Ivermectin administration is associated with lower gastrointestinal complications and greater ventilator-free days in ventilated patients with COVID-19: A propensity score analysis

Open AccessPublished:December 30, 2021DOI:https://doi.org/10.1016/j.jiac.2021.12.024

      Abstract

      Introduction

      COVID-19 patients have been reported to have digestive symptoms with poor outcome. Ivermectin, an antiparasitic drug, has been used in COVID-19 patients. The objective of this study was to evaluate whether ivermectin has effects on gastrointestinal complications and ventilator-free days in ventilated patients with COVID-19.

      Methods

      COVID-19 patients who were mechanically ventilated in the ICU were included in this study. The ventilated patients who received ivermectin within 3 days after admission were assigned to the Ivermectin group, and the others were assigned to the Control group. Patients in the Ivermectin group received ivermectin 200 μg/kg via nasal tube. The incidence of gastrointestinal complications and ventilator-free days within 4 weeks from admission were evaluated as clinical outcomes using a propensity score with the inverse probability weighting method.

      Results

      We included 88 patients in this study, of whom 39 patients were classified into the Ivermectin group, and 49 patients were classified into the Control group. The hazard ratio for gastrointestinal complications in the Ivermectin group as compared with the Control group was 0.221 (95% confidence interval [CI], 0.057 to 0.855; p = 0.029) in a Cox proportional-hazard regression model. The odds ratio for ventilator-free days as compared with the Control group was 1.920 (95% CI, 1.076 to 3.425; p = 0.027) in a proportional odds logistic regression model.

      Conclusions

      Ivermectin improved gastrointestinal complications and the number of ventilator-free days in severe COVID-19 patients undergoing mechanical ventilation. Prevention of gastrointestinal symptoms by SARS-Cov-2 might be associated with COVID-19 outcome.

      Keywords

      1. Introduction

      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/COVID-19) pandemic is an emergency situation throughout the world. As treatment, dexamethasone has been used as an effective anti-inflammatory drug [
      • Group R.C.
      • Horby P.
      • Lim W.S.
      • Emberson J.R.
      • Mafham M.
      • Bell J.L.
      • et al.
      Dexamethasone in hospitalized patients with covid-19.
      ], but dexamethasone weakens host immunity [
      • Salem M.A.
      A response to the recommendations for using dexamethasone for the treatment of covid-19: the dark side of dexamethasone.
      ]. Remdesivir, an antiviral drug, is a nucleoside analogue prodrug used for various viral infections and decreases the time to clinical improvement in adults with severe COVID-19 [
      • Wang Y.
      • Zhang D.
      • Du G.
      • Du R.
      • Zhao J.
      • Jin Y.
      • et al.
      Remdesivir in adults with severe covid-19: a randomised, double-blind, placebo-controlled, multicentre trial.
      ]. However, there are limited data in patients with mechanical ventilation [
      • Beigel J.H.
      What is the role of remdesivir in patients with covid-19?.
      ].
      Ivermectin is a drug that has been used to treat parasitic infections such as onchocerciasis and lymphatic filariasis throughout the world for more than 30 years, with more than 3.7 billion doses dispensed in Africa and Central and South America to control tropical diseases [
      • Yagisawa M.
      • Foster P.
      • Hanaki H.
      • Omura S.
      Global trends in clinical studies of ivermectin in covid-19.
      ]. Ivermectin shows in vitro activity against a broad range of viruses, including not only HIV, dengue, influenza, and Zika virus but also SARS-CoV-2 [
      • Wehbe Z.
      • Wehbe M.
      • Iratni R.
      • Pintus G.
      • Zaraket H.
      • Yassine H.M.
      • et al.
      Repurposing ivermectin for covid-19: molecular aspects and therapeutic possibilities.
      ]. Clinical research by Rajter et al. [
      • Rajter J.C.
      • Sherman M.S.
      • Fatteh N.
      • Vogel F.
      • Sacks J.
      • Rajter J.J.
      Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ivermectin in covid nineteen study.
      ] found that ivermectin treatment was associated with lower mortality in 280 COVID-19 patients in a propensity score-matching study. Contrastingly, in a randomized clinical trial of 400 patients with mild COVID-19, ivermectin administration did not decrease the time to resolution of symptoms within 21 days [
      • Lopez-Medina E.
      • Lopez P.
      • Hurtado I.C.
      • Davalos D.M.
      • Ramirez O.
      • Martinez E.
      • et al.
      Effect of ivermectin on time to resolution of symptoms among adults with mild covid-19: a randomized clinical trial.
      ]. Thus, the effects of ivermectin are controversial, and there are few clinical data on intubated COVID-19 patients in the intensive care unit (ICU).
      COVID-19 causes gastrointestinal (GI) symptoms such as nausea or vomiting, diarrhea, and loss of appetite as reported in a systemic review of 6686 patients [
      • Mao R.
      • Qiu Y.
      • He J.S.
      • Tan J.Y.
      • Li X.H.
      • Liang J.
      • et al.
      Manifestations and prognosis of gastrointestinal and liver involvement in patients with covid-19: a systematic review and meta-analysis.
      ]. There is little research on established treatment for these GI symptoms [
      • D'Amico F.
      • Baumgart D.C.
      • Danese S.
      • Peyrin-Biroulet L.
      Diarrhea during covid-19 infection: pathogenesis, epidemiology, prevention, and management.
      ]. As we have been struggling against refractory diarrhea and regurgitation in our patients with COVID-19, we planned to use an antiviral oral drug for intestinal prophylaxis, and we selected ivermectin as the drug. Therefore, the objective of this study was to evaluate whether ivermectin improved GI complications and respiratory conditions in mechanically ventilated patients with COVID-19.

