LitCovid-sample-sentences  

PMC:7441788 / 1687-42371 JSONTXT 26 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T17 0-2 Sentence denotes 1.
T18 4-16 Sentence denotes Introduction
T19 17-223 Sentence denotes Coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly spreading worldwide, resulting in the third outbreak of coronaviruses in the 21st century.
T20 224-301 Sentence denotes The pandemic of COVID-19 constitutes a serious threat to the whole world [1].
T21 302-509 Sentence denotes To control the pandemic of COVID-19, effective and easily accessible antiviral drugs and vaccines are urgently needed, in addition to the implementation of epidemiological measures such as strict quarantine.
T22 510-595 Sentence denotes However, until now, no drugs have been demonstrated to be effective against COVID-19.
T23 596-866 Sentence denotes Among the various drugs under investigation are repurposed anti-malarial drugs chloroquine (CQ) and its analog hydroxychloroquine (HCQ), which are among the most used drugs because they are easy to obtain and have a proven favorable safety record at relatively low cost.
T24 867-910 Sentence denotes CQ/HCQ are derivatives of 4-aminoquinoline.
T25 911-1074 Sentence denotes They are lipophilic weak bases that quickly pass across cell membranes and accumulate in acidic organelles, such as lysosomes, endoplasmic reticulum and Golgi [2].
T26 1075-1317 Sentence denotes CQ/HCQ are used to treat and prevent malaria attacks due to their anti-plasmodium activity and to treat autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) owing to their immunomodulatory activity [3].
T27 1318-1401 Sentence denotes In addition, CQ/HCQ display antibacterial, antifungal and antiviral activities [4].
T28 1402-1633 Sentence denotes In vitro studies have shown that CQ/HCQ possess antiviral activity against RNA viruses, such as HIV [5], rabies virus [6] and polio virus [7] and various DNA viruses as diverse as hepatitis B virus [8] and herpes simplex virus [9].
T29 1634-1746 Sentence denotes This article reviews the current status of CQ/HCQ against SARS-CoV-2 and their use in the treatment of COVID-19.
T30 1748-1750 Sentence denotes 2.
T31 1752-1827 Sentence denotes Antiviral activity of CQ/HCQ against human coronavirus in vitro and in vivo
T32 1828-2195 Sentence denotes The antiviral activity of CQ against MERS-CoV and HCoV-229E was assessed in the human hepatoma cell line (Huh-7) and found that the 50% effective concentrations (EC50) were 3.0(±1.1) μM and 3.3(±1.2) μM, the 50% cytotoxic concentrations (CC50) were 58.1(±1.1) μM and >50, and the selectivity indexes (SI; calculated as CC50/EC50) were 19.4 and >15, respectively [10].
T33 2196-2261 Sentence denotes CQ could inhibit an early step in the MERS-CoV replication cycle.
T34 2262-2354 Sentence denotes Addition of CQ to VeroE6 cells 1 h after MERS-CoV infection did not affect virus production.
T35 2355-2522 Sentence denotes However, when CQ was added 1 h before MERS-CoV infection, 16 μm and 32 μM concentrations of CQ could reduce the virus production of 1-log and 2-log, respectively [10].
T36 2523-2710 Sentence denotes In VeroE6 cells, the antiviral activity of CQ/HCQ against SARS-CoV had an EC50 of 4.1 (±1.0) μM and 34(±5) μM, CC50 of >128 μM and CC50 > 100 and SI of >31 and SI>3, respectively [10,11].
T37 2711-2792 Sentence denotes SARS-CoV replication was inhibited by 99% at 16 μM CQ 3 days post-infection [12].
T38 2793-2865 Sentence denotes The data indicates that CQ has stronger anti-SARS-CoV activity than HCQ.
T39 2866-2934 Sentence denotes In addition, CQ has both a prophylactic and a therapeutic advantage.
T40 2935-3425 Sentence denotes Vincent et al. tested various concentrations of CQ (0.1–10 µM) added 20–24 h prior to SARS-CoV infection and found that 0.1, 1, and 10 µM CQ reduced infectivity by 28%, 53%, and 100%, respectively; when CQ was added immediately after virus adsorption, 0.1–1 µM and 33–100 µM reduced the infection by 50% up to 90–94%; addition of CQ 3 and 5 h after virus adsorption was still significantly effective, yet to achieve equivalent antiviral effect, a higher concentration of CQ was needed [13].
T41 3426-3572 Sentence denotes In HRT-18 cells, the antiviral activity of CQ against HCoV-OC43 had an EC50 of 0.306 (±0.091) μM, CC50 of 419.0 (±192.5) μM, and SI of 1.369 [14].
T42 3573-3678 Sentence denotes An in vivo study found that CQ could exert anti-HCoV-OC43 activity transplacentally or via maternal milk.
T43 3679-3941 Sentence denotes The data from mouse models showed that 98.6% of the pups survived when pregnant mice were treated with 15 mg/kg of CQ, and survival rates decreased in a dose-dependent manner, with 88% and 13% survival when treated with 5 mg/kg and 1 mg/kg CQ, respectively [14].
T44 3942-4029 Sentence denotes The survival rate of newborn mice via maternal milk was 69.0% with 15 mg/kg of CQ [14].
T45 4030-4179 Sentence denotes In another mouse study, CQ strongly attenuated HCoV-OC43 replication in the brain and prevented the infection from spreading to the spinal cord [15].
T46 4180-4282 Sentence denotes The above studies confirmed that CQ/HCQ have a broad-spectrum anti-HCoV activity in vitro and in vivo.
T47 4284-4286 Sentence denotes 3.
T48 4288-4344 Sentence denotes Antiviral activity of CQ/HCQ against SARS-CoV-2 in vitro
T49 4345-4453 Sentence denotes In VeroE6 cells, the EC50, CC50 and SI of CQ against SARS-CoV-2 were 1.13 μM, >100 and >88.50, respectively.
