Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis
M.D. Kentaro Shimizu, Haruhiko Hirata, Daijiro Kabata, Natsuko Tokuhira, Moe Koide, Akiko Ueda, Jotaro Tachino, Ayumi Shintani, Akinori Uchiyama, Yuji Fujino, Hiroshi Ogura
Journal of Infection and Chemotherapy, doi:10.1016/j.jiac.2021.12.024
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conclusions The administration of ivermectin improved GI complications and VFD in ventilated patients with COVID-19. The beneficial influence of ivermectin on the intestines may improve outcome in these patients. Further research is needed to investigate the mechanism and effects of ivermectin treatment.
Conflict of interest The authors declare that they have no conflict of interests.
References
Bone, Balk, Cerra, Dellinger, Fein et al., Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The accp/sccm consensus conference committee. American college of chest physicians/society of critical care medicine, Chest
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of sars-cov-2 in vitro, Antiviral Res
Clark, Coopersmith, Intestinal crosstalk: A new paradigm for understanding the gut as the "motor" of critical illness, Shock
D'amico, Baumgart, Danese, Peyrin-Biroulet, Diarrhea during covid-19 infection: Pathogenesis, epidemiology, prevention, and management, Clin Gastroenterol Hepatol
Group, Horby, Lim, Emberson, Mafham et al., Dexamethasone in hospitalized patients with covid-19, N Engl J Med
Hashimoto, Perlot, Rehman, Trichereau, Ishiguro et al., Ace2 links amino acid malnutrition to microbial ecology and intestinal inflammation, Nature
Lopez-Medina, Lopez, Hurtado, Davalos, Ramirez et al., Effect of ivermectin on time to resolution of symptoms among adults with mild covid-19: A randomized clinical trial, JAMA
Lv, Gu, Jiang, Yan, Chen et al., Gut mycobiota alterations in patients with covid-19 and h1n1 infections and their associations with clinical features, Commun Biol
Mao, Qiu, He, Tan, Li et al., Manifestations and prognosis of gastrointestinal and liver involvement in patients with covid-19: A systematic review and meta-analysis, Lancet Gastroenterol Hepatol
Mikasa, Aoki, Aoki, Abe, Iwata et al., JAID/JSC guidelines for the treatment of respiratory infectious diseases: The japanese association for infectious diseases/japanese society of chemotherapy -the JAID/JSC guide to clinical management of infectious disease/guideline-preparing committee respiratory infectious disease wg. J Infect J o u r n a l P r e -p r o, o f Chemother
Rajter, Sherman, Fatteh, Vogel, Sacks et al., Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: The ivermectin in covid nineteen study, Chest
Salem, A response to the recommendations for using dexamethasone for the treatment of covid-19: The dark side of dexamethasone, J Pharm Pract
Schmith, Zhou, Lohmer, The approved dose of ivermectin alone is not the ideal dose for the treatment of covid-19, Clin Pharmacol Ther
Schoenfeld, Bernard, Network, Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome, Crit Care Med
Shimizu, Hibino, Biros, Irisawa, Shimazu, Emergency medicine in japan: Past, present, and future, International Journal of Emergency Medicine
Wang, Zhang, Du, Du, Zhao et al., Remdesivir in adults with severe covid-19: A J o u r n a l P r e -p r o o f randomised, double-blind, placebo-controlled, multicentre trial, Lancet
Wehbe, Wehbe, Iratni, Pintus, Zaraket et al., Repurposing ivermectin for covid-19: Molecular aspects and therapeutic possibilities, Front Immunol
White, Dhillon, Hughes, Faggian, Soni, A national strategy to diagnose covid-19 associated invasive fungal disease in the icu, Clin Infect Dis,
doi:10.1093/cid/ciaa1298Wu, Cheng, Jiang, Tang, Tang, Altered oral and gut microbiota and its association with sars-cov-2 viral load in covid-19 patients during hospitalization, NPJ Biofilms Microbiomes
Xiao, Tang, Zheng, Liu, Li et al., Evidence for gastrointestinal infection of sars-cov-2, Gastroenterology
Yagisawa, Foster, Hanaki, Omura, Global trends in clinical studies of ivermectin in covid-19, Jpn J Antibiot