      2. Methods

      2.1 Patients

      Patients who were more than 20 years old, were placed on a ventilator within 3 days after admission to the ICU, and were diagnosed as having COVID-19 in the Department of Traumatology and Acute Critical Medicine and Intensive Care Unit, Osaka University Hospital during the period December 2020 to May 2021 were eligible for enrollment in this retrospective study [
      • Bone R.C.
      • Balk R.A.
      • Cerra F.B.
      • Dellinger R.P.
      • Fein A.M.
      • Knaus W.A.
      • 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.
      ]. The emergency medical system in our country has three designated levels according to the perceived acuity of the patients. Our designated tertiary hospital deals with patients who need to be managed in the operating room or the ICU [
      • Shimizu K.
      • Hibino S.
      • Biros M.H.
      • Irisawa T.
      • Shimazu T.
      Emergency medicine in Japan: past, present, and future.
      ]. During the study period, only severe COVID-19 patients who required a ventilator were transferred to our hospital.

      2.2 Interventions

      The use of ivermectin has been approved for strongyloidiasis and scabies (200 μg/kg per 2 weeks) in Japan. The off-label use for COVID-19 was approved in Osaka University Hospital from February 2021. The ventilated patients who provided informed consent for the use of ivermectin within 3 days after admission received ivermectin and were assigned to the Ivermectin group, and the patients who did not receive ivermectin within 3 days were assigned to the Control group. Patients in the Ivermectin group received ivermectin 200 μg/kg per 2 weeks via nasal tube. Antibiotics were administered under the same policy during the entire study period [
      • Mikasa K.
      • Aoki N.
      • Aoki Y.
      • Abe S.
      • Iwata S.
      • Ouchi K.
      • 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.
      ]. This study was approved by the institutional review board of Osaka University (approval no. 21163). Informed consent was obtained from the family of each patient.

      2.3 Outcome variables

      Diarrhea was defined as the acute onset of continuous loose or liquid stools occurring more than twice. Regurgitation was defined as reflux volume from the gastric tube of more than 300 mL/day. GI complications were defined as diarrhea or regurgitation. Ventilator-free days (VFD) were defined as the number of days alive and free of mechanical ventilation within 4 weeks from admission [
      • Schoenfeld D.A.
      • Bernard G.R.
      • Network A.
      Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
      ]. The primary outcome was VFD. The secondary outcomes included diarrhea, regurgitation, and GI complications within 4 weeks from admission.

      2.4 Statistical analysis

      All patient characteristics are summarized using medians with interquartile ranges (IQR) and proportions with counts for continuous variables and categorical variables, respectively. The differences in distributions of the covariates between the Ivermectin and Control groups were assessed using standardized mean differences (SMD).
      We estimated the cumulative event-free probabilities of the first incidence of diarrhea, regurgitation, and GI complications using the Kaplan-Meier method. Then, we estimated the effect of ivermectin use on these events using Cox proportional-hazard regression models. Furthermore, we assessed the effect of ivermectin use on VFD and the number of ICU-free days within 28 days from ICU admission using proportional-odds logistic regression models. To reduce the biases that were introduced by the imbalances of the covariates’ distributions between the groups, we used the inverse probability weighting (IPW) method. The probability of receiving ivermectin, which is referred to as the propensity score, was estimated by a multivariable logistic regression model considering the following covariates of age, sex, P/F ratio, extracorporeal membrane oxygenation, use of concomitant drugs (remdesivir, favipiravir, dexamethasone, and methylprednisolone), and comorbidities (hypertension, hyperlipidemia, diabetes mellitus, hyperuricemia, cardiovascular disease, chronic obstructive pulmonary disease, and chronic kidney disease). To avoid variance inflation due to the extreme weights, which were introduced by the extremely high and low estimated propensity scores, we trimmed the propensity scores in the un-overlapped area of the propensity score distributions in both groups.
      All statistical inferences were made with a two-sided 5% significance level using R software (https://cran.r-project.org/).

