779

Sentence

denotes

Should antibiotics be administered?

T57

7780-7962

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

7963-8200

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

8201-8448

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

8449-8863

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

8864-8875

Sentence

denotes

Question 5.

T62

8876-8908

Sentence

denotes

Should steroids be administered?

T63

8909-9062

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

9063-9206

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

9207-9653

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

9654-9886

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

9887-9898

Sentence

denotes

Question 6.

T68

9899-9980

Sentence

denotes

Should other immunosuppressive and/or immunomodulatory therapies be administered?

T69

9981-10135

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

10136-10462

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

10463-10932

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

10933-11138

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

11139-11457

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

11458-11469

Sentence

denotes

Question 7.

T75

11470-11521

Sentence

denotes

What is the optimal timing of treatment initiation?

T76

11522-11817

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

11818-12088

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

12089-12360

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

12361-12747

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

12748-12759

Sentence

denotes

Question 8.

T81

12760-12799

Sentence

denotes

What is the optimal treatment duration?

T82

12800-13099

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

13100-13227

Sentence

denotes

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

T84

13228-13505

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

13506-13623

Sentence

denotes

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

T86

13624-13894

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

13895-14270

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

14271-14446

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

14447-14598

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

14599-14665

Sentence

denotes

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

T91

14666-14858

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

14859-14936

Sentence

denotes

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

T93

14937-15016

Sentence

denotes

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

T94

15017-15405

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

15406-15559

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

15560-15732

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

15733-15774

Sentence

denotes

Open-label RCT (NCT04307693, recruiting).

T98

15775-15834

Sentence

denotes

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

T99

15835-15938

Sentence

denotes

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

T100

15939-15988

Sentence

denotes

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

T101

15989-16158

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

16159-16261

Sentence

denotes

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

T103

16262-16303

Sentence

denotes

Open-label RCT (NCT04252885, recruiting).

T104

16304-16380

Sentence

denotes

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

T105

16381-16506

Sentence

denotes

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

T106

16507-16548

Sentence

denotes

Open-label RCT (NCT04276688, recruiting).

T107

16549-16631

Sentence

denotes

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

T108

16632-16775

Sentence

denotes

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

T109

16776-16817

Sentence

denotes

Open-label RCT (NCT04255017, recruiting).

T110

16818-17093

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

17094-17206

Sentence

denotes

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

T112

17207-17258

Sentence

denotes

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

T113

17259-17353

Sentence

denotes

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

T114

17354-17470

Sentence

denotes

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

T115

17471-17520

Sentence

denotes

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

T116

17521-17703

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

17704-17886

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

17887-17936

Sentence

denotes

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

T119

17937-17998

Sentence

denotes

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

T120

17999-18168

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

18169-18218

Sentence

denotes

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

T122

18219-18280

Sentence

denotes

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

T123

18281-18460

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

18461-18502

Sentence

denotes

Open-label RCT (NCT04251871, recruiting).

T125

18503-18580

Sentence

denotes

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

T126

18581-18796

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

18797-18850

Sentence

denotes

Partly blinded RCT (NCT04331470, not yet recruiting).

T128

18851-18932

Sentence

denotes

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

T129

18933-19044

Sentence

denotes

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

T130

19045-19106

Sentence

denotes

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

T131

19107-19183

Sentence

denotes

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

T132

19184-19353

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

19354-19407

Sentence

denotes

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

T134

19408-19479

Sentence

denotes

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

T135

19480-19779

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

19780-19831

Sentence

denotes

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

T137

19832-20025

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

20026-20163

Sentence

denotes

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

T139

20164-20213

Sentence

denotes

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

T140

20214-20272

Sentence

denotes

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

T141

20273-20677

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

20678-20727

Sentence

denotes

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

T143

20728-20795

Sentence

denotes

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

T144

20796-20826

Sentence

denotes

Remdesivir Adenosine analogue.