Zein, Sulistiyana, Raffaelo, Pranata, Ivermectin and mortality in patients with covid-19: A systematic review, meta-analysis, and meta-regression of randomized controlled trials, Diabetes Metab Syndr
Zuo, Zhang, Lui, Yeoh, Li et al., Alterations in gut microbiota of patients with covid-19 during time of hospitalization, Gastroenterology
{ 'indexed': { 'date-parts': [[2021, 12, 31]],
'date-time': '2021-12-31T05:45:18Z',
'timestamp': 1640929518258},
'reference-count': 26,
'publisher': 'Elsevier BV',
'license': [ { 'start': { 'date-parts': [[2021, 12, 1]],
'date-time': '2021-12-01T00:00:00Z',
'timestamp': 1638316800000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/'}],
'funder': [ { 'DOI': '10.13039/501100001691',
'name': 'Japan Society for the Promotion of Science',
'doi-asserted-by': 'publisher',
'award': ['19H03760', '19H03761']}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'short-container-title': ['Journal of Infection and Chemotherapy'],
'published-print': {'date-parts': [[2021, 12]]},
'DOI': '10.1016/j.jiac.2021.12.024',
'type': 'journal-article',
'created': { 'date-parts': [[2021, 12, 31]],
'date-time': '2021-12-31T03:15:54Z',
'timestamp': 1640920554000},
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': [ 'Ivermectin administration is associated with lower gastrointestinal complications and greater '
'ventilator-free days in ventilated patients with COVID-19: A propensity score analysis'],
'prefix': '10.1016',
'author': [ { 'ORCID': 'http://orcid.org/0000-0003-0631-9365',
'authenticated-orcid': False,
'given': 'Kentaro',
'family': 'Shimizu',
'sequence': 'first',
'affiliation': []},
{'given': 'Haruhiko', 'family': 'Hirata', 'sequence': 'additional', 'affiliation': []},
{'given': 'Daijiro', 'family': 'Kabata', 'sequence': 'additional', 'affiliation': []},
{'given': 'Natsuko', 'family': 'Tokuhira', 'sequence': 'additional', 'affiliation': []},
{'given': 'Moe', 'family': 'Koide', 'sequence': 'additional', 'affiliation': []},
{'given': 'Akiko', 'family': 'Ueda', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jotaro', 'family': 'Tachino', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ayumi', 'family': 'Shintani', 'sequence': 'additional', 'affiliation': []},
{'given': 'Akinori', 'family': 'Uchiyama', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yuji', 'family': 'Fujino', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hiroshi', 'family': 'Ogura', 'sequence': 'additional', 'affiliation': []}],
'member': '78',
'reference': [ { 'key': '10.1016/j.jiac.2021.12.024_bib1',
'doi-asserted-by': 'crossref',
'first-page': '693',
'DOI': '10.1056/NEJMoa2021436',
'article-title': 'Dexamethasone in hospitalized patients with covid-19',
'volume': '384',
'author': 'Group',
'year': '2021',
'journal-title': 'N Engl J Med'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib2',
'doi-asserted-by': 'crossref',
'first-page': '179',
'DOI': '10.1177/0897190020979608',
'article-title': 'A response to the recommendations for using dexamethasone for the '
'treatment of covid-19: the dark side of dexamethasone',
'volume': '34',
'author': 'Salem',
'year': '2021',
'journal-title': 'J Pharm Pract'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib3',
'doi-asserted-by': 'crossref',
'first-page': '1569',
'DOI': '10.1016/S0140-6736(20)31022-9',
'article-title': 'Remdesivir in adults with severe covid-19: a randomised, double-blind, '
'placebo-controlled, multicentre trial',
'volume': '395',
'author': 'Wang',
'year': '2020',
'journal-title': 'Lancet'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib4',
'doi-asserted-by': 'crossref',
'article-title': 'What is the role of remdesivir in patients with covid-19?',
'author': 'Beigel',
'year': '2021',
'journal-title': 'Curr Opin Crit Care',
'DOI': '10.1097/MCC.0000000000000866'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib5',
'first-page': '44',
'article-title': 'Global trends in clinical studies of ivermectin in covid-19',
'volume': '74',
'author': 'Yagisawa',
'year': '2021',
'journal-title': 'Jpn J Antibiot'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib6',