      3. Results

      All of the patients tolerated ivermectin, and there were no clear adverse events in any patients. Patient characteristics are listed in Table 1.
      Table 1Baseline patients’ clinical and demographical characteristics.
      [Original cohort][Weighted cohort]
      IvermectinControlSMDIvermectinControlSMD
      N394970.7874.36
      Age60.00 [54.00, 64.50]68.00 [58.00, 74.00]0.80760.00 [56.00, 67.00]62.00 [55.64, 72.45]0.417
      Male79.5 (31)83.7 (41)0.10885.3 (60.3)84.7 (63.0)0.016
      Respiratory condition
       P/F ratio246.00 [173.00, 307.50]236.00 [144.00, 344.00]0.007243.77 [144.07, 305.68]226.45 [138.70, 334.04]0.054
       ECMO7.7 (3)8.2 (4)0.0179.7 (6.9)9.0 (6.7)0.024
      Concomitant drugs
       Remdesivir35.9 (14)32.7 (16)0.06831.5 (22.3)31.6 (23.5)0.002
       Favipiravir28.2 (11)36.7 (18)0.18339.6 (28.1)37.4 (27.8)0.045
       Dexamethasone100.0 (39)100.0 (49)<0.001100.0 (70.8)100.0 (74.4)<0.001
       Methylprednisolone12.8 (5)14.3 (7)0.04311.4 (8.1)12.0 (8.9)0.018
      Comorbidities
       Hypertension48.7 (19)40.8 (20)0.15943.6 (30.8)40.8 (30.3)0.057
       Hyperlipidemia28.2 (11)24.5 (12)0.08424.6 (17.4)22.3 (16.6)0.052
       Diabetes mellitus20.5 (8)32.7 (16)0.27733.8 (23.9)32.5 (24.2)0.027
       Hyperuricemia17.9 (7)8.2 (4)0.29411.6 (8.2)6.9 (5.2)0.161
       Cardiovascular disease15.4 (6)10.2 (5)0.15617.7 (12.5)9.9 (7.4)0.225
       COPD5.1 (2)10.2 (5)0.1922.8 (2.0)6.7 (5.0)0.184
       Chronic kidney disease0.0 (0)14.3 (7)0.5770.0 (0.0)9.4 (7.0)0.456
      Values are expressed as median [interquartile range] or percentage (frequency). SMD; standardized mean difference, ECMO; extracorporeal membrane oxygenation, COPD; chronic obstructive pulmonary disease.
      The Ivermectin group contained 39 patients, and the Control group contained 49 patients. Patients in the Ivermectin group had significantly lower age and less chronic kidney disease than those in the Control group. To adjust for age, sex, respiratory condition, concomitant drugs, and comorbidities, we used propensity score via the IPW method. Most patients were intubated on admission, and median time from admission to intubation had no significant differences between the Ivermectin group (median 0, IQR -0.5–0 days) and Control group (median 0, IQR -1–0 days). There were no significant differences in blood test results except for that of serum creatinine (Table 2).
      Table 2Laboratory data on admission.
      UnitsIvermectinControlP value
      Hematology
       Red blood cells× 104/μL457 ± 11.0438 ± 9.60.207
       Hemoglobing/dL13.6 ± 0.313.3 ± 0.30.491
       Hematocrit%39.7 ± 0.939.0 ± 0.70.565
       White blood cells/μL9700 ± 9479500 ± 8280.840
       Neutrophil%88.7 ± 1.187.3 ± 1.00.340
       Lymphocyte%7.9 ± 0.99.1 ± 0.80.368
       Monocyte%3.3 ± 0.33.1 ± 0.30.593
       Eosinophil%0.1 ± 0.00.1 ± 0.00.335
       Basophil%0.2 ± 0.00.2 ± 0.00.884
       Platelets× 104/μL21.2 ± 12.918.5 ± 11.30.119
      Biochemistry
       NamEq/l138 ± 1.0139 ± 1.00.113
       KmEq/l4.2 ± 0.14.2 ± 0.10.866
       ClmEq/l103 ± 1.0102 ± 1.00.460
       Urea nitratemg/dL27 ± 2.021 ± 2.00.031
       Uric acidmg/dL4.1 ± 0.75.1 ± 0.60.305
       Creatininemg/dL1.2 ± 0.10.8 ± 0.20.043
       Calciummg/dL8.3 ± 0.18.3 ± 0.10.693
       Inorganic phosphatemg/dL3.4 ± 0.33.6 ± 0.20.444
       Magnesiummg/dL2.2 ± 0.12.2 ± 0.00.940
       ASTU/L51 ± 5.050 ± 4.00.765
       ALTU/L48 ± 5.044 ± 5.00.551
       γGTU/L97 ± 1574 ± 130.253
       AlkaliphosphataseU/L74 ± 6.074 ± 6.00.997
       Lactate dehydrogenaseU/L511 ± 37516 ± 320.922
       Creatinine kinaseU/L152 ± 99331 ± 870.177
       AmylaseU/L90 ± 2194 ± 190.893
       Total bilirubinmg/dL0.6 ± 0.20.6 ± 0.30.781
       C-reactive proteinmg/dL9.2 ± 1.09.4 ± 0.90.908
       Total proteing/dL6.2 ± 0.16.3 ± 0.10.849
       Albuming/dL2.7 ± 0.12.7 ± 0.10.687
      Coagulation