T145

20827-20992

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

20993-21036

Sentence

denotes

Double-blind RCT (NCT04257656, recruiting).

T147

21037-21126

Sentence

denotes

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

T148

21127-21209

Sentence

denotes

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

T149

21210-21253

Sentence

denotes

Double-blind RCT (NCT04252664, recruiting).

T150

21254-21327

Sentence

denotes

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

T151

21328-21415

Sentence

denotes

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

T152

21416-21457

Sentence

denotes

Open-label RCT (NCT04252664, recruiting).

T153

21458-21565

Sentence

denotes

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

T154

21566-21655

Sentence

denotes

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

T155

21656-21697

Sentence

denotes

Open-label RCT (NCT04292730, recruiting).

T156

21698-21744

Sentence

denotes

Primary endpoint: discharged status at day 14.

T157

21745-21810

Sentence

denotes

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

T158

21811-21854

Sentence

denotes

Double-blind RCT (NCT04280705, recruiting).

T159

21855-21926

Sentence

denotes

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

T160

21927-22042

Sentence

denotes

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

T161

22043-22101

Sentence

denotes

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

T162

22102-22172

Sentence

denotes

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

T163

22173-22342

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

22343-22396

Sentence

denotes

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

T165

22397-22468

Sentence

denotes

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

T166

22469-22536

Sentence

denotes

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

T167

22537-22717

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

22718-22759

Sentence

denotes

Open-label RCT (NCT04252274, recruiting).

T169

22760-22874

Sentence

denotes

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

T170

22875-23181

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

23182-23357

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

23358-23399

Sentence

denotes

Open-label RCT (NCT04310228, recruiting).

T173

23400-23453

Sentence

denotes

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

T174

23454-23858

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

23859-23908

Sentence

denotes

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

T176

23909-23976

Sentence

denotes

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

T177

23977-24085

Sentence

denotes

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

T178

24086-24127

Sentence

denotes

Open-label RCT (NCT04304053, recruiting).

T179

24128-24245

Sentence

denotes

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

T180

24246-24345

Sentence

denotes

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

T181

24346-24389

Sentence

denotes

Double-blind RCT (NCT04319900, recruiting).

T182

24390-24561

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

24562-24637

Sentence

denotes

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

T184

24638-24687

Sentence

denotes

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

T185

24688-24800

Sentence

denotes

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

T186

24801-25205

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

25206-25255

Sentence

denotes

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

T188

25256-25323

Sentence

denotes

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

T189

25324-25616

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

25617-25773

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

25774-25823

Sentence

denotes

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

T192

25824-25892

Sentence

denotes

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

T193

25893-26272

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

26273-26397

Sentence

denotes

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

T195

26398-26595

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

26596-26682

Sentence

denotes

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

T197

26683-26734

Sentence

denotes

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

T198

26735-26803

Sentence

denotes

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

T199

26804-26940

Sentence

denotes

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

T200

26941-26990

Sentence

denotes

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

T201

26991-27218

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

27219-27268

Sentence

denotes

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

T203

27269-27342

Sentence

denotes

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

T204

27343-27469

Sentence

denotes

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

T205

27470-27521

Sentence

denotes

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

T206

27522-27732

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

27733-27841

Sentence

denotes

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

T208

27842-27893

Sentence

denotes

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

T209

27894-27956

Sentence

denotes

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

T210

27957-28069

Sentence

denotes

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

T211

28070-28121

Sentence

denotes

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

T212

28122-28139

Sentence

denotes

Primary endpoint:

T213

28140-28228

Sentence

denotes

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

T214

28229-28350

Sentence

denotes

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

T215

28351-28394

Sentence

denotes

Double-blind RCT (NCT04308668, recruiting).