'doi-asserted-by': 'crossref',
'first-page': '663586',
'DOI': '10.3389/fimmu.2021.663586',
'article-title': 'Repurposing ivermectin for covid-19: molecular aspects and therapeutic '
'possibilities',
'volume': '12',
'author': 'Wehbe',
'year': '2021',
'journal-title': 'Front Immunol'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib7',
'doi-asserted-by': 'crossref',
'first-page': '85',
'DOI': '10.1016/j.chest.2020.10.009',
'article-title': 'Use of ivermectin is associated with lower mortality in hospitalized '
'patients with coronavirus disease 2019: the ivermectin in covid '
'nineteen study',
'volume': '159',
'author': 'Rajter',
'year': '2021',
'journal-title': 'Chest'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib8',
'doi-asserted-by': 'crossref',
'first-page': '1426',
'DOI': '10.1001/jama.2021.3071',
'article-title': 'Effect of ivermectin on time to resolution of symptoms among adults '
'with mild covid-19: a randomized clinical trial',
'volume': '325',
'author': 'Lopez-Medina',
'year': '2021',
'journal-title': 'JAMA'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib9',
'doi-asserted-by': 'crossref',
'first-page': '667',
'DOI': '10.1016/S2468-1253(20)30126-6',
'article-title': 'Manifestations and prognosis of gastrointestinal and liver involvement '
'in patients with covid-19: a systematic review and meta-analysis',
'volume': '5',
'author': 'Mao',
'year': '2020',
'journal-title': 'Lancet Gastroenterol Hepatol'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib10',
'doi-asserted-by': 'crossref',
'first-page': '1663',
'DOI': '10.1016/j.cgh.2020.04.001',
'article-title': 'Diarrhea during covid-19 infection: pathogenesis, epidemiology, '
'prevention, and management',
'volume': '18',
'author': "D'Amico",
'year': '2020',
'journal-title': 'Clin Gastroenterol Hepatol'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib11',
'doi-asserted-by': 'crossref',
'first-page': '1644',
'DOI': '10.1378/chest.101.6.1644',
'article-title': 'Definitions for sepsis and organ failure and guidelines for the use of '
'innovative therapies in sepsis. The accp/sccm consensus conference '
'committee. American college of chest physicians/society of critical '
'care medicine',
'volume': '101',
'author': 'Bone',
'year': '1992',
'journal-title': 'Chest'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib12',
'doi-asserted-by': 'crossref',
'first-page': '2',
'DOI': '10.1186/s12245-020-00316-7',
'article-title': 'Emergency medicine in Japan: past, present, and future',
'volume': '14',
'author': 'Shimizu',
'year': '2021',
'journal-title': 'Int J Emerg Med'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib13',
'doi-asserted-by': 'crossref',
'first-page': 'S1',
'DOI': '10.1016/j.jiac.2015.12.019',
'volume': '22',
'author': 'Mikasa',
'year': '2016',
'journal-title': 'J Infect Chemother'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib14',
'doi-asserted-by': 'crossref',
'first-page': '1772',
'DOI': '10.1097/00003246-200208000-00016',
'article-title': 'Statistical evaluation of ventilator-free days as an efficacy measure '
'in clinical trials of treatments for acute respiratory distress '
'syndrome',
'volume': '30',
'author': 'Schoenfeld',
'year': '2002',
'journal-title': 'Crit Care Med'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib15',
'doi-asserted-by': 'crossref',
'first-page': '102186',
'DOI': '10.1016/j.dsx.2021.102186',
'article-title': 'Ivermectin and mortality in patients with covid-19: a systematic '
'review, meta-analysis, and meta-regression of randomized controlled '
'trials',
'volume': '15',
'author': 'Zein',
'year': '2021',
'journal-title': 'Diabetes Metab Syndr'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib16',
'doi-asserted-by': 'crossref',
'first-page': '104787',
'DOI': '10.1016/j.antiviral.2020.104787',
'article-title': 'The FDA-approved drug ivermectin inhibits the replication of sars-cov-2 '
'in vitro',
'volume': '178',
'author': 'Caly',
'year': '2020',
'journal-title': 'Antivir Res'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib17',
'doi-asserted-by': 'crossref',
