Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study
Identifieur interne : 001837 ( Pmc/Corpus ); précédent : 001836; suivant : 001838Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study
Auteurs : Lisi Deng ; Chunna Li ; Qi Zeng ; Xi Liu ; Xinghua Li ; Haitang Zhang ; Zhongsi Hong ; Jinyu XiaSource :
- The Journal of Infection [ 0163-4453 ] ; 2020.
Abstract
Patients were given oral arbidol and LPV/r in the combination group and oral LPV/r only in the monotherapy group for 5–21 days. Our study shows that oral arbidol and LPV/r in the combination group is associated with a significant elevated negative conversion rate of coronavirus’ test in 7-day and 14-day, compared with LPV/r only in the monotherapy group. Combination therapy is associated with a significantly improved the chest CT scans in 7-day. We suppose that reducing the viral load as soon as possible could benefit the delay of the progression of lung lesions.
Url:
DOI: 10.1016/j.jinf.2020.03.002
PubMed: 32171872
PubMed Central: 7156152
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study</title><author><name sortKey="Deng, Lisi" sort="Deng, Lisi" uniqKey="Deng L" first="Lisi" last="Deng">Lisi Deng</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Li, Chunna" sort="Li, Chunna" uniqKey="Li C" first="Chunna" last="Li">Chunna Li</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Zeng, Qi" sort="Zeng, Qi" uniqKey="Zeng Q" first="Qi" last="Zeng">Qi Zeng</name><affiliation><nlm:aff id="aff0002">Cancer Center, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Liu, Xi" sort="Liu, Xi" uniqKey="Liu X" first="Xi" last="Liu">Xi Liu</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Li, Xinghua" sort="Li, Xinghua" uniqKey="Li X" first="Xinghua" last="Li">Xinghua Li</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Zhang, Haitang" sort="Zhang, Haitang" uniqKey="Zhang H" first="Haitang" last="Zhang">Haitang Zhang</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Hong, Zhongsi" sort="Hong, Zhongsi" uniqKey="Hong Z" first="Zhongsi" last="Hong">Zhongsi Hong</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Xia, Jinyu" sort="Xia, Jinyu" uniqKey="Xia J" first="Jinyu" last="Xia">Jinyu Xia</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32171872</idno><idno type="pmc">7156152</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156152</idno><idno type="RBID">PMC:7156152</idno><idno type="doi">10.1016/j.jinf.2020.03.002</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">001837</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001837</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study</title><author><name sortKey="Deng, Lisi" sort="Deng, Lisi" uniqKey="Deng L" first="Lisi" last="Deng">Lisi Deng</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Li, Chunna" sort="Li, Chunna" uniqKey="Li C" first="Chunna" last="Li">Chunna Li</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Zeng, Qi" sort="Zeng, Qi" uniqKey="Zeng Q" first="Qi" last="Zeng">Qi Zeng</name><affiliation><nlm:aff id="aff0002">Cancer Center, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Liu, Xi" sort="Liu, Xi" uniqKey="Liu X" first="Xi" last="Liu">Xi Liu</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Li, Xinghua" sort="Li, Xinghua" uniqKey="Li X" first="Xinghua" last="Li">Xinghua Li</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Zhang, Haitang" sort="Zhang, Haitang" uniqKey="Zhang H" first="Haitang" last="Zhang">Haitang Zhang</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Hong, Zhongsi" sort="Hong, Zhongsi" uniqKey="Hong Z" first="Zhongsi" last="Hong">Zhongsi Hong</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author><author><name sortKey="Xia, Jinyu" sort="Xia, Jinyu" uniqKey="Xia J" first="Jinyu" last="Xia">Jinyu Xia</name><affiliation><nlm:aff id="aff0001">Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Infection</title><idno type="ISSN">0163-4453</idno><idno type="eISSN">1532-2742</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Highlights</title><p><list list-type="simple" id="celist0001"><list-item id="celistitem0001"><label>•</label><p id="para0002">Patients were given oral arbidol and LPV/r in the combination group and oral LPV/r only in the monotherapy group for 5–21 days.</p></list-item><list-item id="celistitem0002"><label>•</label><p id="para0003">Our study shows that oral arbidol and LPV/r in the combination group is associated with a significant elevated negative conversion rate of coronavirus’ test in 7-day and 14-day, compared with LPV/r only in the monotherapy group.