T50 4454-4538 Sentence denotes CQ functioned at the entry, and post-entry stages of SARS-CoV-2 infected cells [16].
T51 4539-4769 Sentence denotes In the same cell line, at different multiplicities of infection (MOIs, 0.01, 0.02, 0.2, and 0.8) of SARS-CoV-2, the EC50 for CQ (2.71, 3.81, 7.14, and 7.36 μM) was slightly lower than that of HCQ (4.51, 4.06, 17.31, and 12.96 μM).
T52 4770-4902 Sentence denotes Consequently, the SI of CQ (100.81, 71.71, 38.26, and 37.12) was slightly higher than that of HCQ (55.32, 61.45, 14.41, 19.25) [17].
T53 4903-5008 Sentence denotes These results indicate that the anti-SARS-CoV-2 activity of CQ seems to be more potent than HCQ in vitro.
T54 5009-5436 Sentence denotes However, another in vitro cell experiment showed that after SARS-CoV-2 infection of VeroE6 cells, the EC50 values for CQ were 23.90 μM and 5.47 μM, and EC50 values for HCQ were 6.14 μM and 0.72 μM, at 24 and 48 h, respectively; When administered prior to SARS-CoV-2 infection of VeroE6 cells, EC50 values for CQ were >100 μM and 18.01 μM, and the EC50 values for HCQ were 6.14 μM and 0.72 μM, at 24 and 48 h, respectively [18].
T55 5437-5526 Sentence denotes These results showed that the anti-SARS-CoV-2 activity of CQ was worse than HCQ in vitro.
T56 5527-5649 Sentence denotes The conflicting results of these two studies may be related to different cell culture methods and experimental conditions.
T57 5650-5737 Sentence denotes In short, these in vitro studies show that CQ/HCQ have strong anti-SARS-CoV-2 activity.
T58 5739-5741 Sentence denotes 4.
T59 5743-5784 Sentence denotes Mechanisms of CQ/HCQ in treating COVID-19
T60 5786-5790 Sentence denotes 4.1.
T61 5792-5810 Sentence denotes Antiviral activity
T62 5812-5818 Sentence denotes 4.1.1.
T63 5820-5861 Sentence denotes Hindrance of receptor recognition process
T64 5862-5953 Sentence denotes The S protein of SARS-CoV-2 is cleaved by host proteases into two subunits, S1 and S2 [19].
T65 5954-6137 Sentence denotes The S1 subunit binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2) for virus attachment, and the S2 subunit fuses the virus and the host cell membrane [19].
T66 6138-6526 Sentence denotes The investigation of the effect of CQ on ACE2 in VeroE6 cells showed that effective anti-SARS-CoV-2 concentrations of CQ had no significant effect on the synthesis and glycosylation of S protein on the surface of SARS-CoV, and although it had no significant effect on the cell surface expression of ACE2, CQ could destroy the glycosylation at the terminal glycosylation site of ACE2 [13].
T67 6527-6800 Sentence denotes Therefore, the mechanism of anti-CoV activity of CQ/HCQ may be at least partly related to the impairment of terminal glycosylation of ACE2, which may result in reduced binding affinities between ACE2 and SARS CoV S protein, thereby blocking receptor recognition (Figure 1).
T68 6801-6810 Sentence denotes Figure 1.
T69 6811-6929 Sentence denotes Schematic representation of the possible mechanisms of CQ/HCQ against CoVs replication and modulating immune response.
T70 6930-7561 Sentence denotes CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells.
T71 7562-7912 Sentence denotes ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α.
T72 7913-8198 Sentence denotes In addition to protein membrane receptors, infection of host cells by HCoVs also relies on sialic acid-containing glycoproteins and gangliosides, which are used by a broad range of viruses as receptors, such as influenza [20] and HCoVs including SARS-CoV [21] and HCoV-OC43 [13,22,23].
T73 8199-8397 Sentence denotes A recent molecular structure analysis showed that SARS-CoV-2 not only uses ACE2 as a receptor, but also recognizes highly conserved gangliosides on the host cell surface through sialic acid [24,25].
T74 8398-8538 Sentence denotes CQ/HCQ binds sialic acids and gangliosides with high affinity, which can prevent the attachment of SARSCoV-2 S protein to gangliosides [25].
T75 8539-8646 Sentence denotes CQ had inhibitory effect on quinone reductase 2 (QR2) involved in the biosynthesis of sialic acids [26,27].
T76 8647-8798 Sentence denotes Hence, the mechanism of anti-CoV activity of CQ/HCQ may also be related to hindering the recognition process of sialic acid and ganglioside (Figure 1).
T77 8800-8806 Sentence denotes 4.1.2.
T78 8808-8851 Sentence denotes Interference of the membrane fusion process
T79 8852-8979 Sentence denotes CoVs are enveloped RNA viruses, and their cell entry processes involve a principal route of receptor-mediated endocytosis [28].
T80 8980-9144 Sentence denotes Membrane fusion takes place in the endosomal compartment after endocytosis, which needs additional triggers such as pH acidification or proteolytic activation [29].
T81 9145-9384 Sentence denotes Multiple cellular proteases, such as trypsin, furin, proprotein convertase (PC) family, cathepsins, transmembrane protease/serine (TMPRSS) proteases and elastase, are involved in S protein activation, which can induce membrane fusion [30].
T82 9385-9619 Sentence denotes Among them, cathepsin L, with anoptimal pH of 3.0 to 6.5, is most commonly associated with activation of a variety of CoV S proteins [30], such as SARS-CoV [19], MERS-CoV [31], HCoV-229E [32], and mouse hepatitis virus 2 (MHV-2) [33].
T83 9620-9782 Sentence denotes A recent study found that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, in which cathepsin L is critical for priming of SARS-CoV-2 S protein [24].
