key: cord-0865429-cgdyea7a
authors: Yadullahi Mir, Wasey Ali; Siddiqui, Abdul Hasan; Valecha, Gautam; Patel, Shawn; Ayub, Fatima; Upadhyay, Riddhi; Alhajri, Sana Ahmed; Gaire, Suman; Shrestha, Dhan Bahadur
title: A Narrative Review of Existing Options for COVID-19-Specific Treatments
date: 2021-11-12
journal: Adv Virol
DOI: 10.1155/2021/8554192
sha: 47f779bf4d3e34d977b12351ce4d19f629eda1f5
doc_id: 865429
cord_uid: cgdyea7a

The new coronavirus disease 2019 (COVID-19) was declared a global pandemic in early 2020. The ongoing COVID-19 pandemic has affected morbidity and mortality tremendously. Even though multiple drugs are being used throughout the world since the advent of COVID-19, only limited treatment options are available for COVID-19. Therefore, drugs targeting various pathologic aspects of the disease are being explored. Multiple studies have been published to demonstrate their clinical efficacy until now. Based on the current evidence to date, we summarized the mechanism, roles, and side effects of all existing treatment options to target this potentially fatal virus.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in early 2020. As of July 19, 2020, COVID-19 has claimed around four million lives worldwide, with total cases of more than 189 million. e United States alone corresponds to more than 33 million cases around the globe [1] .

COVID-19 continues to impact many countries globally. Primary treatment continues to be centered on alleviating symptoms and managing the complications of COVID-19.

Since the advent of COVID-19, several drugs and drug combinations have been studied [2] . Many of these treatments are based on the in vitro activity against SARS-CoV and MERS-CoV. However, diligent work in finding an effective treatment is still in the process, including observational studies, randomized controlled trials, and case series.

ere are limited evidence and data to support any effective and gold standard therapy against COVID-19. It is a general understanding that most of the patients who have minimal to mild symptoms of COVID-19 do not require any COVID-19-specific treatment, and therefore, supportive measures are usually sufficient. For example, we rely on quarantine, isolation, and infection control measures to prevent disease spread and supportive care for those who become ill. However, patients with moderate to severe symptoms, including subjective dyspnea, hypoxia, recurrent fever, or signs of organ failure, may be candidates for COVID-19-specific therapy.

tocilizumab, leronlimab, convalescent plasma, azithromycin, lopinavir-ritonavir, ribavirin, favipiravir, oseltamivir, and umifenovir.

e treatments reviewed in this summary can be divided into five categories: immunomodulatory drugs, antiviral, COVID-19, specific immunoglobulins, convalescent plasma, and various drugs (Table 1) .

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause severe illness in up to 20% of patients, which can be attributed to a systemic hyperinflammatory response. erefore, de-escalation of this response is a potential therapeutic target. Some of the immunomodulators studied and recommended for the treatment of COVID-19 will be discussed in this section.

Chloroquine (CQ) and hydroxychloroquine (HCQ) emerged earlier in the pandemic and have gained tremendous public attention. On March 30th, 2020, the U.S. Food and Drug Administration (US FDA) issued an emergency use authorization (EUA) for CQ/HCQ to treat hospitalized patients with COVID-19 [3] . Guidelines were formulated for this drug to be administered to hospitalized patients who had evidence of pneumonia, and it continues to be widely used in acute COVID-19 worldwide [4] .

CQ and HCQ have been long used to treat and prevent malaria in many malaria-endemic countries. Apart from malaria, HCQ is also the cornerstone of the treatment of several autoimmune and inflammatory disorders. ere is convincing evidence from in vitro studies that HCQ has antiviral activity against SARS-CoV-2 [5] . It has antiviral potential through multiple mechanisms, mainly through interference with the terminal glycosylation of the cellular receptor ACE2, thereby preventing virus-receptor binding and entry into cell [6] . Secondly, HCQ increases the pH of acidic cellular organelles, hampering various viral proteins [7] . HCQ has an immunomodulatory effect, which could be explained by its propensity to alter intracellular pH leading to the inhibition of lysosomal activity in antigen-presenting cells and B cells, thereby preventing T-cell activation and cytokine production, respectively [7] . e other possible immunomodulatory action is partly mediated by inhibiting tumor necrosis factor (TNF) release from the monocytes and macrophages that play a significant role in activating other immune cells apart from starting the endothelial cells [8] [9] [10] .