</p></list-item><list-item id="celistitem0003"><label>•</label><p id="para0004">Combination therapy is associated with a significantly improved the chest CT scans in 7-day.</p></list-item><list-item id="celistitem0004"><label>•</label><p id="para0005">We suppose that reducing the viral load as soon as possible could benefit the delay of the progression of lung lesions.</p></list-item></list></p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Wang, D" uniqKey="Wang D">D. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Infect</journal-id><journal-id journal-id-type="iso-abbrev">J. Infect</journal-id><journal-title-group><journal-title>The Journal of Infection</journal-title></journal-title-group><issn pub-type="ppub">0163-4453</issn><issn pub-type="epub">1532-2742</issn><publisher><publisher-name>The British Infection Association. Published by Elsevier Ltd.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32171872</article-id><article-id pub-id-type="pmc">7156152</article-id><article-id pub-id-type="publisher-id">S0163-4453(20)30113-4</article-id><article-id pub-id-type="doi">10.1016/j.jinf.2020.03.002</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study</article-title></title-group><contrib-group><contrib contrib-type="author" id="au0001"><name><surname>Deng</surname><given-names>Lisi</given-names></name><xref rid="aff0001" ref-type="aff">a</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au0002"><name><surname>Li</surname><given-names>Chunna</given-names></name><xref rid="aff0001" ref-type="aff">a</xref><xref rid="fn1" ref-type="fn">1</xref></contrib><contrib contrib-type="author" id="au0003"><name><surname>Zeng</surname><given-names>Qi</given-names></name><xref rid="aff0002" ref-type="aff">b</xref></contrib><contrib contrib-type="author" id="au0004"><name><surname>Liu</surname><given-names>Xi</given-names></name><xref rid="aff0001" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0005"><name><surname>Li</surname><given-names>Xinghua</given-names></name><xref rid="aff0001" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0006"><name><surname>Zhang</surname><given-names>Haitang</given-names></name><xref rid="aff0001" ref-type="aff">a</xref></contrib><contrib contrib-type="author" id="au0007"><name><surname>Hong</surname><given-names>Zhongsi</given-names></name><email>hongzhs@mail.sysu.edu.cn</email><xref rid="aff0001" ref-type="aff">a</xref><xref rid="cor0001" ref-type="corresp">⁎</xref></contrib><contrib contrib-type="author" id="au0008"><name><surname>Xia</surname><given-names>Jinyu</given-names></name><email>xiajinyu@mail.sysu.edu.cn</email><xref rid="aff0001" ref-type="aff">a</xref><xref rid="cor0001" ref-type="corresp">⁎</xref></contrib></contrib-group><aff id="aff0001"><label>a</label>Department of Infectious Diseases, the Fifth Affiliated Hospital, Sun Yat-sen University, 52 East Meihua Road, Zhuhai 519000, Guangdong Province, China</aff><aff id="aff0002"><label>b</label>Cancer Center, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province, China</aff><author-notes><corresp id="cor0001"><label>⁎</label>Corresponding authors. <email>hongzhs@mail.sysu.edu.cn</email><email>xiajinyu@mail.sysu.edu.cn</email></corresp><fn id="fn1"><label>1</label><p id="notep0001">Equal contribution.</p></fn></author-notes><pub-date pub-type="pmc-release"><day>11</day><month>3</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="epub"><day>11</day><month>3</month><year>2020</year></pub-date><history><date date-type="accepted"><day>6</day><month>3</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder></copyright-holder><license><license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p></license></permissions><abstract abstract-type="author-highlights" id="abs0001"><title>Highlights</title><p><list list-type="simple" id="celist0001"><list-item id="celistitem0001"><label>•</label><p id="para0002">Patients were given oral arbidol and LPV/r in the combination group and oral LPV/r only in the monotherapy group for 5–21 days.</p></list-item><list-item id="celistitem0002"><label>•</label><p id="para0003">Our study shows that oral arbidol and LPV/r in the combination group is associated with a significant elevated negative conversion rate of coronavirus’ test in 7-day and 14-day, compared with LPV/r only in the monotherapy group.</p></list-item><list-item id="celistitem0003"><label>•</label><p id="para0004">Combination therapy is associated with a significantly improved the chest CT scans in 7-day.