key: cord-0722397-p5cz7t52
authors: Bassetti, Matteo; Giacobbe, Daniele Roberto; Aliberti, Stefano; Barisione, Emanuela; Centanni, Stefano; De Rosa, Francesco Giuseppe; Di Marco, Fabiano; Gori, Andrea; Granata, Guido; Mikulska, Malgorzata; Petrosillo, Nicola; Richeldi, Luca; Santus, Pierachille; Tascini, Carlo; Vena, Antonio; Viale, Pierluigi; Blasi, Francesco
title: 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)
date: 2020-04-29
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.04.031
sha: 08facf5aadfcaff28707580c3b59dbc3441f3a76
doc_id: 722397
cord_uid: p5cz7t52

Abstract Background SARS-CoV-2 is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. 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. Objectives To narratively summarize the available literature on the management of COVID-19, in the attempt to combine current evidence and frontline opinions and provide balanced answers to pressing clinical questions. Sources Inductive PubMed search for publications relevant to the topic. Content The available literature and the authors’ frontline-based opinion are summarized in brief narrative answers to selected clinical questions, plus a conclusive statement for each answer. Implications Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, being 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 in randomized clinical trials (RCT). Access to well-designed RCT should be expanded as much as possible, being the most secure way to change for the better our approach to COVID-19 patients.

expanded as much as possible, being the most secure way to change for the better our approach to COVID-19 patients.

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] . The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure, with the true proportion of severe cases still remaining partly unclear due to incomplete denominator and possible lack of adjustment for relevant confounding factors [4, 5] . Nonetheless, of particular clinical concern at the present time is not the relative frequency of severe cases 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] .

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

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.

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 draw a balance between current evidence, frontline experiences, and expert opinions.

A panel of 17 experts from the Italian Society of Antiinfective Therapy (SITA) and the Italian Society of Pneumology (SIP) were selected and developed a list of 8 practical therapeutic questions to be addressed. The members of the panel (that 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. All the answers and statements were ultimately reviewed and discussed by the entire panel, until a consensus was reached. A brief summary of questions and conclusive statements is available in table 1, whereas table 2 summarizes available or ongoing RCT information for off-label/compassionate drugs mostly used for the treatment of COVID-19 patients. Of note, we focused on pneumological and anti-infective/anti-inflammatory treatments, whereas the discussion of the therapeutic approach to COVID-19-related cardiovascular/coagulative disorders is outside the scope of this narrative review.

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. The prevalence of hypoxic respiratory failure in patients with COVID-19 may be as high as 19% [8] . In observational studies conducted in China, 4% to 13% of COVID-19 patients received non-invasive positive pressure ventilation, and 2.3% to 12% required invasive mechanical ventilation [8] [9] [10] .

In general, oxygen treatment should be used in patients with shortness of breath, hypoxemia or those in shock, aimed at maintaining an appropriate level of peripheral capillary oxygen saturation (SpO2), avoiding values of SpO2 lower than 90% (92-95% in pregnant women). During oxygen supplementation, SpO2 should not surpass 96% [11] .

An alternative to conventional oxygen supplementation is supplementation through high flow nasal cannula (HFNC). HFNC is an oxygen supply system that provides a mixture of air and oxygen with a known concentration. HFNC provides high concentrations of humidified oxygen, low levels of positive end-expiratory pressure, and can facilitate the elimination of carbon dioxide, potentially reducing the need for intubation compared with standard oxygen supplementation [12] [13] [14] . 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 SARS-CoV-2 is still limited (and without adjusted comparison to standard oxygen supplement) to provide universal recommendations, at least pending further data [9] . Other relevant things to be considered are: (i) HFNC should be used in settings with rapid availability of endotracheal intubation in the case of rapid deterioration [15] ; (ii) the possible increased risk of contracting the infection for healthcare personnel due to the aerosol generation should be appropriately managed (HFNC should be used in negative pressure rooms) [16] . These last two considerations also apply to continuous positive airway pressure (CPAP) with helmet (the most frequent system of non-invasive mechanical ventilation employed in real life), that 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 [PaO2/FiO2] has a decreasing trend) and