In one of the earliest reports from China containing 100 patients from 10 hospitals, HCQ was associated with improved radiologic findings, enhanced viral clearance, and decreased disease progression [11] . In an open-label, nonrandomized French study by Gautret et [15] . In contrast, Arshad et al. showed that in patients with COVID-19 treated with HCQ alone and combined with AZT, it was correlated with a decline in COVID-19-associated mortality [16] .

A study among 368 COVID-19 patients in which 97 received HCQ alone, 113 received HCQ and AZT, and 158 were unexposed to HCQ resulted in a higher risk of death in patients treated with HCQ alone, without any difference between these groups for the risk of ventilation [17] . In a study of 1438 patients, HCQ use was not associated with decreased in-hospital mortality, whether associated with AZT or used alone [18] . In a survey from Brazil among mildto-moderate COVID-19 cases, the use of HCQ alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P � 1.00) or with AZT (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P � 1.00), did not improve clinical status at 15 days as compared with standard care [19] . Prolongation of the corrected QT interval and elevated liver-enzyme levels were more frequent in patients receiving HCQ, alone or with AZT [19] . In a randomized clinical trial of 75 patients treated with HCQ with a higher dose loading dose of 1200 mg/day for three days followed by 800 mg/day for 2 or 3 weeks, compared with 75 patients receiving standard of care alone, there was no difference in viral clearance at day 28 and no clinical difference between the two groups [20] . A recent study in ambulatory patients with mild symptoms also indicated that HCQ did not reduce symptom severity at 14 days [21] . Similarly, Mitjà et al. reported no benefit of HCQ in patients with mild COVID-19 beyond routine care [22] . Boulware [23] . In contrast, in a similar study in healthcare workers, consumption of four or more maintenance doses of HCQ was associated with a significant decline in the odds of getting infected (AOR: 0.44; 95% CI: 0.22-0.88), leaving the question of utility of HCQ postexposure prophylaxis open in that high-risk population [24] . CQ and HCQ, due to their inhibitory effect on potassium channels (IKr current), increase the risk of several arrhythmias and EKG changes [25] . is side effect is dosedependent; however, serious arrhythmias have been reported even at therapeutic doses. ese severe cardiac side effects, including QT prolongation, Torsade de Pointes, and arrhythmia, were reported in many studies [18, [26] [27] [28] [29] . In a randomized trial, adverse events were observed in about 30% of patients who received HCQ compared with only 9% of patients in a control group [20] . A QTc >500 ms was observed in 11% to 20% of patients receiving HCQ and AZT [30, 31] . is was frequently seen with a high dose of HCQ (1200 mg/day for ten days) combined with AZT [32] . Among 40 patients with severe infection (admitted to intensive care units) who received either HCQ or HCQ + AZT, there was an increase in QTc in 37 of 40 patients (93%) after drug administration [33] . Besides cardiotoxicity, HCQ also increases the risk of retinopathy, acute pancreatitis, neutropenia, hepatotoxicity, and anaphylaxis [28, 34] .

Both CQ and HCQ have clinically significant drug interactions. AZT is a macrolide that may prolong the QT/QTc interval leading to a higher risk of cardiac death [35, 36] . e FDA has warned that AZT can lead to potentially fatal arrhythmias and discourages the use of this antibiotic among patients with underlying heart disease and those with known electrolyte imbalance [37] . erefore, CQ or HCQ and AZT's concomitant use potentially places patients at a higher risk of cardiotoxicity. Other treatments used in managing COVID-19 patients may show drug interaction with CQ/ HCQ. Lopinavir/ritonavir strongly inhibits CYP3A4 and has a large number of significant drug interaction concerns [38] . In in vitro studies, remdesivir appears to be a substrate for the drug-metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4 [39] . erefore, significant potential drug interactions need to be acknowledged when selecting a treatment.

Taken in totality, the available evidence is limited, and most studies are hampered by limited sample size and study design. Furthermore, meta-analysis does not suggest any efficacy of HCQ in patients with COVID- 19 [40] . Early results from in vitro studies and uncontrolled case studies created a massive hype for HCQ, aggravated by media and social excitement, which caused a massive demand despite limited data.