T216

28395-28542

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

28543-28658

Sentence

denotes

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

T218

28659-28717

Sentence

denotes

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

T219

28718-28788

Sentence

denotes

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

T220

28789-28900

Sentence

denotes

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

T221

28901-28962

Sentence

denotes

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

T222

28963-29039

Sentence

denotes

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

T223

29040-29198

Sentence

denotes

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

T224

29199-29248

Sentence

denotes

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

T225

29249-29428

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

29429-29598

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

29599-29652

Sentence

denotes

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

T228

29653-29724

Sentence

denotes

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

T229

29725-30087

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

30088-30129

Sentence

denotes

Open-label RCT (NCT04244591, recruiting).

T231

30130-30196

Sentence

denotes

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

T232

30197-30279

Sentence

denotes

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

T233

30280-30321

Sentence

denotes

Open-label RCT (NCT04273321, recruiting).

T234

30322-30378

Sentence

denotes

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

T235

30379-30579

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

30580-30631

Sentence

denotes

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

T237

30632-30699

Sentence

denotes

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

T238

30700-30782

Sentence

denotes

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

T239

30783-30824

Sentence

denotes

Open-label RCT (NCT04263402, recruiting).

T240

30825-30906

Sentence

denotes

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

T241

30907-31015

Sentence

denotes

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

T242

31016-31065

Sentence

denotes

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

T243

31066-31117

Sentence

denotes

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

T244

31118-31234

Sentence

denotes

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

T245

31235-31485

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

31486-31535

Sentence

denotes

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

T247

31536-31638

Sentence

denotes

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

T248

31639-31742

Sentence

denotes

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

T249

31743-31784

Sentence

denotes

Open-label RCT (NCT04310228, recruiting).

T250

31785-31838

Sentence

denotes

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

T251

31839-31918

Sentence

denotes

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

T252

31919-31970

Sentence

denotes

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

T253

31971-32042

Sentence

denotes

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

T254

32043-32179

Sentence

denotes

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

T255

32180-32229

Sentence

denotes

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

T256

32230-32363

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

32364-32519

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

32520-32569

Sentence

denotes

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

T259

32570-32587

Sentence

denotes

Primary endpoint:

T260

32588-32604

Sentence

denotes

28-day survival.

T261

32605-32806

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

32807-32856

Sentence

denotes

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

T263

32857-32950

Sentence

denotes

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

T264

32951-33152

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

33153-33202

Sentence

denotes

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

T266

33203-33270

Sentence

denotes

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

T267

33271-33387

Sentence

denotes

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

T268

33388-33437

Sentence

denotes

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

T269

33438-33620

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

33621-33658

Sentence

denotes

Anakinra Antagonist of IL-1 receptor.

T271

33659-33915

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

33916-33965

Sentence

denotes

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

T273

33966-34012

Sentence

denotes

Primary endpoint: treatment success at day 15.

T274

34013-34214

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

34215-34264

Sentence

denotes

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

T276

34265-34332

Sentence

denotes

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

T277

34333-34466

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

34467-34650

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

34651-35170

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

35172-35283

Sentence

denotes

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

T281

35284-35487

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

35488-35586

Sentence

denotes

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

T283

35587-35789

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

35790-36078

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

36079-36144

Sentence

denotes

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

T286

36145-36257

Sentence

denotes

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

T287

36258-36359

Sentence

denotes

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

T288

36360-36641

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

36642-36956

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

36957-37339

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

37340-37802

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

37803-37952

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

37953-38340

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

38341-38679

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

38680-38814

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

38815-39115

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

39117-39137

Sentence

denotes

Question 1 statement

T298

39138-39334

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

39335-39639

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

39640-39722

Sentence

denotes

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

T301

39723-39977

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

39979-40031

Sentence

denotes

Question 2. should antiviral agents be administered?