there is no urgent indication for endotracheal intubation. As for HFNC, also in the case of CPAP with helmet close monitoring and short interval assessment for worsening of respiratory failure is mandatory. 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 [17] , arguing that success rates in critically ill COVID-19 patients may be limited and there could be a risk of delayed intubation unfavorably influencing the outcome. On the other hand, considering the atypical physiopathology of acute lung injury in patients with COVID-19 [18] , gentle ventilation with a positive end expiratory pressure (PEEP) not higher than 10-12 centimeters of water may represent a reasonable approach for avoiding excessive damage during CPAP with helmet, and possibly also the need for intubation. Large studies, possibly RCT, are urgently needed to definitely clarify the precise role of CPAP with helmet in patients with COVID-19. Finally, borrowing from what is already known and used in intensive care, pronation, although certainly more difficult to implement during non-invasive than invasive mechanical ventilation, may allow to improve gas exchange, decrease respiratory distress and promote lung recruitment [19] .

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%. 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 centimeter of water) if the patient does not respond to standard/HFNC oxygen supplementation and there is no urgent indication for endotracheal intubation (expert opinion). However, no clear indications/criteria can be provided pending further experience. Finally, it should be kept in mind that patients with COVID-19 can get worse in a few hours, thus they should be very carefully monitored for worsening respiratory function for rapidly prompting tracheal intubation and mechanical ventilation.

Several antiviral agents have demonstrated in vitro activity against SARS-CoV-2 or other coronaviruses, but currently there are not approved antiviral agents for coronavirus-related diseases, and there are still no favorable efficacy results from RCT available at the present time. Lopinavir is a protease inhibitor used for the treatment of HIV patients, administered in combination with ritonavir to improve its serum half-life. Based on its activity against SARS-CoV-1 and/or MERS-CoV observed in in vitro and animal studies [20] [21] [22] , lopinavir/ritonavir (LPV/RTV) was compared to supportive care alone for the treatment of COVID-19 patients in an open-label RCT in China [23] . 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). Overall, 199 patients were enrolled (99 and 100 in the LPV/RTV and supportive care arms, respectively). No differences were observed in the intent-to-treat (ITT) population with regard to clinical improvement (hazard ratio [HR] 1.24 with standard of care as reference, 95% CI 0.90 to 1.72). In addition, no associations were observed with regard to 28-day mortality, although a lower 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). Although some important considerations preclude a definite judgement on the possible efficacy of LPV/RTV (for example, 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 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, see table 3), unless   favorable results from other ongoing RCT in specific subgroups of patients are available   (see table 2 ). Furthermore, harmful drug interactions of antivirals with other drugs (such as hydroxychloroquine) cannot be excluded a priori, since there are currently no large clinical data about the use of these combinations.

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 favorable effects in animal MERS models [24] [25] [26] [27] .

Following these promising pre-clinical findings, RCT in COVID-19 patients have been initiated (see table 2 ). 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/expanded access frameworks.

Oseltamivir and zanamivir are neuraminidase inhibitors used for treating influenza, that are also being tested in RCT for treating COVID-19 patients (see table 2 ). However, no apparent activity of oseltamivir and zanamivir was previously observed against SARS-CoV-1 in vitro [28] , 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 co-infection) with influenza [29] . Overall, this is currently insufficient for supporting the use of these agents in COVID-19 patients, unless in the presence of suspected/proven concomitant influenza.

Other antiviral agents currently being investigated in RCT for the treatment of COVID-19 patients are favipiravir, an RNA-dependent RNA polymerase inhibitor with antiinfluenza activity, and umifenovir, and anti-influenza membrane fusion inhibitor [30] .

Despite the fact that these two agents attracted important media attention in the last couple of months, and that some favorable preliminary results especially for favipiravir have been released on pre-print servers, we advocate caution in using these agents outside investigational studies until completion of standard peer-review processes of the first released trials. For example, in a recent RCT 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, but it is of note that the allcause mortality was 0% in the entire study population, making it uncertain as to whether, if confirmed, these favorable results may be extrapolated to relevant survival endpoints in critically ill COVID-19 patients [31] . Finally, antiviral activity against SARS-CoV-2 in vitro has been recently reported for ivermectin, but clinical data is still lacking [32] . CoV proteins, although other mechanisms may also contribute [33] [34] [35] [36] . With regard to the immunomodulatory effects, the attenuated production of TNFα, IL6, and interferons that follows the administration of chloroquine might help counteracting an exaggerated proinflammatory response, which is thought to contribute to the organ damage observed in SARS-CoV-2-infected patients [37, 38] . On the other hand, some authors pointed out that also an unfavorable immunomodulatory effect cannot be excluded, based on a reduced T helper 2 differentiation [39] . In our opinion, hydroxychloroquine should be preferred over chloroquine because of its less toxic profile (reduced ocular toxicity and less drug interactions) and its more potent in vitro activity against SARS-CoV-2 [40] .