</p></list-item><list-item id="celistitem0004"><label>•</label><p id="para0005">We suppose that reducing the viral load as soon as possible could benefit the delay of the progression of lung lesions.</p></list-item></list></p></abstract><abstract id="abs0002"><title>Summary</title><sec><title>Background</title><p>Corona Virus Disease 2019 (COVID-19) due to the 2019 novel coronavirus (SARS-CoV-2) emerged in Wuhan city and rapidly spread throughout China. We aimed to compare arbidol and lopinavir/ritonavir(LPV/r) treatment for patients with COVID-19 with LPV/r only.</p></sec><sec><title>Methods</title><p>In this retrospective cohort study, we included adults (age≥18years) with laboratory-confirmed COVID-19 without Invasive ventilation, diagnosed between Jan 17, 2020, and Feb 13, 2020. Patients, diagnosed after Jan 17, 2020, were given oral arbidol and LPV/r in the combination group and oral LPV/r only in the monotherapy group for 5–21 days. The primary endpoint was a negative conversion rate of coronavirus from the date of COVID-19 diagnosis(day7, day14), and assessed whether the pneumonia was progressing or improving by chest CT (day7).</p></sec><sec><title>Results</title><p>We analyzed 16 patients who received oral arbidol and LPV/r in the combination group and 17 who oral LPV/r only in the monotherapy group, and both initiated after diagnosis. Baseline clinical, laboratory, and chest CT characteristics were similar between groups. The SARS-CoV-2 could not be detected for 12(75%) of 16 patients’ nasopharyngeal specimens in the combination group after seven days, compared with 6 (35%) of 17 in the monotherapy group (<italic>p</italic> < 0·05). After 14 days, 15 (94%) of 16 and 9 (52·9%) of 17, respectively, SARS-CoV-2 could not be detected (<italic>p</italic> < 0·05). The chest CT scans were improving for 11(69%) of 16 patients in the combination group after seven days, compared with 5(29%) of 17 in the monotherapy group (<italic>p</italic> < 0·05).</p></sec><sec><title>Conclusion</title><p>In patients with COVID-19, the apparent favorable clinical response with arbidol and LPV/r supports further LPV/r only.</p></sec></abstract><kwd-group id="keys0001"><title>Keywords</title><kwd>Corona Virus Disease 2019</kwd><kwd>Arbidol</kwd><kwd>Lopinavir/ritonavir</kwd><kwd>Antiviral intervention</kwd><kwd>Combination therapy</kwd></kwd-group></article-meta></front><body><sec id="sec0001"><title>Introduction</title><p id="para0010">Since it was first described in December 2019, more than seventy thousand cases of Corona Virus Disease 2019 (COVID-19) have been confirmed, beyond two thousand patients of which were fatal.<xref rid="bib0001" ref-type="bibr">1</xref>, <xref rid="bib0002" ref-type="bibr">2</xref>, <xref rid="bib0003" ref-type="bibr">3</xref>, <xref rid="bib0004" ref-type="bibr">4</xref> So far, the infection keeps spreading, and more and more exported cases were confirmed in other provinces in China, and other countries. Indicating that the disease is a serious threat to global health.<xref rid="bib0005" ref-type="bibr"><sup>5,</sup></xref><xref rid="bib0006" ref-type="bibr"><sup>6</sup></xref> The management of patients with COVID-19 consists of a combination of supportive measures, antimicrobial therapy for any associated bacterial or viral infections, and strict implementation of appropriate infection control precautions.<xref rid="bib0001" ref-type="bibr">1</xref>, <xref rid="bib0002" ref-type="bibr">2</xref>, <xref rid="bib0003" ref-type="bibr">3</xref>, <xref rid="bib0004" ref-type="bibr">4</xref></p><p id="para0011">The number of this disease is still multiplying, and effective antiviral treatment is therefore required urgently.<xref rid="bib0005" ref-type="bibr"><sup>5,</sup></xref><xref rid="bib0006" ref-type="bibr"><sup>6</sup></xref> It has been hypothesized that the immunopathological response was triggered by the viral antigen; the most strategic treatment was, therefore, to stop the viral replication at the beginning so that the peak viral load and the subsequent immunopathological damage will be minimised.<xref rid="bib0007" ref-type="bibr"><sup>7</sup></xref></p><p id="para0012">We report the findings of Results and outcomes in patients with COVID-19 that compare a combination of arbidol and lopinavir/ritonavir(LPV/r) against LPV/r only. Placebo-controlled studies are difficult to perform in an epidemic of such a life-threatening condition.