T84 9783-10132 Sentence denotes A study investigated the detailed mechanism of action of CQ/HCQ in inhibiting SARS-CoV-2 entry, and co-localization of SARS-CoV-2 with early endosomes (EEs) or endolysosomes (ELs) in VeroE6 cells, and the results showed that CQ/HCQ hampered the transport of SARS-CoV-2 from EEs to ELs, indicating that CQ/HCQ might inhibit endosomal maturation [17].
T85 10133-10396 Sentence denotes These studies revealed that the mechanism of anti-CoV activity of CQ/HCQ may involve the inhibition of the endosome acidification process, which might inactivate lysosomal proteases, thus interfering with the fusion of virus and host membranes [34,35] (Figure 1).
T86 10398-10404 Sentence denotes 4.1.3.
T87 10406-10466 Sentence denotes Effects on cell signaling pathway and host defense machinery
T88 10467-10643 Sentence denotes The mitogen-activated protein kinase (MAPK) pathway transmits signals from the cell surface to the nucleus involved in the infection of CoVs such as MHV [36] and SARS-CoV [37].
T89 10644-10783 Sentence denotes CQ could inhibit HCoV-229E replication in human embryonic lung epithelial cells (L132) through suppressing the activation of p38 MAPK [38].
T90 10784-10949 Sentence denotes Moreover, HCQ could markedly induce the production of cellular reactive oxygen species (ROS), which play an important role in the activation of innate immunity [39].
T91 10950-11107 Sentence denotes HCQ also could trigger the host defense mechanism through the mitochondrial antiviral signaling (MAVS) pathway, resulting in anti-dengue virus activity [39].
T92 11108-11268 Sentence denotes Therefore, CQ/HCQ may also exert their antiviral activity by suppressing the activation of p38 MAPK pathway and affecting the host defense machinery (Figure 1).
T93 11270-11274 Sentence denotes 4.2.
T94 11276-11338 Sentence denotes Inhibitory effect on T cell activation and cytokine production
T95 11339-11441 Sentence denotes CQ/HCQ regulate the release of various pro-inflammatory factors, which are important immunomodulators.
T96 11442-11627 Sentence denotes Intracellular alkalinization by CQ/HCQ inhibits lysosomal activity, preventing antigen processing, major histocompatibility complex (MHC) class II expression and immune activation [40].
T97 11628-11738 Sentence denotes This process can inhibit T cell activation and block expression of CD154 on the surface of CD4 + T cells [41].
T98 11739-11871 Sentence denotes CQ also reduces cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor-α (TNF-α) produced by T cells and B cells [42].
T99 11872-12062 Sentence denotes At the same time, changes of endosomal pH can interfere with Toll-like receptor (TLR) signaling, such as TLR7 and TLR9 processing, inhibiting the activation and production of cytokines [43].
T100 12063-12214 Sentence denotes CQ/HCQ also weaken the cyclic GMP-AMP (cGAMP) synthase (cGAS) activity by inhibiting cytosolic DNA, thereby reducing type I interferon production [44].
T101 12215-12363 Sentence denotes In vitro, CQ/HCQ can also inhibit phospholipase A2, altering the metabolism of arachidonic acid, and reducing the production of prostaglandins [45].
T102 12364-12659 Sentence denotes Some clinical studies have found that high concentrations of cytokines and pro-inflammatory factors such as IL-6 and IL-10 are elevated in the plasma of critically ill patients infected with SARS-CoV-2 [46,47], suggesting that cytokine release syndrome (CRS) is associated with disease severity.
T103 12660-12786 Sentence denotes In the aspect of immune response, HCQ/CQ therefore are likely to inhibit CRS, delaying the progression of COVID-19 (Figure 1).
T104 12788-12790 Sentence denotes 5.
T105 12792-12848 Sentence denotes Clinical efficacy of CQ/HCQ in the treatment of COVID-19
T106 12849-12948 Sentence denotes Only two published clinical reports have studied the efficacy of CQ in COVID-19 patients (Table 1).
T107 12949-13202 Sentence denotes One study used CQ to treat more than 100 patients with COVID-19 and claimed that CQ was superior to the control group in suppressing the deterioration of pneumonia, improving lung imaging, promoting viral conversion and shortening the course of disease.
T108 13203-13268 Sentence denotes Serious adverse effects were not observed in these patients [48].
T109 13269-13405 Sentence denotes However, this report did not provide any details about the study design and patient data, thus it is difficult to evaluate the validity.
T110 13406-13508 Sentence denotes Recently, a parallel, double-blind, randomized, phase IIB clinical trial was performed in Brazil [49].
T111 13509-13590 Sentence denotes In this study, 81 severe COVID-19 patients were randomly divided into two groups:
T112 13591-13758 Sentence denotes 41 patients received high-dose CQ (600 mg/2 times/day for 10 day) and 40 patients received low-dose CQ (450 mg/2 times on day 1 and then 450 mg/1 time/day for 4 days).
T113 13759-13870 Sentence denotes The 13-day mortality rate in the high-dose group was more than double that in low-dose group (39.0% vs. 16.0%).
T114 13871-14047 Sentence denotes The high-dosage group exhibited more instance of corrected QT (QTc) interval prolongation (>500 milliseconds (ms); 7 of 37 [18.9%]) than the low-dosage group (4 of 36 [11.1%]).
T115 14048-14170 Sentence denotes These findings suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 [49].
T116 14171-14179 Sentence denotes Table 1.
T117 14180-14289 Sentence denotes Outcomes and advantage/limitation of chloroquine (CQ)/hydroxychloroquine (HCQ) clinical studies for COVID-19.
T118 14290-14371 Sentence denotes Author (Reference) Study design Patients Treatment Outcomes Advantage Limitations
T119 14372-14387 Sentence denotes Gao et al [48].
T120 14388-14617 Sentence denotes Rough and simple description Not mentioned CQ (No specific dosage was mentioned) CQ was superior to control in suppressing pneumonia deterioration, improving lung imaging, promoting viral conversion and shortening disease course.