Recently, Cortegiani and colleagues 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 U.S. registries [41] . They found 23 studies; all being conducted in China. 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 (see table   2 ). In particular, results of registered RCT are very much awaited to firmly guide (or discourage) the use of chloroquine/hydroxychloroquine in two different settings: (i) prophylaxis of exposed individuals; (ii) treatment of proven cases, stratified for the severity of clinical presentation/progression. In the meantime, a small controlled, non-randomized study of COVID-19 patients treated with hydroxychloroquine has been recently published [42] . Gautret (see table 3 ).

Pending results of RCT, we currently suggest the use of hydroxychloroquine for treating worsening patients with COVID-19, provided no important drug interactions can be anticipated and with close monitoring of hepatic, renal function, and QT prolongation. This

suggestion is based on its demonstrated activity in vitro against SARS-CoV-2 (although weak) and on the availability of low-level clinical evidence of anticipation of viral clearance from a small controlled, non-randomized study, although it should also be kept in mind that the study was highly susceptible to bias and there is still no data regarding hard clinical endpoints such as crude mortality. For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies. When this is unfeasible, off-label use may be considered according to local protocols and consent procedures. In view of the absence of evidence, we are currently unable to support the use of hydroxychloroquine in asymptomatic or mildly symptomatic non-hospitalized patients outside investigational studies. The same applies to prophylactic use.

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. Information regarding the prevalence of bacterial co-infection or super-infection is scant [29, 45, 46] . According to the available reports, prevalence of bacterial infections in patients with COVID-19 ranges between 1% and 10% [29, 45, 47] . In these reports, bacterial infections were due to gram-negative bacteria including

Enterobacterales and non-fermenting rods [29, 45] . It is of note that up to 98% of COVID-19 patients in available experiences received intravenous broad-spectrum empirical antibiotics [29, 45, 46, 48] , probably reflecting the frequent inability to exclude the presence of bacterial coinfection at the onset of severe clinical presentations of COVID-19.

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

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 [49] . With similar prevalence, bacterial pneumonia occurred in about 20% of patients hospitalized for primary influenza virus infection [50, 51] . In these studies, mortality related to influenza was mostly due to secondary bacterial pneumonia [50, 51] . There is currently no large data regarding any possible favorable effects in COVID-19 patients related to possible anti-inflammatory or antiviral effect of azithromycin.

Furthermore, small experiences of using azithromycin in COVID-19 patients have provided conflicting results (see previous section).

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

This suggestion is based on the fact that bacterial coinfection: (i) is common in patients with viral pneumonia; (ii) can be associated with a substantial risk of delaying appropriate treatment, thereby potentially increasing mortality. Because of the limited available data on both the microbiological epidemiology (and the prevalence of antimicrobial resistance) of bacterial superinfections in COVID-19 patients, it is difficult to provide specific pathogenoriented recommendations. 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 most suited antimicrobial agent/s based on local guidelines and local antibiotic susceptibility patterns, with early deescalation or discontinuation according to microbiology results, whenever available.

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 [17, 55, 56] .

In With regard to patient with mild clinical presentation, a randomised controlled trial including 16 not critically ill patients with SARS-CoV-1 did not report a beneficial effect of hydrocortisone administration. Of note, a higher viremia was observed in the second and third weeks after infection in the hydrocortisone group than the control group [57] .

Moreover, as reported in a systematic review and meta-analysis of observational studies on corticosteroids given 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 viral clearance [58] .