Although steroids are usually considered an essential treatment modality in inflammatory conditions, their role in COVID-19 remains debatable. One of the frequently observed causes of mortality is hemophagocytic lymphohistiocytosis (sHLH), another hypercytokinemia syndrome associated with multiorgan failure, thought to be precipitated COVID-19 [41] . Evidence from the limited literature suggests an increased production of cytokines leading to the activation of other inflammatory cells and endothelium activation, resulting in multiorgan damage and failure. e most crucial role of corticosteroids is reducing the exudative fluid in lung tissue, thereby improving hypoxia and minimizing the risk of respiratory failure [42] . Corticosteroids were increasingly used worldwide in as much as 50% of patients affected by COVID-19 particularly in China [39, 43] . e few retrospective studies earlier in the pandemic reported inconclusive results, including patients with severe COVID-19 patients with pulmonary involvement [44] [45] [46] [47] [48] . Among the five studies (4 retrospective and one quasiprospective study), three studies have shown a benefit, and the other two studies reported no use. Complicating the decision making, one study observed significant harm, especially in critical and severe cases (propensity-matched adjusted hazard ratio [HR] 2.90; 95% CI, 1.17-7.16; P � 0.021) [44] [45] [46] [47] [48] . Taken as a whole, the studies suggest that corticosteroids improve the condition of severe and critically ill COVID-19 patients in many ways, including decreased duration of hospital stay, improvement in the status of oxygenation, the reduced requirement to intubate and subsequent ventilation, prevention of ventilator parameters worsening, progression to ARDS, and death [46] [47] [48] .

A large prospective study conducted in the UK ( e RECOVERY Trial) randomized 2104 patients to dexamethasone 6 mg per day (oral or intravenous) for ten days, with 4321 patients receiving usual care [43] . Patients included in this study had various comorbidities, including diabetes (24%), heart disease (27%), and chronic lung disease (21%), and 56% had at least one major comorbidity. In this study, 54% of patients were below 70 years, and 22% were between 70 and 80 years. e primary endpoint was mortality within 28 days, which was significantly less in the dexamethasone group compared with the routine care group (21.6% vs. 24.6%; age-adjusted rate ratio [RR], 0.83; 95% CI, 0.74-0.92; P < 0.001). No benefit was observed in mild or moderate cases without oxygen requirement in mortality reduction at the end of 28 days (17.0% vs.13.2%; RR, 1.22; 95% CI, 0.93-1.61; P � 0.14). However, there was 35% reduction in mortality in intubated patients (29.0% vs. 40.7%; RR, 0.65; 95% CI, 0.48-0.88; P � 0.003) and 20% reduction among the patients on supplemental oxygen therapy (21.5% vs. 25.0%; RR, 0.80; 95% CI, 0.67-0.96; P � 0.0021). is study also reported a shorter duration of hospital stay with dexamethasone compared with standard routine care (median 12 days vs. 13 days) and a higher probability of discharge within 28 days with dexamethasone (11%; RR, 1.11; 95% CI, 1.04-1.19; P � 0.002) [49] . e most frequently used corticosteroids are methylprednisolone and dexamethasone, secondary to their high bioavailability in the lungs. Some studies have reported that corticosteroid usage is associated with delayed viral clearance in patients with a previous viral illness; the same results were reported in COVID-19 patients [50] [51] [52] . Zhou et al. reported delayed clearance of the virus and increased mortality risk with the early administration of corticosteroid in COVID-19 patients [53] . However, a short Advances in Virology course of corticosteroids in some studies was beneficial in this regard [54] . Furthermore, corticosteroid use could predispose patients to secondary bacterial infection and various electrolytes derangements, including hypokalemia hyperglycemia [54] . However, there is inconsistent data to show any superiority among dexamethasone or methylprednisone use in COVID-19 [55, 56] .

Although the data from retrospective studies do not strongly support corticosteroid use in COVID-19, the RE-COVERY trial, in particular, indicates a beneficent role in reducing mortality and duration of hospital stay among moderate to moderately severe cases.

Tocilizumab is a recombinant humanized monoclonal antibody targeted against the IL-6 receptor. It is approved for the treatment of various autoimmune and inflammatory disorders, including rheumatoid arthritis [57] . A retrospective study by Ruan et al. reported higher IL-6 levels associated with disease progression and fatal outcome [58] . e role of IL-6 in mediating the inflammatory response in COVID-19 is a vital target in halting the marked inflammatory response. In critically ill COVID-19 patients who have elevated levels of IL 6, the efficacy of tocilizumab has been reported by retrospective studies [59] . 20 critically ill patients who received tocilizumab, there was a marked improvement in fever and other clinical symptoms [60] . Moreover, 15 of 20 required less oxygen, and there was an overall improvement in the CT scans in 19 patients. ere were no significant adverse reactions observed. Of the 21 patients, 20 fully recovered after tocilizumab treatment and were discharged within two weeks [60] . A retrospective study in fifteen critically ill patients evaluated the efficacy and safety of tocilizumab as a monotherapy or in combination with methylprednisolone. ere was a clinical improvement and a decrease in IL-6 and C-reactive protein (CRP) levels [59] .