T121 14618-14634 Sentence denotes Not significant.
T122 14635-14761 Sentence denotes No study design and the specific number of patients and controls were provided and thus the result appears to be unconvincing.
T123 14762-14779 Sentence denotes Borba et al [49].
T124 14780-15266 Sentence denotes Randomized controlled trial High-dose CQ group: n = 40;Low-dose CQ group:n = 41 high-dose CQ (600 mg/2 times/day, for 10 day);low-dose CQ (450 mg/2 times/day for 5 days, double dose on 1st day) The mortality rate in the high-dose group was more than double that in low-dose group Double-blind study; 2 dosages of CQ for the first time in severe COVID-19 Small sample size; single-center design; Lack of a placebo control; Lack of exclusion criteria based on the QTc interval at baseline
T125 15267-15485 Sentence denotes Chen et al.[50] Randomized trial HCQ group: n = 31; control group: n = 30 HCQ (200 mg/2 times/day for 5 days) HCQ group have small improvement in body temperature and cough compered with control group Randomized trial.
T126 15486-15570 Sentence denotes Small sample size; Single-center design; Small improvement in temperature and cough.
T127 15571-15590 Sentence denotes Mahévas et al [53].
T128 15591-15809 Sentence denotes Comparative study HCQ group: n = 84; control group: n = 97 HCQ 600 mg/day for 7 days Compared with control group, a reduction of admissions to ICU or death 7 days after hospital admission was not observed in HCQ group.
T129 15810-15876 Sentence denotes Relatively larger sample size in HCQ treatment and control groups.
T130 15877-15987 Sentence denotes Nonrandomized design; In propensity score model, four possible important prognostic variables were unbalanced.
T131 15988-16004 Sentence denotes Tang et al [54].
T132 16005-16086 Sentence denotes Open label, randomized controlled trial HCQ group: n = 70; control group: n = 80.
T133 16087-16293 Sentence denotes HCQ 1200 mg daily for 3 days, 800 mg daily for 2 weeks (mild to moderate disease)/3 weeks(severe disease) HCQ did not show additional benefits of vial elimination in patients with mild to moderate COVID-19.
T134 16294-16322 Sentence denotes Randomized controlled study.
T135 16323-16521 Sentence denotes Lack of a placebo control group; Design introduces the possibility of biased investigator determined assessment and unbalanced dosage adjustment; Randomization of sequential envelopes may be biased.
T136 16522-16705 Sentence denotes The antiviral efficacy of HCQ was not assessed at an earlier stage; Most patients are mild to severe, and the effect of HCQ on disease progression or regression could not be provided.
T137 16706-16782 Sentence denotes The trial terminated early due to the difficulty to recruit enough patients.
T138 16783-16995 Sentence denotes Some secondary endpoints could not be analyzed by the cutoff date; Viral RNA specimens are mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.
T139 16996-17015 Sentence denotes Geleris et al [55].
T140 17016-17259 Sentence denotes Observational study HCQ group: n = 811; no-HCQ group: n = 565 HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) No correlation between the HCQ use and significant higher or lower risk of intubation or death was observed.
T141 17260-17431 Sentence denotes Large sample size; Minimization of the unmeasured confusion and error through multivariable Cox model with inverse probability weighting according to the propensity score.
T142 17432-17541 Sentence denotes Single-center design; missing of some variables; Potential for inaccuracies in the electronic health records.
T143 17542-17556 Sentence denotes Yu et al [56].
T144 17557-17731 Sentence denotes Retrospective study HCQ group: n = 48; no-HCQ group: n = 502 HCQ (200 mg/2 times/day, for 7 to 10 days) The fatalities of HCQ group was significantly lower than no-HCQ group.
T145 17732-17860 Sentence denotes HCQ treatment was related to significantly reduced mortality in critically ill COVID-19 patients and greatly lowered IL-6 level.
T146 17861-17951 Sentence denotes Mortality was used as a measure of outcome and the study included critically ill patients.
T147 17952-18033 Sentence denotes Retrospective design of the study and the number of HCQ group patients was small.
T148 18034-18304 Sentence denotes Gautret et al.[57] Open label, nonrandom cohort study HCQ group: n = 12; HCQ＋azithromycin group: n = 6; control group: n = 12 HCQ (200 mg/3 times/day for 10 days) HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days.
T149 18305-18366 Sentence denotes Nasopharyngeal virus determination was used as main endpoint.
T150 18367-18516 Sentence denotes Small sample size; Six patients dropped out due to critical illness or intolerance to the drug; Lack of clinical outcomes; Limited follow-up results.
T151 18517-18536 Sentence denotes Gautret et al [58].
T152 18537-18780 Sentence denotes Observational study HCQ group: n = 80; no control HCQ, 200 mg/3 times/day for 10 days combined with azithromycin 500 mg on the 1st day, 250 mg/day afterward for 5 days The nasopharynx viral load in most patients received HCQ decreased rapidly.
T153 18781-18819 Sentence denotes Observation of nasopharynx viral load.
T154 18820-18904 Sentence denotes Observational study design and no control group; No clinical outcomes were analyzed.
T155 18905-18952 Sentence denotes Possible confounding factors were not adjusted.
T156 18953-18974 Sentence denotes Magagnoli et al [59].
T157 18975-19071 Sentence denotes Retrospective study HCQ group:n = 97HCQ＋azithromycin: n = 113No HCQ group:n = 158 Not specified.
T158 19072-19294 Sentence denotes The use of HCQ, either with or without azithromycin, didn’t reduce the risk of mechanical ventilation in patients hospitalized with COVID-19; Patients treated with HCQ alone was associated with increased overall mortality.
T159 19295-19516 Sentence denotes The study data comes from a comprehensive electronic medical record; Strictly defined covariates and outcomes; Using propensity scores adjustment for a large number of relevant confounders to make results more persuasive.