In critically ill patients, corticosteroids may be employed to decrease the inflammation-coagulation-fibroproliferation observed during acute respiratory distress syndrome (ARDS) [59] [60] [61] [62] . 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 intensive care unit length of stay [63] . A recent multicentre RCT included 277 patients with ARDS to assess the effects of dexamethasone treatment. 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. 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). The proportion of adverse events did not differ significantly between the dexamethasone and the control group [64] . Data on the use of corticosteroids in critically ill patients with SARS-CoV-1 and MERS-CoV infection is available, albeit with conflicting results. In a retrospective, observational study of 152 SARS-CoV-1 infected, critically ill patients, corticosteroids administration 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). The study did not report increased secondary infections or other complications with corticosteroids administration [65] . 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/day was not associated with a difference in 90-day mortality. In addition, corticosteroid administration was associated with delayed clearance of MERS-CoV RNA from the patients' respiratory tract [66] . 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) depicted increased mortality (risk ratio: Tocilizumab is a recombinant humanized monoclonal antibody inhibiting membrane-bound and soluble interleukin-6 (IL-6) receptors [69] , and is currently approved for the treatment of patients with rheumatoid arthritis, giant cell arteritis, juvenile idiopathic arthritis, and patients with chimeric antigen receptor (CAR) T cell-induced severe or lifethreatening cytokine release syndrome (CRS) [69, 70] . In this regard, tocilizumab may help to mitigate the CRS by decreasing cytokine concentrations and acute phase reactants production [71] . In a recent pre-print paper, Xiaoling Xu and colleagues reported their experience of treating 21 COVID-19 patients with tocilizumab. In their still to be peerreviewed case series, the following were observed after tocilizumab administration: (i) reduction in body temperature ( [72] .

Interestingly, no adverse reactions were observed after tocilizumab administration, but long-term follow-up was not available [72] . 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. 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 role in impacting COVID-19 outcomes, and their tolerability. admission) and safety [34, 41, 42, [84] [85] [86] . There is no standard steroid treatment duration, with different consensus/study groups suggesting steroid administration for no longer than 7-10 days [55, 86] .

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 is currently unavailable. Early discontinuation should be considered in the presence of adverse effects (e.g., QT prolongation or hepatic/renal toxicity, see table   3 ). If the administration of remdesivir is approved within compassionate/expanded access programs, treatment duration should follow compassionate or expanded access protocols (e.g., up to ten days according to the most recent compassionate protocol at the time of this review). If corticosteroids are administered, we suggest a total treatment duration of 7-10 days, with progressive dosage reduction. 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.

In these first phases of the COVID-19 pandemics where there are not clearly supported and approved treatments, there are two apparently mutually exclusive forces driving therapeutic choices supported only by pre-clinical and/or low-level clinical evidence: (i) the willingness to administer potentially active therapies to COVID-19 patients; (ii) the willingness not to harm by administering potentially inactive therapies that may unfavorably influence the outcome because of either expected or unexpected toxicity. Finding the right balance between these two forces is certainly not simple, but also remains more necessary than ever if we want to rapidly find effective and safe treatment. For this reason,

RCT should always the first option to be proposed to patients, since they are the only way for providing high-level efficacy and safety information for optimizing the treatment of future patients. However, even when rapidly implemented during rapidly 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 [87, 88] . For some of these patients, off-label uses (for drugs approved for other indications) and

compassionate/expanded-access programs (for investigational drugs) may represent an ethically justifiable option, in the case of worsening conditions and unlikely survival with only supportive care.

Against this background, the role of the attending physician is crucial, by favoring and not discouraging RCT participation (in favor of off-label administration) whenever the former is possible. 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. 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). Notably, this is what, in our opinion, happened with LPV/RTV: (i) pre-clinical data supported activity against coronaviruses; (ii) patients were enrolled in RCT whenever possible, otherwise they were offered off-label administration when not spontaneously improving; (iii) since many patients were rapidly enrolled in the first RCT, evidence rapidly become available that in our opinion discourage an universal off-label use of LPV/RTV in COVID-19 patients.

Many off-label antiviral and anti-inflammatory drugs are being administered in this first phase of the COVID-19 pandemic. While we do not discourage their use, physicians must be aware that, being not supported by high-level evidence, they may be ethically justifiable only in those worsening patients unlikely to improve with only supportive care, and that cannot be enrolled in RCT. Implementation of well-designed RCT should be expanded as much as possible, being the most secure way to change for the better our approach to COVID-19 patients, including our frontline opinions.