Another phase III clinical trial approved by the FDA evaluates tocilizumab in hospitalized patients with severe COVID-19 pneumonia [NCT04320615]. . Notably, in the latest trial of tocilizumab (COVACTA trial) among 452 patients, tocilizumab (n � 294) did not meet the primary endpoint of improved clinical status after seven days of administration (P � 0.36) compared with the placebo group (n � 144). Moreover, there was no difference in mortality at day 28 between tocilizumab (19.7%) and placebo (19.4%) (0.3% [95% CI, −7.6 to 8.2]; P � 0.94) [61] . In a randomized, controlled, open-label trial including 4116 patients (RECOVERY), there was a decrease in 28 days mortality in the tocilizumab arm (rate ratio 0·86; 95% confidence interval [CI] 0·77-0·96; P � 0.007). Furthermore, tocilizumab also decreased the chances of mechanical ventilation and death in those patients who were not ventilated. e mortality benefits of tocilizumab were seen in patients taking steroids [62] . However, there is a need for more robust studies to identify the role of tocilizumab in reducing mortality benefits for COVID-19 patients.

Interferons are a broad spectrum of immunomodulators with antiviral properties. IFN-α has been used to treat coronavirus diseases previously, such as SARS and MERS [63, 64] . In addition, interferon -α (IFNα) and −β (IFNβ) have been recommended for the treatment of COVID-19 [65] [66] [67] .

Interferons bind to its receptor on the cell membrane and then phosphorylate STAT1 and other transcription factors. STAT1 translocates to the nucleus, leading to interferon-stimulated genes (ISGs), which mediates the immunomodulatory effects and interferes with viral replication [67] . IFNα and IFNβ are frequently studied as a combination therapy with ribavirin and or lopinavir-ritonavir [29, [68] [69] [70] . IFNβ has superior efficacy against coronaviruses compared to IFNα [70] [71] [72] . Furthermore, some in vitro studies indicate that IFNβ induces anti-inflammatory adenosine secretion and maintains endothelial barriers when used in early stages of infection [67] . IFNα, in combination with ribavirin, has been recommended for COVID-19 patients in China [72] . SARS-CoV-2 is more sensitive to prophylactic IFN-1 administration [67, [70] [71] [72] . In vitro pretreatment studies with INF-1 have confirmed this [73] . Due to limited evidence, routine usage cannot be recommended until further data can support its efficacy and safety profile.

Leronlimab is a monoclonal antibody against CCR5, inhibiting the entry of SARS-CoV-2 into cells. CCR5 receptors are located on several antigen-presenting cells (e.g., T cells, dendritic cells, macrophages, and Langerhans cells) [74] . On March 31st, 2020, the FDA gave clearance for the initiation of a phase II trial evaluating leronlimab in patients with mild to moderate respiratory complications. However, multiple further studies to assess the efficacy, and benefits are still needed.

Developed during the Ebola virus outbreak in 2016, remdesivir is a promising therapy in treating COVID-19 [29, 70, 75] . It is a broad-spectrum antiviral agent. It prevents viral replication by inhibiting RNA-dependent RNA polymerase [2] . Remdesivir has also been used to treat SARS, MERS-CoV, and other viral illnesses. Remdesivir has a superior anti-MERS activity compared with lopinavir and ritonavir both in vitro and in vivo and displayed anti-SARS-CoV-2 ability in vitro [7, 69] . A randomized, placebo-controlled, clinical trial of 1059 COVID-19 patients revealed a median recovery time of 11 days (95% confidence interval [CI], 9-12) versus 15 days (95% CI, [13] [14] [15] [16] [17] [18] [19] in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P < 0.001). However, there was no significant difference in mortality (7.1% vs. 11.9% hazard ratio for death, 0.70; 95% CI, 0.47-1.04) [76] . A randomized, double-blind, placebo-controlled, multicenter, phase-III trial was conducted in China to evaluate the efficacy of remdesivir [75] . e study included 237 severely ill COVID-19 patients among whom 158 received remdesivir and 79 received placebo. e primary endpoint was time to clinical improvement [7, 77] . Patients receiving remdesivir had a faster time to clinical improvement than those receiving placebo, but this was not statistically significant (hazard ratio, 1·52 [0·95-2·43]). In the USA, compassionate use of remdesivir displayed clinical improvement in 36 of 53 hospitalized severe COVID-19 patients and 14 of 17 patients in an infectious disease ward [78, 79] . In meta-analysis with four studies, remdesivir was found to reduce 14 days mortality (OR, 0.61, CI 0.41-0.91) and need for mechanical ventilation (OR, 0.73; CI, 0.54-0.97) [80] . Remdesivir was given an "emergency use authorization" approval by FDA for patients with severe COVID-19 on May 1st, 2020 [81] .