T303

40032-40313

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

40314-40462

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

40463-40764

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

40765-41013

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

41014-41117

Sentence

denotes

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

T308

41118-41315

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

41316-41584

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

41585-42231

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

42232-42446

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

42447-42614

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

42615-42634

Sentence

denotes

Drug Adverse events

T314

42635-42720

Sentence

denotes

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

T315

42721-42764

Sentence

denotes

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

T316

42765-42816

Sentence

denotes

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

T317

42817-42850

Sentence

denotes

• Increased serum ALT (grade 3/4:

T318

42851-42857

Sentence

denotes

1–11%)

T319

42858-42874

Sentence

denotes

• Nausea (5–16%)

T320

42875-42916

Sentence

denotes

• Upper respiratory tract infection (14%)

T321

42917-42941

Sentence

denotes

• Abdominal pain (1–11%)

T322

42942-42959

Sentence

denotes

• Vomiting (2–7%)

T323

42960-42974

Sentence

denotes

• Fatigue (8%)

T324

42975-43021

Sentence

denotes

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

T325

43022-43039

Sentence

denotes

• Headache (2–6%)

T326

43040-43057

Sentence

denotes

• Skin rash (≤5%)

T327

43058-43083

Sentence

denotes

• Neutropenia (grade 3/4:

T328

43084-43089

Sentence

denotes

1–5%)

T329

43090-43104

Sentence

denotes

• Anxiety (4%)

T330

43105-43121

Sentence

denotes

• Insomnia (≤4%)

T331

43122-43192

Sentence

denotes

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

T332

43193-43444

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

43445-43551

Sentence

denotes

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

T334

43552-43607

Sentence

denotes

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

T335

43608-43643

Sentence

denotes

• Increased LDL cholesterol (9–10%)

T336

43644-43677

Sentence

denotes

• Injection site reaction (4–10%)

T337

43678-43701

Sentence

denotes

• Neutropenia (grade 3:

T338

43702-43729

Sentence

denotes

2–7% of all adult patients)

T339

43730-43747

Sentence

denotes

• Headache (1–7%)

T340

43748-43769

Sentence

denotes

• Hypertension (1–6%)

T341

43770-43786

Sentence

denotes

• Dizziness (3%)

T342

43787-43809

Sentence

denotes

• Hypothyroidism (<2%)

T343

43810-43831

Sentence

denotes

• Abdominal pain (2%)

T344

43832-43868

Sentence

denotes

• Oral mucosa or gastric ulcers (2%)

T345

43869-44042

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

44043-44087

Sentence

denotes

Anakinra • Injection site reactionb (24–71%)

T347

44088-44201

Sentence

denotes

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

T348

44202-44234

Sentence

denotes

• Headache and vomiting (12–14%)

T349

44235-44256

Sentence

denotes

• Arthralgia (10–12%)

T350

44257-44273

Sentence

denotes

• Fever (10–12%)

T351

44274-44368

Sentence

denotes

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

T352

44369-44398

Sentence

denotes

• Nausea and diarrhoea (7–8%)

T353

44399-44426

Sentence

denotes

• Serious infectionc (2–3%)

T354

44427-44560

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

44561-44690

Sentence

denotes

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

T356

44691-44831

Sentence

denotes

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

T357

44832-44900

Sentence

denotes

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

T358

44901-44984

Sentence

denotes

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

T359

44985-45240

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

45241-45344

Sentence

denotes

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

T361

45345-45576

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

45577-45736

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

45737-46046

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

46047-46224

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

46225-46478

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

46479-46841

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

46842-47307

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

47308-47448

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

47450-47470

Sentence

denotes

Question 2 statement

T370

47471-47601

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

47602-47746

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

47747-47979

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

47980-48161

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

48162-48269

Sentence

denotes

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

T375

48271-48337

Sentence

denotes

Question 3. should chloroquine/hydroxychloroquine be administered?

T376

48338-48517

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

48518-48851

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

48852-49200

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

49201-49356

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

49357-49579

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

49580-49839

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

49840-49892

Sentence

denotes

They found 23 studies, all being conducted in China.