<xref rid="bib0007" ref-type="bibr"><sup>7</sup></xref></p></sec><sec id="sec0002"><title>Methods</title><sec id="sec0003"><title>Study design and participants</title><p id="para0013">This single-center, retrospective cohort study included individuals who were diagnosed with laboratory-confirmed COVID-19 between Jan 17, 2020, and Feb 13, 2020, at The Fifth Affiliated Hospital of Sun Yat-Sen University. Eligible patients were those aged 18 years or older with pneumonia without Invasive or non-invasive ventilation. No other exclusion criteria were applied at this stage.</p><p id="para0014">COVID-19 was diagnosed by real-time reverse-transcriptase polymerase-chain-reaction (RT-PCR) assay for nasal and pharyngeal swab specimens.<xref rid="bib0007" ref-type="bibr"><sup>7</sup></xref> Only the laboratory-confirmed cases were included in the analysis. All patients with COVID-19 enrolled in this study were diagnosed according to World Health Organization interim guidance.<xref rid="bib0008" ref-type="bibr"><sup>8</sup></xref></p><p id="para0015">From Jan 17, 2020, all eligible patients were offered treatment with arbidol and LPV/r in combination group or oral LPV/r only in monotherapy group, after informed consent had been obtained from the patients themselves or their next of kin. The treatment protocol was approved by Pharmacy and Therapeutics Committee. The study was approved by The Research Ethics Committee at the The Fifth Affiliated Hospital of Sun Yat-Sen University to allow retrospective access to patients’ records and files (No·ZDWY[2020] Lunzi No·K22-1).</p></sec><sec id="sec0004"><title>Procedures</title><p id="para0016">Once the nasopharyngeal specimens were positive for SARS-CoV-2 tested by RT-PCR for patients with COVID-19 and patients with abnormal radiological findings, oral drugs were given. We strictly manage all patients, regardless of the severity of the illness, carefully monitor the laboratory examination and chest CT scans. Specifically, arbidol was given at a dose of 200 mg every 8 h and lopinavir (400 mg)/ritonavir (100 mg) orally every 12 h until coronavirus is detected negative by RT-PCR for tree times. The administration period is about 5–21 days. All patients received appropriate supportive care and regular clinical and laboratory monitoring. Normal renal function, liver enzymes, and blood count were assessed at baseline and every other day throughout the treatment course. RT-PCR was performed for nasopharyngeal specimens every other day and daily once negative for SARS-CoV-2′s test after admission to hospital, it was tested daily for stools. In addition to stools were collected from all 33 patients for RT-PCR analysis, and the chest CT scans were performed at days 1, 4, 7,10 and 14 . All patients were monitored for any clinical signs of depression or acute confusion.</p></sec><sec id="sec0005"><title>Outcomes</title><p id="para0017">The primary endpoint was a negative conversion rate of SARS-CoV-2 from the date of COVID-19 diagnosis(day7, day14), and assessed whether the pneumonia was progressing or improving by chest CT (day7).</p></sec><sec id="sec0006"><title>Statistical analysis</title><p id="para0018">We used χ² and Fischer's exact tests for categorical variables, whereas we used the student's <italic>t</italic>-test for continuous variables to assess the differences in means of the two groups. The graphical and statistical tests suggested that the proportional hazard assumption was not violated. We did statistical analyses using SPSS software version 13·0(SPSS, Chicago, Illinois). The significance for all statistical analyses was defined as <italic>p</italic> < 0·050.</p></sec></sec><sec id="sec0007"><title>Results</title><p id="para0019">Fifty-six individuals(age≥18years) were diagnosed with COVID-19 infection between Jan 17, 2020, and Feb 13, 2020. Recent research has reported that,<xref rid="bib0004" ref-type="bibr"><sup>4</sup></xref> 82·1% and 36·2% of patients had lymphopenia and thrombocytopenia, respectively. Overall, leukopenia was observed in 33·7% of patients. Most patients demonstrated high levels of C-reactive protein, but high levels of alanine aminotransferase, aspartate aminotransferase, creatine kinase and D-dimer were less common. Similar characteristics were observed in all patients. Furthermore, we found that stools of 25(45%) in 56 patients were positive for SARS-CoV-2′s test by RT-PCR. In addition to that, 50% of patients’ counts of peripheral CD4 and CD8 T cells were reduced by flow cytometric analysis.