T160 19517-19710 Sentence denotes Retrospective nature of the study; The subjects included only men and most of them were black; Despite adjustments to many possible confounding factors, there may still be undiscovered factors.
T161 19711-20217 Sentence denotes Rosenberg et al[60] Retrospective multicenter cohort study HCQ group:n = 271;HCQ ＋azithromycin group:n = 735control group:n = 221 HCQ:200 mg/400 mg/600 mg/other/unknown, frequency: once a day/twice a day/other/unknownazithromycin:200 mg/250 mg/400 mg/500 mg/other/unknown, methods:Oral/IV/unknown,frequency: only once/once a day/twice a day/other/unknown Treatment with HCQ, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality.
T162 20218-20300 Sentence denotes This study include a large, random sample from 25 metropolitan New York hospitals.
T163 20301-20465 Sentence denotes The sample was drawnearly in the epidemic to include patients with long, complicated, and ongoing hospital stays; In-hospital mortality was used as primary outcome.
T164 20466-20607 Sentence denotes Retrospective study design; There may be missing information; Mortality was limited to in-hospital death; There may be potential confounders.
T165 20608-20687 Sentence denotes The dosing in the doses and frequencies of HCQ and azithromycin varied greatly.
T166 20688-20747 Sentence denotes The confidence intervals for some of the findings are wide.
T167 20748-21206 Sentence denotes Mehraet al[61] Multinational real-world analysis Teatment groups: n = 14,888Control group: n = 81,144 Mean daily dose: CQ 765 mg, (SD 308); HCQ 596 mg(126); CQ with a macrolide 790 mg(320); HCQ with a macrolide 597 mg(128).mean duration:CQ 6.6 days(2.4); HCQ 4.2 days(1.9);CQ with a macrolide 6.8 days(2.5); HCQ with a macrolide 4.3 days (2.0) A benefit of HCQ or CQ, when used alone or witha macrolide, on in-hospital outcomes for COVID-19 was not observed.
T168 21207-21281 Sentence denotes Large multinational real-world data and large number of study populations.
T169 21282-21600 Sentence denotes There may be potential confounders; It did not measure QT intervals and stratify the arrhythmia pattern; It did not determine whether the increased risk of death in-hospital and use of drug treatment regimens were directly related to cardiovascular risk; It did not observe the risk of the drug dose-response analysis.
T170 21601-21686 Sentence denotes Several trials evaluated the efficacy of HCQ for the treatment of COVID-19 (Table 1).
T171 21687-21839 Sentence denotes In a randomized clinical trial from Wuhan about HCQ treatment of mild COVID-19 [50], 31 out of 62 patients received HCQ (200 mg/2 times/day for 5 days).
T172 21840-22195 Sentence denotes The results showed that the temperature recovery time in the HCQ group was improved compared with the control group (average days, 2.2 vs. 3.2); the cough relief time was shorter in the HCQ group than the control group (average days, 2.4 vs. 3.1); and the improvement rate of pneumonia in the HCQ group was higher than the control group (80.6% vs. 54.8%).
T173 22196-22358 Sentence denotes However, only 48% of patients (15/31) in HCQ group and 71% of patients (22/31) in control group had cough at baseline and the duration of cough was not described.
T174 22359-22435 Sentence denotes Improvement of symptoms were small and the trial was terminated prematurely.
T175 22436-22530 Sentence denotes These factors and the low sample size compromise the reliability of the results of this study.
T176 22531-22737 Sentence denotes Importantly, evaluation of HCQ in the COVID-19 pandemic areas have shown that HCQ can help patients with mild symptoms, and may potentially reduce transmission in areas lacking isolation facilities [51,52].
T177 22738-22922 Sentence denotes However, in areas with strict isolation standards, the use of HCQ to reduce transmission or for treatment of mild COVID-19 cases may not be beneficial in risk-benefit analysis [51,52].
T178 22923-23048 Sentence denotes Nevertheless, there is an urgent need for drugs and therapeutics in severe cases, which require randomized controlled trials.
T179 23049-23175 Sentence denotes A study from four French tertiary care centers included 181 patients hospitalized for COVID-19 and requiring oxygen (2 L/min):
T180 23176-23290 Sentence denotes 84 patients received HCQ (600 mg/day) within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group) [53].
T181 23291-23476 Sentence denotes The results showed that the patients transferred to the ICU or died within 7 days and developed ARDS within 7 days had no significant differences between the HCQ group and no-HCQ group.
T182 23477-23570 Sentence denotes Eight patients in the HCQ group (9.5%) discontinued HCQ due to electrocardiogram alterations.
T183 23571-23685 Sentence denotes These results do not support the use of HCQ for treating hospitalized COVID-19-related hypoxic pneumonia patients.
T184 23686-23893 Sentence denotes It is worth noting that in the study’s propensity score model, four possible important prognostic variables were unbalanced and a center effect was not considered, which all can cause bias for study results.
T185 23894-24188 Sentence denotes In a multicenter, randomized, parallel trial about HCQ in patients with mainly mild to moderate COVID-19 [54], 80 patients received ‘standard care’ and 70 patients received HCQ (1200 mg daily for 3 days, and then 800 mg daily for 2 weeks [mild to moderate disease] or 3 weeks [severe disease]).
T186 24189-24342 Sentence denotes The results showed that the 28-days negative conversion probability in ‘standard care’＋HCQ group was 85.4%, similar to the ‘standard care’ group (81.2%).
T187 24343-24444 Sentence denotes HCQ did not show additional benefits of viral elimination in patients with mild to moderate COVID-19.
T188 24445-24589 Sentence denotes However, the study could not evaluate the antiviral effect of HCQ at early stages of disease, which is a critical period of antiviral treatment.
T189 24590-24749 Sentence denotes In addition, viral RNA specimens were mostly from the upper respiratory tract rather than bronchoalveolar lavage fluid, which may cause false negative results.