T383

49893-50082

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

50083-50363

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

50364-50506

Sentence

denotes

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

T386

50507-50760

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

50761-50842

Sentence

denotes

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

T388

50843-50977

Sentence

denotes

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

T389

50978-51333

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

51334-51565

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

51566-51914

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

51916-51936

Sentence

denotes

Question 3 statement

T393

51937-52195

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

52196-52404

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

52405-52577

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

52578-52702

Sentence

denotes

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

T397

52703-52812

Sentence

denotes

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

T398

52813-53009

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

53010-53047

Sentence

denotes

The same applies to prophylactic use.

T400

53049-53096

Sentence

denotes

Question 4. should antibiotics be administered?

T401

53097-53299

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

53300-53400

Sentence

denotes

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

T403

53401-53535

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

53536-53668

Sentence

denotes

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

T405

53669-53967

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

53968-54053

Sentence

denotes

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

T407

54054-54296

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

54297-54435

Sentence

denotes

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

T409

54436-54541

Sentence

denotes

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

T410

54542-54728

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

54729-54900

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

54901-55029

Sentence

denotes

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

T413

55031-55051

Sentence

denotes

Question 4 statement

T414

55052-55234

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

55235-55473

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

55474-55721

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

55722-56136

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

56138-56182

Sentence

denotes

Question 5. should steroids be administered?

T419

56183-56425

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

56426-56834

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

56835-57051

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

57052-57240

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

57241-57388

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

57389-57710

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

57711-57915

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

57916-58185

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

58186-58292

Sentence

denotes

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

T428

58293-58439

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

58440-58719

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

58720-58841

Sentence

denotes

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

T431

58842-58990

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

58991-59239

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

59240-59359

Sentence

denotes

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

T434

59360-59594

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

59595-59734

Sentence

denotes

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

T436

59735-59976

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

59977-60056

Sentence

denotes

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

T438

60057-60164

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

60165-60240

Sentence

denotes

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

T440

60242-60262

Sentence

denotes

Question 5 statement

T441

60263-60416

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

60417-60583

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

60584-61045

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

61046-61274

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

61276-61369

Sentence

denotes

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

T446

61370-61655

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

61656-61791

Sentence

denotes

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

T448

61792-62164

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

62165-62320

Sentence

denotes

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

T450

62321-62440

Sentence

denotes

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

T451

62441-62831

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

62832-62958

Sentence

denotes

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

T453

62959-63117

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

63118-63300

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

63301-63498

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

63499-63641

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

63642-63838

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

63839-63938

Sentence

denotes

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

T459

63939-64210

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

64212-64232

Sentence

denotes

Question 6 statement

T461

64233-64387

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

64388-64714

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

64715-65191

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

65192-65411

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

65412-65750

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

65752-65815

Sentence

denotes

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

T467

65816-66016

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

66017-66200

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

66201-66604

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

66605-66733

Sentence

denotes

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

T471

66734-66953

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

66954-67201

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

67202-67306

Sentence

denotes

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

T474

67307-67803

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

67804-67951

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

67952-68210

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

68212-68232

Sentence

denotes

Question 7 statement

T478

68233-68529

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

68530-68801

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

68802-69074

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

69075-69458

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

69460-69511

Sentence

denotes

Question 8. what is the optimal treatment duration?

T483

69512-69815

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

69816-69863

Sentence

denotes

Nonetheless, suggested durations vary markedly.

T485

69864-70269

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

70270-70431

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

70433-70453

Sentence

denotes

Question 8 statement

T488

70454-70761

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

70762-70898

Sentence

denotes

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

T490

70899-71176

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

71177-71301

Sentence

denotes

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

T492

71302-71557

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

71559-71578

Sentence

denotes

Future perspectives

T494

71579-72089

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

72090-72262

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

72263-72476

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

72477-72792

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

72793-73086

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

73087-73284

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

73285-73559

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

73560-73850

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

73851-74320

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

74322-74333

Sentence

denotes

Conclusions

T504

74334-74455

Sentence

denotes

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

T505

74456-74717

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

74718-74919

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

74921-74945

Sentence

denotes

Transparency Declaration

T508

74946-75015

Sentence

denotes

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

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