None. 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%. 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 centimeter of water) if the patient does not respond to standard/HFNC oxygen supplementation and there is no urgent indication for endotracheal intubation (expert opinion). However, no clear indications/criteria can be provided pending further experience. Finally, it should be kept in mind that patients with COVID-19 can get worse in a few hours, thus they should be very carefully monitored for worsening respiratory function for rapidly prompting tracheal intubation and mechanical ventilation.

At the present time, evidence from the first published RCT does not support off-label treatment with LPV/RTV in COVID-19 patients. This result should also discourage the use of other protease inhibitors (e.g., darunavir), at least until results of dedicated RCT are available. Although promising in pre-clinical studies, remdesivir should be currently used for treating COVID-19 patients only within RCT (preferentially) or compassionate/expanded-access programs, owing to its investigational nature. Pending high-level supporting evidence, favipiravir and umifenovir should not be used outside RCT, at least in those countries where they are not approved for other indications. Oseltamivir or zanamivir should be used only in the presence of suspected/proven concomitant influenza.

Pending results of RCT, we currently suggest the use of hydroxychloroquine for treating worsening patients with COVID-19, provided no important drug interactions can be anticipated and with close monitoring of hepatic, renal function, and QT prolongation. This suggestion is based on its demonstrated activity in vitro against SARS-CoV-2 (although weak) and on the availability of lowlevel clinical evidence of anticipation of viral clearance from a small controlled, non-randomized study, although it should also be kept in mind that the study was highly susceptible to bias and there is still no data regarding hard clinical endpoints such as crude mortality. For these reasons, hydroxychloroquine should be preferentially administered within the framework of investigational studies. When this is unfeasible, off-label use may be considered according to local protocols and consent procedures. In view of the absence of evidence, we are currently unable to support the use of hydroxychloroquine in asymptomatic or mildly symptomatic non-hospitalized patients outside investigational studies. The same applies to prophylactic use.

In our opinion, it might be prudent to consider empiric antibiotic treatment in all critically ill patients with pneumonia due to COVID-19 in whom bacterial infection cannot be excluded. This suggestion is based on the fact that bacterial coinfection: (i) is common in patients with viral pneumonia; (ii) can be associated with a substantial risk of delaying appropriate treatment, thereby potentially increasing mortality. Because of the limited available data on both the microbiological epidemiology (and the prevalence of antimicrobial resistance) of bacterial superinfections in COVID-19 patients, it is difficult to provide specific pathogen-oriented recommendations. 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 most suited antimicrobial agent/s based on local guidelines and local antibiotic susceptibility patterns, with early de-escalation or discontinuation according to microbiology results, whenever available.

So far, no definitive efficacy or effectiveness data are available on the benefit of corticosteroid administration in patients with SARS-CoV-2 infection. As the World Health Organization (WHO) underlines, there is an important need for efficacy data from RCT for supporting corticosteroids therapy in patients with SARS-Cov-2. 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).

On the other hand, in the absence of convincing evidence the following cannot currently be supported: (i) steroid administration stratified according to inflammatory markers; (ii) steroid administration in non-critically ill COVID-19 patients.

Should other immunosuppressive and/or immunomodulatory therapies be administered?

Owing to the lack of high-level evidence, administration of tocilizumab in patients with COVID-19 should preferentially occur within the framework of RCT. 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). 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, non-comparative, observational experience (very low evidence from an unreviewed cases series) and that it only supports a potential favorable effect on inflammatory signs and symptoms, while there is no information on any possible effect on survival.

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. 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 role in impacting COVID-19 outcomes, and their tolerability.

Supportive therapy (symptomatic therapy, rehydration and oxygen supplementation, if necessary), should be initiated as soon as the patient presents with respiratory or systemic symptoms including severe asthenia, high fever, persistent cough, and/or clinical or radiological signs of lung involvement. Pending further evidence, in our opinion antiviral treatments should not be initiated in patients with SARS-CoV-2 infection outside RCT or compassionate use programs (with the exception of early oseltamivir initiation in patients with suspected concomitant influenza). 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. Although based on low-level evidence and pending RCT results, in our opinion early hydroxychloroquine administration should be considered in COVID-19 patients presenting with moderate to severe symptoms, whereas further data is needed to better delineate the true balance between possible favorable effects and toxicity of hydroxychloroquine in mildly symptomatic and asymptomatic patients.