</p><p id="para0020">Baseline characteristics were generally similar between patients who received oral arbidol and LPV/r therapy, and those who received oral LPV/r only (<xref rid="tbl0001" ref-type="table">Table 1</xref>), with the exception that organ dysfunction was present in four patients who were admitted and transferred to the ICU, ten patients treated with other antiviral drugs(the data are not yet public)and no abnormal radiological findings was present in nine patients (<xref rid="fig0001" ref-type="fig">Fig. 1</xref>). After excluding ineligible patients, 33 patients were included in the study. The mean age of all 33 patients was 44·56 years (SD 15·73), and 17 (52%) were men (<xref rid="tbl0001" ref-type="table">Table 1</xref>). The median number of comorbidities was 0·7 (range 0–2). Mean blood indices on the day of COVID-19 diagnosis include peripheral white cell count 5·19 × 10⁹/L (SD 1·47 × 10⁹/L), lymphocyte count 1·59 × 10⁹/L (0·71 × 10⁹/L), platelets 196·59 × 10⁹/L (64·76 × 10⁹/L), bilirubin 9·39 µmol/L (4·76 µmol/L). Overall, 11 (33%) of 33 patients needed a double nasal catheter for oxygen, 24 (73%) of all patients received Immunoglobulin therapy, and 20 (61%) received broad-spectrum antibacterial therapy.<table-wrap position="float" id="tbl0001"><label>Table 1</label><caption><p>Baseline characteristics on day of diagnosis of Corona Virus Disease 2019, by patient group.</p></caption><alt-text id="alt0004">Table 1</alt-text><table frame="hsides" rules="groups"><thead><tr><th valign="top"></th><th valign="top">Combination group (<italic>n</italic> = 16)</th><th valign="top">Monotherapy group (<italic>n</italic> = 17)</th><th valign="top"><italic>p</italic> value</th></tr></thead><tbody><tr><td valign="top">Men</td><td valign="top">7(43·8%)</td><td valign="top">10 (58·8%)</td><td valign="top">0·494</td></tr><tr><td valign="top">Age, years</td><td valign="top">41·8(14·08)</td><td valign="top">47·25(17·25)</td><td valign="top">0·08</td></tr><tr><td valign="top">Chronic obstructive pulmonary disease</td><td valign="top">0</td><td valign="top">1(5·9%)</td><td valign="top">1·00</td></tr><tr><td valign="top">Chronic liver disease</td><td valign="top">1(6·2%)</td><td valign="top">2(11·7%)</td><td valign="top">1·00</td></tr><tr><td valign="top">Diabetes mellitus</td><td valign="top">2(12·5%)</td><td valign="top">3(17·6%)</td><td valign="top">1·00</td></tr><tr><td valign="top">Coronary heart disease</td><td valign="top">2(12·5%)</td><td valign="top">3(17·6%)</td><td valign="top">1·00</td></tr><tr><td valign="top">Hypertension</td><td valign="top">3(18·8%)</td><td valign="top">2(11·7%)</td><td valign="top">1·00</td></tr><tr><td valign="top">Malignant disorder</td><td valign="top">0</td><td valign="top">0</td><td valign="top"></td></tr><tr><td valign="top">Obesity</td><td valign="top">2(12·5%)</td><td valign="top">1(5·9%)</td><td valign="top">1·00</td></tr><tr><td valign="top">HIV infection</td><td valign="top">0</td><td valign="top">0</td><td valign="top"></td></tr><tr><td valign="top">Number of comorbidities</td><td valign="top">0–2</td><td valign="top">0–2</td><td valign="top"></td></tr><tr><td valign="top">Peripheral white cell count (× 10⁹/L)</td><td valign="top">5·34(1·82)</td><td valign="top">5·04(1·08)</td><td valign="top">0·11</td></tr><tr><td valign="top">Lymphocyte count (× 10⁹/L)</td><td valign="top">1·83(0·82)</td><td valign="top">1·36(0·52)</td><td valign="top">0·11</td></tr><tr><td valign="top">Platelet count (× 10⁹/L)</td><td valign="top">194·8(55·1)</td><td valign="top">198·6(77·2)</td><td valign="top">0·69</td></tr><tr><td valign="top">Serum bilirubin (µmol/L)</td><td valign="top">9·23(4·97)</td><td valign="top">9·51(4·86)</td><td valign="top">0·55</td></tr><tr><td valign="top">Lung “total severity score” in “4"</td><td valign="top">5(31·2%)</td><td valign="top">6(35·3%)</td><td valign="top">0·875</td></tr><tr><td valign="top">Tested positive in stool</td><td valign="top">8(50·0%)</td><td valign="top">10(58·9%)</td><td valign="top">0·732</td></tr><tr><td colspan="4" align="left" valign="top">Data are number (%) or mean (SD).</td></tr></tbody></table></table-wrap><fig id="fig0001"><label>Fig. 1</label><caption><p>Study profile.</p></caption><alt-text id="alt0001">Fig 1</alt-text><graphic xlink:href="gr1_lrg"></graphic></fig></p><p id="para0021">An overall lung “total severity score” was reached by summing the five lobe scores. Each of the five lung lobes was assessed for degree of involvement and classified as none (0%), minimal (1 - 25%), mild (26 - 50%), moderate (51 - 75%), or severe (76 - 100%). None corresponded to a lobe score of 0, minimal to a lobe score of 1, mild to a lobe score of 2, moderate to a lobe score of 3, and severe to a lobe score of 4.