Lopinavir/ritonavir is a combination antiretroviral drug that has been used to treat HIV and has also been part of clinical trials in the treatment of MERS-CoV and SARS-CoV-2. Lopinavir, an HIV-1 protease inhibitor, prevents viral gag-pol polyprotein cleavage, which results in immature, noninfectious viral particles; it was found to have activity against SARS-CoV-2 when used with ritonavir, a P450 CPY3A inhibitor, which increases plasma levels of lopinavir [82] [83] [84] [85] . It has been widely used for the COVID-19 treatment in South Korea and ailand. However, there is limited data on the efficacy and safety among COVID-19 patients [86] [87] [88] . Cao et al. found no benefit with lopinavirritonavir treatment in 199 hospitalized patients with severe COVID-19, demonstrating similar mortality rates (19.2%) than the standard of care group (25%) [38] . A single-center, controlled trial reached a similar conclusion for hospitalized patients with mild to moderate COVID-19 as compared with standard treatment [89] . In another study by Cheng et al., lopinavir/ritonavir did not shorten the duration of SARS-CoV-2 shedding [89, 90] . Gastrointestinal disturbance was the most common adverse effect associated with lopinavirritonavir, seen in 28% of patients. Moreover, the use of lopinavir/ritonavir was also associated with liver damage in COVID-19 [70, 91] . However, when used in combination with interferon-β-1b and ribavirin, lopinavir/ritonavir was found to be effective and superior to lopinavir/ritonavir alone and was associated with clinical improvement and shorter duration of hospital stay [92] .

Ribavirin acts by inhibiting viral RNAdependent RNA polymerase. Evidence regarding ribavirin use in COVID-19 patients has revealed no definitive role in some studies [27] . However, based on the data available, combination therapy with interferon-α or lopinavir-ritonavir may provide some clinical efficacy [29, 54, 70, 92, 93] . However, dose-dependent adverse events like liver and hematologic toxicities were the limiting factors [29] . erefore, its role in treating COVID-19 patients remains inconclusive due to limited data and research.

Favipiravir is an inhibitor of RNA-dependent RNA polymerase approved for treating influenza, Ebola, and norovirus [58, 70, 94, 95] . Data from preliminary studies revealed significant clinical benefits (i.e., more rapid viral clearance of 4 days vs. 11 days) and improved chest imaging in COVID-19 patients than lopinavir-ritonavir alone (91.4% vs. 62.2%). In addition, there were fewer adverse events in patients administered favipiravir compared with those taking lopinavir-ritonavir alone (11.4% versus 55.6%) [96] . Another prospective, randomized, clinical trial reported better control of fever, cough, and respiratory symptoms among COVID-19 patients, with an improved recovery rate in patients receiving favipiravir compared with umifenovir (71.4% versus 55.9%) [70, 97] . However, these studies were limited by only evaluating noncritically ill patients.

Oseltamivir is a neuraminidase inhibitor long used for the treatment of influenza A and B [29, 54] . However, current evidence has failed to find any efficacy and benefit for the treatment of COVID-19 patients, and hence, its use in any form should be discouraged [92] .