What is the optimal treatment duration?

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 is currently unavailable. Early discontinuation should be considered in the presence of adverse effects (e.g., QT prolongation or hepatic/renal toxicity, see table 3 ). If the administration of remdesivir is approved within compassionate/expanded access programs, treatment duration should follow compassionate or expanded access protocols (e.g., up to ten days according to the most recent compassionate protocol at the time of this review). If corticosteroids are administered, we suggest a total treatment duration of 7-10 days, with progressive dosage reduction. 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.

ARDS, acute respiratory distress syndrome; HFNC, high-flow nasal cannula; ICU, intensive care unit; RCT, randomized controlled trials; WHO; World Health Organization. ITT, intent-to-treat; mITT, modified intent-to-treat; RCT, randomized controlled trial; RT-PCR, real-time polymerase chain reaction.

* Off-label drugs mostly used in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience. Of note, there are registered RCT also for other drugs to be investigated in patients with COVID-19 (e.g. the Janus kinase family inhibitors ruxolitinib, baricitinib, and tofacitinib). Table 3 . Known adverse events of marketed anti-infective and anti-inflammatory drugs mostly used as off-label treatments in the first phase of the COVID-19 pandemic*

The novel Chinese coronavirus (2019-nCoV) infections: Challenges for fighting the storm

Rapidly increasing cumulative incidence of coronavirus disease (COVID-19) in the European Union/European Economic Area and the United Kingdom

Early Introduction of Severe Acute Respiratory Syndrome Coronavirus 2 into Europe

Real estimates of mortality following COVID-19 infection

Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship

COVID-19 and Italy: what next? Lancet

Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure

Research in high flow therapy: mechanisms of action

Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure

Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected

Staff safety during emergency airway management for COVID-19 in Hong Kong

Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected

Covid-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome

Prone positioning in severe acute respiratory distress syndrome

A review of treatment modalities for Middle East Respiratory Syndrome

SARS and MERS: recent insights into emerging coronaviruses

Treatment With Lopinavir/Ritonavir or Interferon-beta1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Discovering drugs to treat coronavirus disease 2019 (COVID-19)

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial

The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus

New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?

Insights from nanomedicine into chloroquine efficacy against COVID-19

Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells

COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression

Could chloroquine /hydroxychloroquine be harmful in Coronavirus Disease 2019 (COVID-19) treatment? Clinical Infectious Diseases

Aminoquinolines Against Coronavirus Disease 2019 (COVID-19): Chloroquine or Hydroxychloroquine

A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

A Rush to Judgment? Rapid Reporting and Dissemination of Results and Its Consequences Regarding the Use of Hydroxychloroquine for COVID-19

No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the

Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza

pandemic influenza A (H1N1): pathology and pathogenesis of 100 fatal cases in the United States

Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season

Myocardial injury and bacterial pneumonia contribute to the pathogenesis of fatal influenza B virus infection

Invasive group A streptococcal infection concurrent with 2009 H1N1 influenza

On the use of corticosteroids for 2019-nCoV pneumonia

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients

SARS: systematic review of treatment effects

Pathophysiology of acute respiratory distress syndrome. Glucocorticoid receptor-mediated regulation of inflammation and response to prolonged glucocorticoid treatment

Plasma and BAL cytokine response to corticosteroid rescue treatment in late ARDS

Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids

Effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in early acute respiratory distress syndrome

Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis

Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial

Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience

Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome

The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis

COVID-19: consider cytokine storm syndromes and immunosuppression

Efficacy and safety of tocilizumab in patients with polyarticularcourse juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial

Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial

Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients

Effective treatment of severe COVID-19 patients with tocilizumab

National Health Commission (NHC) of the People's Republic of China. The diagnosis and treatment guide of COVID-19 pneumonia caused by new coronavirus infection 7th Edition

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

The convalescent sera option for containing COVID-19

Convalescent Plasma to Treat COVID-19: Possibilities and Challenges

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma

High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease

Treatment of COVID-19: old tricks for new challenges

Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study

Early Oseltamivir After Hospital Admission Is Associated With Shortened Hospitalization: A 5-Year Analysis of Oseltamivir Timing and Clinical Outcomes

Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

Therapeutic options for patients with COVID-19

Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus p

National Institute for the Infectious Diseases "L. Spallanzani" IRCCS. Recommendations for COVID-19 Clinical Management

Drug Development for Multidrug-Resistant Bacteria: Why Compromise?