<xref rid="bib0009" ref-type="bibr"><sup>9,</sup></xref><xref rid="bib0010" ref-type="bibr"><sup>10</sup></xref> 5 (31%) of 16 patients reached a lobe score of 4 in the combination group and 6(35%) of 17 in the monotherapy group in baseline characteristics, and there is no statistically significant differences between two groups (<xref rid="tbl0001" ref-type="table">Table 1</xref>). However, 1(6%) of 16 received corticosteroid therapy in the combination group compared with 7 (41%) of 17 in the monotherapy group (<italic>p</italic> < 0·05) (<xref rid="tbl0002" ref-type="table">Table 2</xref>). But, no other statistically significant differences in baseline characteristics or support measures were noted between the two groups (<xref rid="tbl0001" ref-type="table">Tables 1</xref> and <xref rid="tbl0002" ref-type="table">2</xref>).<table-wrap position="float" id="tbl0002"><label>Table 2</label><caption><p>Support measures offered and Laboratory indices during the course of Corona Virus Disease 2019, by patient group.</p></caption><alt-text id="alt0005">Table 2</alt-text><table frame="hsides" rules="groups"><thead><tr><th valign="top"></th><th valign="top">Combination group (<italic>n</italic> = 16)</th><th valign="top">Monotherapy group (<italic>n</italic> = 17)</th><th valign="top"><italic>p</italic> value</th></tr></thead><tbody><tr><td valign="top">Double nasal catheter for oxygen</td><td valign="top">5(31·2%)</td><td valign="top">6(35·3%)</td><td valign="top">0·72</td></tr><tr><td valign="top">Immunoglobulin therapy</td><td valign="top">11(68·8%)</td><td valign="top">13(76·5%)</td><td valign="top">0·71</td></tr><tr><td valign="top">Corticosteroid therapy</td><td valign="top">1(6·2%)</td><td valign="top">7(41·2%)</td><td valign="top">0·04</td></tr><tr><td valign="top">Number of antibacterial therapy agents</td><td valign="top">9(56·3%)</td><td valign="top">12(70·6%)</td><td valign="top">0·48</td></tr><tr><td valign="top">Invasive ventilation</td><td valign="top">0</td><td valign="top">0</td><td valign="top"></td></tr><tr><td valign="top">Vasopressor therapy</td><td valign="top">0</td><td valign="top">0</td><td valign="top"></td></tr><tr><td valign="top">Peripheral white cell count, minimum (× 10⁹/L)</td><td valign="top">7(43·8%)</td><td valign="top">10 (58·8%)</td><td valign="top">0·494</td></tr><tr><td valign="top">Minimum lymphocyte count, minimum (× 10⁹/L)</td><td valign="top">41·8(14·08)</td><td valign="top">47·25(17·25)</td><td valign="top">0·08</td></tr><tr><td valign="top">Platelet count, minimum (× 10⁹/L)</td><td valign="top">0</td><td valign="top">1(5·9%)</td><td valign="top">1·00</td></tr><tr><td valign="top">Serum bilirubin, maximum (µmol/L)</td><td valign="top">1(6·2%)</td><td valign="top">2(11·7%)</td><td valign="top">1·00</td></tr><tr><td colspan="4" align="left" valign="top">Data are number (%) or mean (SD).</td></tr></tbody></table></table-wrap></p><p id="para0022">After treatment for 7 days, 12 (75%) of 16 patients’ nasopharyngeal specimens were negative for SARS-CoV-2′s test by RT-PCR in the combination group, compared with 6 (35%) of 17 in the monotherapy group (<italic>p</italic> < 0·05, <xref rid="fig0002" ref-type="fig">Fig. 2</xref>). After 14 days, 15 (94%) of 16 and 9 (53%) of 17, respectively, coronavirus could not be detected (<italic>p</italic> < 0·05, <xref rid="fig0002" ref-type="fig">Fig. 2</xref>). Furthermore, the chest CT scans were improving for 11 (69%) of 16 patients in the combination group after 7 days, compared with 5 (29%) of 17 in the monotherapy group (<italic>p</italic> < 0·05, <xref rid="fig0003" ref-type="fig">Fig. 3</xref>). However, three patients in the monotherapy group were still positive for the stools’ test and one in the combination group (<italic>p</italic> > 0·05, <xref rid="fig0003" ref-type="fig">Fig. 3</xref>). No other significant differences in laboratory indices between the two groups were noted during the treatment period.<fig id="fig0002"><label>Fig. 2</label><caption><p>Nasopharyngeal swab tests of SARS-CoV-2 nucleic acid by RT-PCR between two grous. Note: C refer to combination group; M refers to monotherapy group.</p></caption><alt-text id="alt0002">Fig 2</alt-text><graphic xlink:href="gr2_lrg"></graphic></fig><fig id="fig0003"><label>Fig. 3</label><caption><p>(A) Chest CT imaging changes between two groups; (B) Stool specimen tests for SARS-CoV-2 nucleic acid . Note: C refers to combination group; M refers to monotherapy group.