T190 24750-24901 Sentence denotes Due to the small number of severe patients, this study could not provide evidence regarding the effect of HCQ on the disease progression or regression.
T191 24902-25138 Sentence denotes In another large observational study involving 1376 cases of COVID-19 from New York, 811 patients received HCQ (600 mg/2 times on the first day, then 400 mg once a day for 4 days) within 24 or 48 hours of admission and 565 did not [55].
T192 25139-25249 Sentence denotes This study found no correlation between HCQ use and significantly higher or lower risk of intubation or death.
T193 25250-25425 Sentence denotes However, in this study, even after the propensity score-matching, the diseases in patients receiving HCQ were more severe at baseline than those in the patients not receiving.
T194 25426-25575 Sentence denotes Notably, according to another recent study [56], low dose of HCQ reduced fatality of critically ill patients with COVID-19 without apparent toxicity.
T195 25576-25745 Sentence denotes This retrospective study included 550 patients who need mechanical ventilation, of which 48 received HCQ treatment (200 mg/2 times/day for 7 to 10 days) and 502 did not.
T196 25746-26036 Sentence denotes The fatalities of the HCQ group was significantly lower than no-HCQ group (18.8% vs 47.4%, P < 0.05), and the inflammatory cytokine IL-6 in the HCQ group decreased significantly from 22.2 (8.3 to 118.9 pg/mL) at the beginning of treatment to 5.2 (3.0 to 23.4 pg/mL) at the end of treatment.
T197 26037-26228 Sentence denotes The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19.
T198 26229-26341 Sentence denotes Yet, this study is flawed due to its retrospective nature and the small number of HCQ treated patients included.
T199 26342-26606 Sentence denotes In short, some initial studies have shown that HCQ appears to have a curative effect on patients with mild COVID-19, but subsequent studies indicate that HCQ had no significant benefit in COVID-19 patients with viral conversion and the risk of intubation or death.
T200 26607-26821 Sentence denotes Although some recent studies show that low-dose HCQ could potentially reduce the mortality of severe COVID-19 patients, there are other studies showing that the HCQ use had no effect on risk of intubation or death.
T201 26822-26968 Sentence denotes There are also several reports that investigated the efficacy of CQ or HCQ in combination with a macrolide in the treatment of COVID-19 (Table 1).
T202 26969-27152 Sentence denotes In an open nonrandom clinical trial conducted in France [57], of the 36 participants, 20 patients were given HCQ (200 mg/3 times) with 6 receiving added azithromycin, and 16 controls.
T203 27153-27317 Sentence denotes The results showed that compared with the control group, HCQ alone or in combination with azithromycin could effectively eliminate nasopharyngeal virus in 3–5 days.
T204 27318-27487 Sentence denotes On the 6th day after treatment, the virus clearance rates of HCQ combined with azithromycin, HCQ alone and controls were 100%, 57.1% and 12.5%, respectively (P < 0.001).
T205 27488-27600 Sentence denotes This study indicated that the combined application of azithromycin and HCQ appears to have a synergistic effect.
T206 27601-27810 Sentence denotes However, the trial design and the results were unreliable, as six patients in the HCQ group discontinued treatment early due to critical illness or intolerance to the drugs and were excluded from the analysis.
T207 27811-27894 Sentence denotes The assessment of efficacy was based on viral load rather than a clinical endpoint.
T208 27895-28240 Sentence denotes An observational study in 80 COVID-19 patients evaluated the efficacy of HCQ (200 mg/3 times/day for 10 days) in combination with azithromycin (500 mg on the first day, 250 mg/day afterward for 5 days) and showed that all patients’ clinical symptoms were improved, except for one patient aged over 86 years who died due to critical illness [58].
T209 28241-28413 Sentence denotes The nasopharynx viral load in most patients decreased rapidly, and the negative rates of viral nucleic acid conversion on days 7 and 8 were about 83% and 93%, respectively.
T210 28414-28507 Sentence denotes About 97.5% of patients had negative virus culture in respiratory specimens on the fifth day.
T211 28508-28600 Sentence denotes However, this study had no control group, thus the results were difficult to interpret [58].
T212 28601-28705 Sentence denotes Some recent studies have yielded different results about the efficacy of HCQ combined with azithromycin.
T213 28706-28982 Sentence denotes A retrospective study including 368 patients (97 patients received HCQ, 113 patients received HCQ + azithromycin and 158 patients received no HCQ) from USA [59] showed that the rates of ventilation in the HCQ, HCQ+azithromycin and no HCQ groups had no significant differences.
T214 28983-29114 Sentence denotes Unfortunately, theHCQ group (but not in the HCQ+azithromycin group) had a higher risk of death from any case than the no HCQ group.
T215 29115-29285 Sentence denotes This study showed no evidence that the use of HCQ, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with COVID-19.
T216 29286-29400 Sentence denotes Noticeably, in patients treated with HCQ alone, an association with increased overall mortality was observed [59].
T217 29401-29528 Sentence denotes In this study, the subjects included were only men and most of them were black, which may affect the generality of the results.
T218 29529-29640 Sentence denotes In addition, the patients who received HCQ or azithromycin were more severe, which may also affect the results.
T219 29641-29928 Sentence denotes In a retrospective multicenter cohort study of a random sample of COVID-19 patients from 25 hospitals in New York [60], totaling 1438 patients, 735 received HCQ and azithromycin, 271 received HCQ alone, 211 received azithromycin alone and 221 received neither drug (HCQ or azithromycin).
T220 29929-30108 Sentence denotes The results showed that the hospital mortality rate of patients receiving HCQ＋azithromycin was 25.7%, HCQ alone was 19.9%, azithromycin alone was 10.0% and neither drug was 12.7%.
T221 30109-30339 Sentence denotes In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in hospital mortality rate for patients receiving HC＋azithromycin, HCQ alone, or azithromycin alone.