A look at clinical trial design for new antimicrobials for the adult population

• Comparison of hydroxychloroquine plus darunavir/cobicistat vs. standard of care in patients with COVID-19. Open-label RCT (NCT04304053, recruiting)

Favipiravir Anti-influenza RNA-dependent RNA polymerase inhibitor • In a recent RCT published on a pre-print 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. The

• Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19. Open-label RCT (NCT04310228, recruiting). Primary endpoint: clinical cure (follow-up 3 months)

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

• Comparison of favipiravir vs. standard of care in patients with COVID-19. Open-label RCT (NCT04333589, not yet recruiting). Primary endpoint: viral nucleic acid test negative conversion rate in nasopharyngeal swabs

• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir vs. 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. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time

tocilizumab vs. nivolumab vs. standard of care in patients with advanced or metastatic cancer and COVID-19. Open-label RCT (NCT04333914, not yet recruiting). Primary endpoint

• Comparison of hydroxychloroquine plus azithromycin vs. standard of care in patients with COVID-19. Open-label RCT (NCT04324463, not yet recruiting)

• Comparison of hydroxychloroquine plus azithromycin vs. placebo in hospitalized patients with COVID-19. Doubleblind RCT (NCT04322396, not yet recruiting). Primary endpoint: time to discharge

Primary endpoints: (i) fever to normal time (follow-up 30 days); (ii) pulmonary inflammation resolution time (follow-up 30 days); (iii) negative conversion of throat swab RCT-PCR at EOT • Comparison of lopinavir/ritonavir plus hydroxychloroquine vs. lopinavir/ritonavir plus hydroxychloroquine plus levamisole pill plus budesonide plus formoterol inhaler in patients with non-severe COVID-19 pneumonia. Partly blinded RCT (NCT04331470, not yet recruiting). Primary endpoint: (i) clear CT scan at 3-7 days; (ii) negative RT-PCR at 3-7 days. • Comparison of hydroxychloroquine plus darunavir/cobicistat vs. standard of care in patients with COVID-19. Open-label RCT (NCT04304053, recruiting)

• 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. Single-blind RCT (NCT04323345, not yet recruiting). Primary endpoints: (i) positive to negative swabs at day 14

Resolution of lung inflammation in CT or X-ray (followup 30 days)

• Comparison of hydroxychloroquine vs. close monitoring and quarantine in contacts off COVID-19 patients. Openlabel RCT (NCT04330144, not yet recruiting). Primary endpoint: development of COVID-19

• Comparison of hydroxychloroquine vs. hydroxychloroquine plus azithromycin in patients with COVID-19. Open-label RCT (NCT04321278, recruiting). Primary endpoint: clinical status at day 15

• Comparison of hydroxychloroquine vs. placebo in patients with COVID-19 and at risk of secondary complications. Double-blind RCT (NCT04325893, not yet recruiting). Primary endpoint: composite of death or intubation

• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir vs. 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. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time

• Comparison of hydroxychloroquine vs. placebo in patients with COVID-19. Double-blind RCT (NCT04329611, not yet recruiting). Primary endpoint: composite of hospitalization, invasive mechanical ventilation, or death (follow-up 30 days)

Primary endpoints: (i) changes in nasopharyngeal viral load at day 3; (ii) number of participants by RT-PCR status at day 3

• Comparison of hydroxychloroquine vs. hydroxychloroquine plus azithromycin vs. standard of care in hospitalized patients with COVID-19. Open-label RCT (NCT04322123, not yet recruiting). Primary endpoint: severity rating on a 6

• Comparison of hydroxychloroquine vs. azithromycin in hospitalized patients with COVID-19. Open-label RCT (

• Comparison of hydroxychloroquine vs. placebo in household contacts of COVID-19 patients. Double-blind RCT (NCT04318444, not yet recruiting). Primary endpoint: symptomatic, lab-confirmed COVID-19 at day 14