Umifenovir is a membrane fusion inhibitor, preventing the interaction between viral S-proteins and ACE2 receptors [70] . It has been used as prophylaxis and for the treatment of influenza A and B [54, 97] . Apart from its benefit for influenza, umifenovir has shown antiviral effects for other viruses like hepatitis C virus, hepatitis B virus, Ebola virus, human herpesvirus 8, Lassa virus, and poliovirus [95] . A retrospective cohort study of 16 COVID-19 patients after 14 days of umifenovir and lopinavir-ritonavir administration versus lopinavir-ritonavir treatment alone showed 4% clearance of SARS-CoV-2 in the umifenovir experimental group compared with 53% patients in the control group [98] . Furthermore, there was an improvement in the chest CT scans in the experimental group (69% compared to 29% in lopinavir-ritonavir monotherapy) [98] . In another similar study of 16 patients taking umifenovir (200 mg TID), there was complete clearance of the virus versus 44.1% viral load detection in patients taking lopinavir-ritonavir monotherapy (400 mg/100 mg BID) [99] . However, other studies have found benefits limited to only nonseverely ill patients [100] . Due to the limited data available, its utilization is not routinely recommended at this time.

e data regarding intravenous immunoglobulin (IVIG) efficacy and outcomes in COVID-19 patients is scarce. However, IVIG may help severe SARS-CoV-2 infection through immune modulation by saturating the FccR [101] . In a case series of three critically ill SARS-CoV-2 patients in China who received IVIG at 0.3-0.4 g/kg/ day for five days, all respiratory symptoms showed significant improvements in clinical status, and there were alleviated side effects [102] . However, a clear demonstration of therapeutic benefit will require further studies.

Treatment strategies for critically ill COVID-19 patients continue to be hampered by limited evidence. Administration of convalescent plasma Advances in Virology (CP) has been long practiced to improve the survival rate during viral outbreaks, including SARS-CoV, MERS-CoV, and Ebola virus [70, [103] [104] [105] . A meta-analysis reported a significant reduction in mortality and viral load with CP immunotherapy, leading to the August 23rd, 2020, FDA decision to authorize emergency use in the treatment of COVID-19 [106] . e role of convalescent plasma transfusion in COVID-19 patients is related to both an increase in viral clearance and inhibition of the cytokine storm that plays a major role in precipitating organ damage [107] . Earlier in the current pandemic, small observational studies revealed promising outcomes and clinical improvements from the CP utilization [108] [109] [110] [111] .

e first study from Wuhan reported outcomes of 5 critically ill patients who were administered CP [109] . In four of the five patients, there was remarkable improvement in the clinical status measured by the Alveolar-arterial (A/a) gradient and chest CT scan, and there was a decrease in inflammatory biomarkers, as well [109] . Duan et al. reported that after a single transfusion of convalescent plasma in 10 patients, there were no adverse events [108] . Additionally, similar clinical improvements were reported in other small case studies [109, 111] . e timing of infusion appears to play a role in the success of the treatment. Early data appears to support the fact that transfusions done earlier in the disease proved to have better outcomes, including mortality [106, 112, 113] . Zeng et al. reported poor mortality outcomes when convalescent plasma was administered late [114] . A multicenter cohort study consisting of 35,322 patients reported a sevenday mortality rate of 8.7% [95% CI, 8.3%-9.2%] when plasma was transfused within three days of COVID-19 diagnosis compared with 11.9% [11.4%-12.2%] (P < 0.001) when the transfusion was done after three days of diagnosis. In addition, there was a significant reduction in 30-day mortality in early transfused patients (21.6% vs. 26.7%; P < 0.0001) (NCT04338360). Moreover, in an RCT of 86 patients, the patients were symptomatic for ten days, 79% of tested patients had COVID-19 neutralizing antibodies comparable to median titers with those of donors. As patients developed neutralizing antibodies as early as the first week, convalescent plasma is likely to help only patients with recent clinical symptoms [115] . In another randomized control trial of 103 patients with severe or life-threatening COVID-19 disease, convalescent plasma did not provide any benefit in terms of 28 days mortality (OR, 0.59; 95% CI, 0.22-1.59; P � 0.30) or in terms of time from randomization to discharge(HR, 1.61; 95% CI, 0.88-2.95; P � 0.12) [116] . A randomized controlled trial that enrolled 334 patients to compare convalescent plasma with placebo could not find any difference in terms of clinical outcomes and mortality. e median days of patient randomized after appearance of symptoms was 8 days [117] . e use of plasma transfusion therapy may be an option for critically ill patients if administered early in the disease course. However, many factors, including the number of transfusions, adjustments based on body mass index, donor antibody titers, and other parameters, need to be evaluated to optimize this therapy.

e SARS-CoV-2 interacts with the ACE2 receptor to enter the host cell. Inhibiting this step can be a potential target for COVID-19 treatment [118] . German guidelines recommended the compassionate use of ACE-II inhibitors [119] . However, many clinical experts have discouraged their usage. ey have postulated that blocking ACE-II receptors with ACE inhibitors may lead to poorer outcomes due to the upregulation of the receptors and thus increasing viral entry into the host cells [120] . However, others have challenged this position because receptor upregulation appears to seldom occur at therapeutic doses [121] . erefore, it is currently recommended that patients with cardiovascular comorbidities continue to take ACE inhibitors and ARBs as prescribed [122] .