T222 30340-30454 Sentence denotes In this study, the sample size is large and includes patients with long-term, complex and ongoing hospitalization.
T223 30455-30645 Sentence denotes However, the mortality rate of this study was limited to in-hospital deaths, and patients discharged during the study period were considered alive, which may underestimate the morality rate.
T224 30646-30838 Sentence denotes Recently, a multinational registry analysis about HCQ or CQ with or without second-generation macrolides (especial azithromycin and clarithromycin) for treatment of COVID-19 was reported [61].
T225 30839-30894 Sentence denotes A total of 96,032 patients were included in this study.
T226 30895-31050 Sentence denotes Of these, 1868 received CQ, 3783 received CQ with a macrolide, 3016 received HCQ and 6221 received HCQ with a macrolide and 8114 patients as control group.
T227 31051-31383 Sentence denotes After controlling various confounding factors related to disease, when compared with the mortality in the control group (9.3%), CQ group was 16.4%, CQ with a macrolide group was 22.2%, HCQ group was 18.0% and HCQ group with a macrolide was 23.8%; each group was associated with an increased risk of hospital mortality independently.
T228 31384-31644 Sentence denotes Apart from this, compared with the control group (0.3%), CQ group (4.3%), CQ with a macrolide group (6.5%), HCQ group (6.1%) and HCQ with a macrolide group (8.1%) were independently associated with a risk for ventricular arrhythmia during hospitalization [61].
T229 31645-31834 Sentence denotes This study showed that CQ or HCQ (used alone or combination with a macrolide) was associated with an increased hazard for in-hospital death and an increased risk of ventricular arrhythmias.
T230 31835-31925 Sentence denotes This study included a large number of patients, but it is not a randomized clinical trial.
T231 31926-32143 Sentence denotes In short, some small studies have shown that HCQ combined with azithromycin could quickly and effectively eliminate viruses, but the design of these studies was flawed in many aspects, making the results unconvincing.
T232 32144-32410 Sentence denotes Several subsequent studies have shown that the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) has no obvious correlation with a reduced risk for mechanical ventilation, and may even increase the risk of arrhythmia and in-hospital mortality.
T233 32411-32732 Sentence denotes In summary, although CQ/HCQ appeared to exhibit a favorable effect on COVID-19 patients in some initial studies of small numbers of patients, the most recent studies with larger sample sizes revealed that CQ/HCQ exhibited no significant improvement of disease but even an increased overall mortality in COVID-19 patients.
T234 32733-32858 Sentence denotes The studies on the combination of HCQ or CQ and macrolides (azithromycin or clarithromycin) also showed conflicting findings.
T235 32859-33049 Sentence denotes Therefore, caution should be taken regarding the use of CQ/HCQ treatment in COVID-19 due to the uncertainty of efficacy, the potential adverse effects and the various defects in the studies.
T236 33050-33313 Sentence denotes According to the Chinese Clinical Trial Registry (ChiCTR) (http://www.chictr.org.cn/index.aspx) and the International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), currently, there are more than 200 ongoing clinical trials for CQ/HCQ.
T237 33314-33476 Sentence denotes Current findings suggest that CQ/HCQ alone or in combination with macrolides should not be recommended for widespread use in COVID-19 (except in clinical trials).
T238 33477-33626 Sentence denotes Results from these ongoing prospective, randomized, controlled studies are required before these drugs are recommended for the treatment of COVID-19.
T239 33628-33630 Sentence denotes 6.
T240 33632-33638 Sentence denotes Safety
T241 33639-33734 Sentence denotes CQ/HCQ are basic medications for malaria with a long history of reliable safety records [3,62].
T242 33735-33855 Sentence denotes However, the therapeutic window of CQ is narrow, and the toxic dose is 3 times higher than the therapeutic dose [55,63].
T243 33856-33984 Sentence denotes The most common adverse effects of taking CQ are gastrointestinal discomforts, such as nausea, vomiting, diarrhea, and anorexia.
T244 33985-34056 Sentence denotes These symptoms are mild and can be controlled by reducing the dose [3].
T245 34057-34313 Sentence denotes However, long-term and high-dose CQ intake can cause irreversible damage to the ear, cardiovascular system, and blood system, such as neurological deafness, conduction disorder cardiomyopathy, and leukopenia, though these adverse effects are very rare [3].
T246 34314-34404 Sentence denotes Compared to CQ, HCQ has fewer adverse effects, which may be related to its lower toxicity.
T247 34405-34465 Sentence denotes In animal models, HCQ was about 40% less toxic than CQ [64].
T248 34466-34604 Sentence denotes Reportedly, only overdoses (average daily dose > 5.0 mg/kg) and long-time (more than 5 years) ingestion of HCQ can cause retinopathy [65].
T249 34605-34782 Sentence denotes CQ/HCQ have similar pharmacokinetic characteristics, fast absorption in the gastrointestinal tract, fast excretion in liver and kidney, and a long half-life (40–50 days) [3,66].
T250 34783-34853 Sentence denotes Therefore, liver and kidney dysfunction may aggravate adverse effects.
T251 34854-35030 Sentence denotes High-dose CQ (600 mg/2 times/day for 10 day) is associated with increased QTc interval prolongation in critically ill patients with COVID-19 [49] and should not be recommended.
T252 35031-35178 Sentence denotes In the initial trial from France, of the 84 patients receiving HCQ treatment, 8 patients discontinued HCQ owing to ECG modifications within 4 days.
T253 35179-35331 Sentence denotes Among them, 7 patients had a prolonged QTc interval more than 60 ms, and one patient developed a first-degree atrioventricular block within 2 days [53].
T254 35332-35471 Sentence denotes In a randomized clinical trial from Wuhan, 2 out of 31 patients receiving HCQ treatment had minor adverse effects (headache and rash) [50].
T255 35472-35558 Sentence denotes Prolonged QT interval after taking HCQ may also develop in ICU COVID-19 patients [67].