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine in patients with mild COVID-19. Open-label RCT (NCT04307693, recruiting)

Primary endpoint: early warning score equal to zero at days 3-5 (i.e., 14-20 breaths per minute, oxygen saturation greater than 96%, systolic blood pressure 111 to 180 mmHg, pulse 60-90 beats per minute

• Comparison of hydroxychloroquine vs. placebo in patients with severe COVID-19. Double-blind RCT (NCT04315896, not yet recruiting). Primary endpoint: allcause hospital mortality

• Comparison of hydroxychloroquine vs. placebo for the prevention of COVID-19 in exposed healthcare personnel. Double-blind RCT (NCT04315896, not yet recruiting). Primary endpoint: symptomatic COVID-19 (follow-up 60 days)

• Comparison of hydroxychloroquine vs. placebo in inpatients with symptomatic COVID-19. Double-blind RCT (NCT04332991, not yet recruiting). Primary endpoint: severity rating on a 7

• Comparison of hydroxychloroquine vs. placebo as preexposure prophylaxis in healthcare workers at high-risk of COVID-19. Double-blind RCT (NCT04331834, not yet recruiting). Primary endpoint: seroconversion (follow-up 6 mild to moderate COVID-19. Open-label RCT (NCT04323631, not yet recruiting). Primary endpoint: composite of severe infection or death

Double-blind RCT for outpatients and healthcare workers and open-label RCT for inpatients (NCT04329923, not yet recruiting). Primary endpoints: (i) release from quarantine (outpatients, followup 14 days)

iii) development of COVID-19 (healthcare workers, follow-up 2 months)

• Comparison of hydroxychloroquine vs. ascorbic acid in contacts of COVID-19 patients. Double-blind RCT (NCT04328961, not yet recruiting). Primary endpoint: laboratory-confirmed COVID-19 (follow-up 14 days)

• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19. Open-label RCT (NCT04332094, not yet recruiting)

• Comparison of ciclesonide plus hydroxychloroquine vs. ciclesonide in patients with COVID-19. Open-label RCT (NCT04330586, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication (based on viral load

Primary endpoints: (i) incidence rate of COVID-19 (follow-up 27 weeks); (ii) prevalence of COVID-19 (follow-up 27 weeks); (iii) case fatality rate (follow-up 27 weeks); (iv) ICU admission rate

• Comparison of hydroxychloroquine vs. placebo for the prevention of COVID-19 in healthcare workers at risk. Double-blind RCT (NCT04328467, not yet recruiting). Primary endpoint: prevalence of COVID-19

• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19. Double-blind RCT (NCT04328285, not yet recruiting). Primary endpoint: Occurrence of a symptomatic or asymptomatic SARS-CoV-2 infection

• Comparison of hydroxychloroquine vs. placebo in symptomatic COVID-19 patients or exposed healthcare workers/households. Double-blind RCT (NCT04308668, recruiting)

Primary endpoint: all-cause in-hospital mortality

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19. Double-blind, adaptive RCT (NCT04328012, not yet recruiting). Primary endpoint: NIAID COVID-19 Ordinal Severity Scale

• Comparison of convalescent plasma plus hydroxychloroquine plus azithromycin vs. hydroxychloroquine plus azithromycin in hospitalized patients with COVID-19. Open-label RCT (NCT04332835, not yet recruiting)

• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta-1a vs. remdesivir vs. standard of care in patients with COVID-19. Double-blind, adaptive RCT (NCT04315948, recruiting). Primary endpoint: severity rating on a 7

Injection site reaction*** (24-%-71%) Antibody development (up to 50% of the patients but no correlation of antibody development and adverse effects) Headache and vomiting (12% -14%) Arthralgia (10% -12%) Fever (10% -12%) Hematologic disorder including eosinophilia, leukopenia and change in platelet count (2% -9%) Nausea and diarrhea (7%-8%) Serious Infection**** (2%-3%) * Off-label drugs mostly used in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience.** serum concentration dependent adverse effect; early changes are generally reversible but may progress despite discontinuation if advanced.*** Injection site reactions have been considered as serious in 2-3% of the cases.**** Serious infections include cellulitis, pneumonia, and bone and joint infections)