</p></caption><alt-text id="alt0003">Fig 3</alt-text><graphic xlink:href="gr3_lrg"></graphic></fig></p><p id="para0023">During the treatment period, 68·7% of patients demonstrated elevated levels of bilirubin, mean of top bilirubin was 25·26 µmol/L (10·61 µmol/L) (<xref rid="tbl0002" ref-type="table">Table 2</xref>). 43·7% of patients demonstrated digestive upsets, such as mild diarrhea and nausea, but all patients had no premature discontinuation secondary to adverse effects. Depression or acute confusion was not diagnosed in any of the patients in either group.</p></sec><sec id="sec0008"><title>Discussion</title><p id="para0024">Effective treatment interventions for patients with severe COVID-19 are still urgently needed. Patients with SARS treated with LPV/r appeared to reduce the viral load, and LPV/r was recommended for patients with MERS-CoV.<xref rid="bib0007" ref-type="bibr"><sup>7,</sup></xref><xref rid="bib0011" ref-type="bibr"><sup>11</sup></xref> Arbidol and arbidol mesylate were shown to have a direct antiviral effect in early viral replication in vitro for SARS-CoV.<xref rid="bib0012" ref-type="bibr"><sup>12,</sup></xref><xref rid="bib0013" ref-type="bibr"><sup>13</sup></xref> It has been implied that there was a therapeutic window that could be exploited, provided an active antiviral agent was available.<xref rid="bib0014" ref-type="bibr"><sup>14</sup></xref> The fundamental strategy in the treatment of coronavirus is, therefore, to find an effective antiviral agent that would decrease the peak viral load and thus, the associated degree of immunopathological damage.<xref rid="bib0014" ref-type="bibr"><sup>14</sup></xref> In typical patients without Invasive ventilation, our study shows that oral arbidol and LPV/r in the combination group is associated with a significant elevated negative conversion rate of coronavirus’ test in 7-day and 14-day, compared with LPV/r only in the monotherapy group. Furthermore, combination therapy is associated with a significantly improved the chest CT scans in 7-day. Fortunately, all the patients did not develop acute respiratory failure during the treatment period, but it was not clear whether it was an effect of antiviral drug.</p><p id="para0025">According to that, we suppose that reducing the viral load as soon as possible could benefit the delay of the progression of lung lesions.Stools of a portion of patients were positive for SARS-CoV-2′s test by RT-PCR. And a few cases, patients in the monotherapy group tested remained positive for SARS-CoV-2 in stools after showing negative in respiratory samples. Chest CT scans may be a better way to assess the effect of treatment compared to nasopharyngeal specimens test for coronavirus.</p><p id="para0026">It has been proved that SARS-CoV-2 uses ACE2 as a viral receptor for entry process.<xref rid="bib0015" ref-type="bibr"><sup>15,</sup></xref><xref rid="bib0016" ref-type="bibr"><sup>16</sup></xref> ACE2 mRNA is highly expressed in the gastrointestinal system, providing a prerequisite for SARS-CoV-2 infection.<xref rid="bib0017" ref-type="bibr"><sup>17</sup></xref> About 40% of a total intake dose of arbidol is excreted unchanged within 48 h, mainly with feces (38·9%) and much less with urine (0·12%),<xref rid="bib0018" ref-type="bibr"><sup>18</sup></xref> and 20% of the LPV/r is found unchanged in the stool.<xref rid="bib0019" ref-type="bibr"><sup>19</sup></xref> Oral arbidol combine with LPV/r may achieve a high fecal concentration to stop viral replication at this site. Combination therapy may likely be preferred in patients with stool tested positive.</p><p id="para0027">The physical and biochemical examination of main organs and systems did not reveal any significant differences between arbidol-treated and control groups, indicating good tolerability and safety of arbidol in humans.<xref rid="bib0020" ref-type="bibr"><sup>20</sup></xref> Gastrointestinal symptoms, such as diarrhea and nausea, and elevated levels of bilirubin, are well-recognized complication of LPV/r therapy and was noted previously.<xref rid="bib0021" ref-type="bibr"><sup>21</sup></xref> Treatment with arbidol and LPV/r was well tolerated in our study.</p><p id="para0028">43% of patients received corticosteroid therapy in the monotherapy group, nevertheless (31%) had improved the chest CT scans in day 7. It is likely that corticosteroids didn't conducive to the recovery of lung injury. The use of corticosteroids is controversial. It had been reviewed that although the glucocorticoid group was younger and had fewer underlying diseases, it had more adverse outcomes, increasing the risk of ICU admission and mortality for patients with SARS receiving hormone therapy.