T256 35559-35808 Sentence denotes A recent observation showed that patients who received HCQ for the treatment of pneumonia associated with COVID-19 were at high risk of QTc prolongation (19%), and concurrent use of azithromycin was associated with greater changes in QTc (21%) [68].
T257 35809-36227 Sentence denotes Another observation in COVID-19 patients admitted to ICU showed that QTc intervals increased in 93% of patients receiving HCQ with or without azithromycin, prolonged QTc was observed in 36% of patients after a duration of the treatment for 2 to 5 days, and 6 of 18 (33%) patients treated with HCQ and azithromycin and 1 of 22 (5%) of those treated with HCQ alone developed an increase in QTc of 500 ms or greater [69].
T258 36228-36425 Sentence denotes The use of CQ, CQ with a macrolide, HCQ and HCQ with a macrolide were all found to be independently associated with increased risk for ventricular arrhythmia in hospitalized COVID-19 patients [61].
T259 36426-36540 Sentence denotes Therefore, clinicians should carefully weigh risks and benefits if considering CQ/HCQ with or without a macrolide.
T260 36541-36713 Sentence denotes When CQ/HCQ are used, electrocardiogram examination should be routinely performed before taking the medicine, with close monitoring of QTc and concomitant medication usage.
T261 36714-36919 Sentence denotes CQ/HCQ should be more cautiously used in patients with existing heart disease, and the use of QT interval prolonging drugs, such as antiarrhythmic drugs, antihistamines, and moxifloxacin should be avoided.
T262 36920-37078 Sentence denotes In addition, close attention should be paid to symptoms after taking drugs and the drugs should be stopped in time if there are intolerable adverse reactions.
T263 37079-37247 Sentence denotes In addition, CQ is extremely dangerous for patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency because of the possible induction of hemolytic anemia [70].
T264 37248-37436 Sentence denotes Therefore, more caution should be given for patients with G6PD deficiency when CQ is considered for the treatment and the best way should be to detect G6PD deficiency before the use of CQ.
T265 37438-37440 Sentence denotes 7.
T266 37442-37452 Sentence denotes Discussion
T267 37453-37511 Sentence denotes At present, the COVID-19 pandemic is continuing worldwide.
T268 37512-37609 Sentence denotes It is still an urgent need to find effective therapies and vaccines for treatment and prevention.
T269 37610-37736 Sentence denotes CQ/HCQ have diverse biological activities, and their mechanisms against CoVs including SARS-CoV-2 are not yet fully clarified.
T270 37737-37916 Sentence denotes Current studies show that CQ/HCQ can prevent receptor recognition by CoVs, inhibit endosome acidification, which interferes membrane fusion, and exhibit immunomodulatory activity.
T271 37917-38003 Sentence denotes These multiple mechanisms may work together to exert a therapeutic effect on COVID-19.
T272 38004-38165 Sentence denotes A number of in vitro studies have revealed that CQ/HCQ have inhibitory effects on various CoVs, including SARS-CoV [12,13], MERS-CoV [10] and SARS-CoV-2 [16–18].
T273 38166-38268 Sentence denotes However, conflicting results also exist on the in vitro activity of CQ/HCQ against SARS-CoV-2 [17,18].
T274 38269-38483 Sentence denotes Several clinical studies have shown that CQ/HCQ may alleviate the clinical symptoms of COVID-19, promote viral conversion, and delay the progression of the disease, with less serious adverse effects [48,50,57,58,].
T275 38484-38628 Sentence denotes However, previous studies showed that CQ had anti-Ebola virus activity in cell culture, but it had conflicting results in animal models [71,72].
T276 38629-38793 Sentence denotes In addition, CQ has shown beneficial results against chikungunya virus in vitro, but in animal models it aggravates the infection and lacks therapeutic effect [73].
T277 38794-39039 Sentence denotes More importantly, in recent studies the use of HCQ did not show any favorable effect on patients with COVID-19 and high-dose CQ treatment of severe COVID-19 patients may even increase the risks of mortality and QTc interval prolongation [49,55].
T278 39040-39127 Sentence denotes In addition, the optimal daily dose and duration of treatment course are not yet clear.
T279 39128-39289 Sentence denotes One study suggested that the dose of HCQ should be 400 mg/2 times for 1 day, 200 mg/2 times/day for 4 days based on the physiological pharmacokinetic model [18].
T280 39290-39626 Sentence denotes A prospective study of HCQ on COVID-19 patients (13 cases) admitted to the ICU in France showed that the first daily dose of 800 mg/1 time for 1 day, and 200 mg/2 times/day for 7 days was recommended to maintain the HCQ treatment level (1–2 mg/l) based on physiologically pharmacokinetic (PBPK) models for COVID-19 patients in ICU [67].
T281 39627-39719 Sentence denotes Whether the dosage of CQ or HCQ should be varied according disease severity is also unclear.
T282 39720-39835 Sentence denotes A rodent study showed that CQ could exert anti-HCoV-OC43 activity transplacentally or by way of maternal milk [14].
T283 39836-39991 Sentence denotes However, in humans, the efficacy of CQ in the prevention and treatment of SARS-CoV-2 infection to both the mother and the child remains to be investigated.
T284 39992-40169 Sentence denotes Clinical trials in France showed that HCQ combined with azithromycin could enhance the virus clearance [50], but the subsequent reports did not support this combination [59,61].
T285 40170-40340 Sentence denotes Furthermore, CQ/HCQ alone or in combination with a macrolide induced high rate of adverse effects, especially prolonged QTc, in the use for COVID-19 treatment [61,68,69].
T286 40341-40684 Sentence denotes Therefore, current data are not sufficient enough to support the routine use of CQ/HCQ as therapies for COVID-19 and increasing caution should be taken for the application of CQ/HCQ, alone or in combination with other drugs, in COVID-19 before the conclusive findings are obtained by well-designed, multicenter, randomized, controlled studies.