'first-page': '477',
'DOI': '10.1038/nature11228',
'article-title': 'Ace2 links amino acid malnutrition to microbial ecology and intestinal '
'inflammation',
'volume': '487',
'author': 'Hashimoto',
'year': '2012',
'journal-title': 'Nature'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib18',
'doi-asserted-by': 'crossref',
'first-page': '61',
'DOI': '10.1038/s41522-021-00232-5',
'article-title': 'Altered oral and gut microbiota and its association with sars-cov-2 '
'viral load in covid-19 patients during hospitalization',
'volume': '7',
'author': 'Wu',
'year': '2021',
'journal-title': 'NPJ Biofilms Microbiomes'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib19',
'doi-asserted-by': 'crossref',
'first-page': '1831',
'DOI': '10.1053/j.gastro.2020.02.055',
'article-title': 'Evidence for gastrointestinal infection of sars-cov-2',
'volume': '158',
'author': 'Xiao',
'year': '2020',
'journal-title': 'Gastroenterology'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib20',
'doi-asserted-by': 'crossref',
'first-page': '384',
'DOI': '10.1097/shk.0b013e31805569df',
'article-title': 'Intestinal crosstalk: a new paradigm for understanding the gut as the '
'"motor" of critical illness',
'volume': '28',
'author': 'Clark',
'year': '2007',
'journal-title': 'Shock'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib21',
'doi-asserted-by': 'crossref',
'first-page': '944',
'DOI': '10.1053/j.gastro.2020.05.048',
'article-title': 'Alterations in gut microbiota of patients with covid-19 during time of '
'hospitalization',
'volume': '159',
'author': 'Zuo',
'year': '2020',
'journal-title': 'Gastroenterology'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib22',
'doi-asserted-by': 'crossref',
'first-page': '480',
'DOI': '10.1038/s42003-021-02036-x',
'article-title': 'Gut mycobiota alterations in patients with covid-19 and h1n1 infections '
'and their associations with clinical features',
'volume': '4',
'author': 'Lv',
'year': '2021',
'journal-title': 'Commun Biol'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib23',
'doi-asserted-by': 'crossref',
'first-page': '762',
'DOI': '10.1002/cpt.1889',
'article-title': 'The approved dose of ivermectin alone is not the ideal dose for the '
'treatment of covid-19',
'volume': '108',
'author': 'Schmith',
'year': '2020',
'journal-title': 'Clin Pharmacol Ther'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib24',
'article-title': 'A national strategy to diagnose covid-19 associated invasive fungal '
'disease in the icu',
'author': 'White',
'year': '2020',
'journal-title': 'Clin Infect Dis'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib25',
'doi-asserted-by': 'crossref',
'DOI': '10.1002/rcr2.801',
'article-title': 'Fatal cytomegalovirus pneumonia in a critically ill patient with '
'covid-19',
'volume': '9',
'author': 'Amiya',
'year': '2021',
'journal-title': 'Respirol Case Rep'},
{ 'key': '10.1016/j.jiac.2021.12.024_bib26',
'doi-asserted-by': 'crossref',
'article-title': 'Cytomegalovirus infection in critically ill patients with covid-19',
'author': 'Niitsu',
'year': '2021',
'journal-title': 'J Infect',
'DOI': '10.1016/j.jinf.2021.07.004'}],
'container-title': ['Journal of Infection and Chemotherapy'],
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S1341321X21003603?httpAccept=text/xml',
'content-type': 'text/xml',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://api.elsevier.com/content/article/PII:S1341321X21003603?httpAccept=text/plain',
'content-type': 'text/plain',
'content-version': 'vor',
'intended-application': 'text-mining'}],
'deposited': { 'date-parts': [[2021, 12, 31]],
'date-time': '2021-12-31T03:16:05Z',
'timestamp': 1640920565000},
'score': 1,
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 12]]},
'references-count': 26,
'alternative-id': ['S1341321X21003603'],
'URL': 'http://dx.doi.org/10.1016/j.jiac.2021.12.024',
'relation': {},
'ISSN': ['1341-321X'],
'issn-type': [{'value': '1341-321X', 'type': 'print'}],
'subject': ['Infectious Diseases', 'Pharmacology (medical)', 'Microbiology (medical)'],
'published': {'date-parts': [[2021, 12]]}}