Azithromycin. Azithromycin (AZT), a frequently used antibiotic, has been used in combination therapy with HCQ for COVID-19 patients. A multicenter retrospective study of 1438 hospitalized patients evaluated the efficacy and side effects of HCQ plus AZT combination therapy, compared with HCQ alone, AZT alone, and a placebo control group, and found no significant differences in the experimental groups to the control group [18] . Furthermore, combination therapy was associated with cardiac arrest (OR � 2.13) [18] . Magagnoli et al. reported similar results that combination therapy with HCQ plus AZT did not decrease the risk of death in COVID-19 patients [17] .

Additionally, in patients who were only taking HCQ, the risk of death was even higher [17] . Due to the adverse cardiovascular side effects with HCQ and AZT combination therapy, this combination's clinical use requires frequent ECG monitoring [26, 27] . Based on the above data, routine usage cannot be recommended at this time.

One of the major complications associated with hospitalized COVID-19 patients is lifethreatening thromboembolic events. Abnormal coagulation in COVID-19 patients is independently associated with an increased risk of mortality [123] . erefore, identifying highrisk patients and early institutions of antithrombotic is essential to limit thrombus formation and treat systemic thromboembolic complications in COVID-19 patients. e International Society on rombosis and Hemostasis has recommended antithrombotic prophylaxis with low-molecular-weight heparin (LMWH) for all hospitalized patients, except contraindicated [123] . However, routine thromboprophylaxis is not preferred in ambulatory patients with active medical illness [124] . Apart from its anticoagulation effects, unfractionated heparin has demonstrated antiviral properties in some studies [125] .

Unfractionated heparin is frequently preferred in patients with underlying renal disease [125] . However, the choice of AC should be individualized based on patient clinical status, as many patients might progress from a thrombotic state to a bleeding pattern due to platelet destruction and coagulation factor consumption [122, 123] . In obese patients with BMI ≥40 kg/m 2 , a higher dose of thromboprophylaxis has been shown to decrease VTE risk by 50% [126] .

Aggressive thromboprophylaxis with high doses of anticoagulation can be considered in patients who meet the high sepsis-induced coagulopathy (SIC) score criteria or in patients with markedly elevated D-dimer levels [123] . Tang et al. found that aggressive thromboprophylaxis was associated with better outcomes in a study of 449 COVID-19positive patients [127] . Moreover, in patients on low-molecular-weight heparin (LMWH) with SIC score ≥ four or D-dimer ≥ 6 times, the upper limit had a significantly lower 28-day mortality rate than untreated patients (40.0% vs 64.2%; P � 0.029) [127] .

Few studies have reported improved survival benefits with fibrinolytic therapy in patients with acute lung injury and ARDS [128, 129] . However, in a case series of 3 COVID-19 patients administered tPA (alteplase) suffering from ARDS and respiratory failure, there was an initial, but only transient, improvement in the PaO 2 /FiO 2 ratio [129] .

erefore, more studies are required to evaluate outcomes associated with plasminogen activator in COVID-19 patients [129] . 

is is a review article based on secondary data from other articles so we do not have our own data!

e authors declare that they have no conflicts of interest.

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In VitroCardiovascular effects of dihydroartemisin-piperaquine combination compared with other antimalarials

Recommendations for the measurement of the QT interval during the use of drugs for COVID-19 infection treatment

Infectious diseases society of America guidelines on the treatment and management of patients with COVID-19

Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics

Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review

e QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/azithromycin

Risk of QT interval prolongation associated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19)

Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: preliminary safety results of a randomized, double-blinded

Article ID e208857

Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit

Hydroxychloroquine retinopathy -implications of research advances for rheumatology care

Azithromycin and the risk of cardiovascular death

Cardiac risks associated with antibiotics: azithromycin and levofloxacin

FDA Warns Antibiotic Zithromax Can Cause Irregular Heart Activity

A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

COVID-19: consider cytokine storm syndromes and immunosuppression

Antiinflammatory action of glucocorticoids -new mechanisms for old drugs

Effect of dexamethasone in hospitalized patients with COVID-19 -preliminary report

Systemic corticosteroids show no benefit in severe and critical COVID-19 patients in Wuhan, China: a retrospective cohort study