<xref rid="bib0022" ref-type="bibr"><sup>22</sup></xref> Glucocorticoids could delay the clearance of coronavirus nucleic acids without lower mortality for patients with MERS-CoV infection.<xref rid="bib0023" ref-type="bibr"><sup>23</sup></xref></p><p id="para0029">One of the limitations of our study is its small size. Our review, albeit little, is the most significant clinical investigation so far to assess the use of this combination in the treatment of patients with COVID-19. Although baseline characteristics of our treatment and comparator groups seem to be reasonably balanced, substantial differences might not be apparent because of the small number of patients in the study. Our review is also limited by its retrospective, nonrandomized nature, Inevitably, selection and unmeasured confounding bias cannot be excluded entirely. There could be a few alternative interpretations of the results. Undoubtedly, new interventions should ideally be assessed in randomized, controlled clinical trials. However, such an approach is generally accepted to not always be practically feasible in the context of an emerging and relatively uncommon disease such as MERS-CoV infection at the very beginning.<xref rid="bib0024" ref-type="bibr"><sup>24</sup></xref></p><p id="para0030">We selected our control group carefully, ensuring that the two cohorts were matched as closely as possible in their clinical characteristics, treatment interventions, and chest CT images other than the receipt of arbidol and LPV/r. We removed four individuals be admitted and transferred to the ICU who had organ dysfunction outlying baseline serum creatinine from the comparator group to minimize the risk of any spurious conclusions driven by clinical characteristics that might be potentially detrimental to clinical outcome. Clinical outcomes for each individual were masked from investigators who selected patients and did matching assessments. Such measurements should be included in any future clinical studies exploring the therapeutic benefit of any antiviral intervention for patients with SARS-CoV-2 infection.</p></sec><sec id="sec0009"><title>Conclusions</title><p id="para0031">Recent research has suggested that COVID-19 was frequently associated with the presumed hospital-related transmission, 26% of patients required intensive care unit treatment, and mortality was 4·3% in Wuhan, China.<xref rid="bib0003" ref-type="bibr"><sup>3</sup></xref> The therapeutical emphasis of COVID-19 was, therefore, to antiviral early that would decrease the peak viral load and thus the associated degree of immunopathological damage.<xref rid="bib0025" ref-type="bibr"><sup>25</sup></xref> This would reduce the need for immunosuppressants, which were often associated with an increased risk of nosocomial infections.<xref rid="bib0026" ref-type="bibr"><sup>26</sup></xref> One possible implication of this is that, arbidol combine with LPV/r might benefit to delay of the progression of lung lesions and lower the possibility of respiratory and gastrointestinal transmission for decreasing the viral load of COVID-19 and containing a high fecal concentration. Further randomized, prospective studies are still needed, and the mechanism of its antiviral effect to coronavirus remains unclear.</p></sec><sec id="sec0010"><title>Role of funding source</title><p id="para0032">No external funding was received for this study.</p></sec><sec sec-type="COI-statement"><title>Declaration of Competing Interest</title><p id="para0033">The authors declare no conflict of interest.</p></sec></body><back><ref-list id="cebibl1"><title>References</title><ref id="bib0001"><label>1</label><element-citation publication-type="journal" id="sbref0001"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>D.</given-names></name><name><surname>Hu</surname><given-names>B.</given-names></name><name><surname>Hu</surname><given-names>C.</given-names></name><name><surname>Zhu</surname><given-names>F.</given-names></name><name><surname>Liu</surname><given-names>X.</given-names></name><name><surname>Zhang</surname><given-names>J.</given-names></name></person-group><article-title>Clinical characteristics of 138 hospitalized patients with 2019 Novel Coronavirus-infected pneumonia in Wuhan, China</article-title><source>JAMA</source><year>2020</year><comment>2020-02-07. 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