Adjuvant corticosteroid therapy for critically ill patients with COVID-19

Early short course corticosteroids in COVID-19

Early, low-dose and shortterm application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China

Beneficial effect of corticosteroids in severe COVID-19 pneumonia: a propensity score matching analysis

Dexamethasone in hospitalized patients with covid-19

Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients

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

On the use of corticosteroids for 2019-nCoV pneumonia

Potential benefits of precise corticosteroids therapy for severe 2019-nCoV Pneumonia

e effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis

Comparison of efficacy of dexamethasone and methylprednisolone in moderate to severe covid 19 disease

Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial

An update on current therapeutic drugs treating COVID-19

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

Tocilizumab treatment in COVID-19: a single center experience

Effective treatment of severe COVID-19 patients with tocilizumab

Tocilizumab in hospitalized patients with severe covid-19 pneumonia

Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques

Treatment outcomes for patients with middle eastern respiratory syndrome coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia

A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19

Compounds with therapeutic potential against novel respiratory 2019 coronavirus

Type 1 interferons as a potential treatment against COVID-19

Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial

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

COVID-19: a review of the proposed pharmacological treatments

Broadspectrum antivirals for the emerging Middle East respiratory syndrome coronavirus

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

Type I interferon susceptibility distinguishes SARS-CoV-2 from SARS-CoV

Disruption of the CCL5/ RANTES-CCR5 pathway restores immune homeostasis and reduces plasma viral load in critical COVID-19

Arguments in favour of remdesivir for treating SARS-CoV-2 infections

Remdesivir for the treatment of covid-19 -final report

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebocontrolled, multicentre trial

Compassionate use of remdesivir for patients with severe covid-19

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: clinical outcome and differences in post-treatment hospitalisation status

Remdesivir: a potential gamechanger or just a myth? A systematic review and metaanalysis

FDA Emergency Use Authorization | FDA [Internet]. Food & Drug Administration

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

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset

Coronaviruses -drug discovery and therapeutic options

Case of the index patient who caused tertiary transmission of coronavirus disease 2019 in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 pneumonia monitored by quantitative RT-PCR

Letter to the editor: case of the index patient who caused tertiary transmission of coronavirus disease 2019 in Korea: the application of lopinavir/ritonavir for the treatment of COVID-19 pneumonia monitored by quantitative RT-PCR

Efficacies of lopinavir/ritonavir and abidol in the treatment of novel coronavirus pneumonia

An exploratory randomized controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI)

Lopinavir/ritonavir did not shorten the duration of SARS CoV-2 shedding in patients with mild pneumonia in Taiwan

Clinical features of COVID-19-related liver damage

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

A global treatments for coronaviruses including COVID-19

Favipiravir, an antiviral for COVID-19?

Candidate drugs against SARS-CoV-2 and COVID-19

Experimental treatment with favipiravir for COVID-19: an open-label control study

Favipiravir versus Arbidol for COVID-19: a randomized clinical trial

Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: a retrospective cohort study

Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19

Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: a retrospective study

Intravenous immunoglobulin therapy: how does IgG modulate the immune system?

High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019

Convalescent plasma transfusion for the treatment of COVID-19: systematic review

Convalescent plasma in Covid-19: possible mechanisms of action

Challenges of convalescent plasma therapy on COVID-19

e effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis

Treatment for emerging viruses: convalescent plasma and COVID-19

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Treatment of 5 critically ill patients with COVID-19 with convalescent plasma

Treatment with convalescent plasma for COVID-19 patients in Wuhan, China

Treatment with convalescent plasma for critically ill patients with severe acute respiratory syndrome coronavirus 2 infection

Retrospective comparison of convalescent plasma with continuing highdose methylprednisolone treatment in SARS patients

Use of convalescent plasma therapy in SARS patients in Hong Kong

Effect of convalescent plasma therapy on viral shedding and survival in patients with coronavirus disease 2019

Convalescent Plasma for COVID-19. A randomized clinical trial

Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial

A randomized trial of convalescent plasma in covid-19 severe pneumonia

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Empfehlungen zur intensivmedizinischen erapie von Patienten mit COVID-19

Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?

Risks of ACE inhibitor and ARB usage in COVID-19: evaluating the evidence

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a comment

Efficacy and safety of highdose thromboprophylaxis in morbidly obese inpatients

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Prevention of adult respiratory distress syndrome with plasminogen activator in pigs

Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series