       PT%79 ± 2.074 ± 3.00.215
       PT-INR1.2 ± 0.01.3 ± 0.10.110
       APTT%40 ± 4.045 ± 4.10.387
       Fibrinogenmg/dL478 ± 22519 ± 250.230
       D-dimerμg/ml21.8 ± 6.16.7 ± 7.00.106
       FDPng/ml47.5 ± 14.513.5 ± 16.20.121
      AST; aspartate aminotransferase, ALT; alanine aminotransferase, γGT; γ-glutamyl transpeptidase. PT; prothrombin, APTT; activated partial thromboplastin time, FDP; fibrin/fibrinogen degradation products.
      The frequencies of diarrhea, regurgitation, and GI complications in the Ivermectin group were significantly lower than those in the Control group. The intubation period was significantly lower and the number of VFD was significantly greater in the Ivermectin versus Control group (Table 3). The cumulative event-free probabilities of the first incidence of GI complications and extubation using the Kaplan-Meier method are shown in Fig. 1. The mortality within 28 days did not differ significantly between the groups, but the mortality in the whole ICU stay had significantly lower in the Ivermectin group versus the Control group (0% vs. 16.3%; p < 0.05).
      Table 3Gastrointestinal complications and respiratory outcome.
      Ivermectin (n = 39)Control (n = 49)P value
      Diarrhea10.3 (4)38.8 (19)0.003
      Regurgitation0 (0)22.5 (11)0.002
      GI complications10.3 (4)51.2 (25)<0.001
      Intubation period8 [6, 10]13 [7, 38.5]<0.001
      Ventilator-free days20 [18,22]15 [0, 21]<0.001
      ICU stay10 [7, 13]16 [8, 38.5]<0.001
      Death within 28 days0 (0)4.1 (2)0.501
      Values are expressed as percentage (frequency) or median [interquartile range]. GI; gastrointestinal.
      Fig. 1
      Fig. 1The cumulative event-free probabilities of the first incidence of gastrointestinal complications (a) and extubation (b) using the Kaplan-Meier method.
      In a Cox proportional-hazard regression model, the hazard ratio for GI complications for the Ivermectin group as compared with the Control group was 0.221 (95% confidence interval [CI], 0.057 to 0.855; p = 0.029) after adjustment for covariates using propensity score with IPW method (Table 4)(Fig. 2). In the proportional odds logistic regression model, the odds ratio for VFD as compared with the control group was 1.920 (95% CI, 1.076 to 3.425; p = 0.027) after using the same adjustment method.
      Table 4Analysis of the effects of ivermectin after adjusting for potential confounders.
      VariablesEffect measureEffect95% CIP value
      DiarrheaHazard ratio0.3780.098–1.4510.156
      RegurgitationHazard ratio0.0000.000–0.000<0.001
      GI complicationsHazard ratio0.2210.057–0.8550.029
      Ventilator-free daysOdds ratio1.9201.076–3.4250.027
      ICU-free daysOdds ratio1.7470.980–3.1160.059
      MortalityHazard ratio0.0010.000–0.005<0.001
      CI; confidence interval, GI; gastrointestinal.
      Fig. 2
      Fig. 2The mean difference between treatment groups by inversed probability of weighting for propensity score analysis. COPD; chronic obstructive pulmonary disease, ECMO; extracorporeal membrane oxygenation.

      4. Discussion

      This study showed that the administration of ivermectin reduced the incidences of GI complications and increased VFD in patients with COVID-19 undergoing mechanical ventilation. Regarding clinical research, in a meta-analysis of 9 randomized controlled trials in 1788 COVID-19 patients, ivermectin was associated with decreased mortality [
      • Zein A.
      • Sulistiyana C.S.
      • Raffaelo W.M.
      • Pranata R.
      Ivermectin and mortality in patients with covid-19: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.
      ]. However, these studies did not evaluate GI complications and VFD. In addition, most patients were not intubated when ivermectin was administered. We showed that even after patients worsened and required mechanical ventilation, administration of ivermectin via nasal tube could attenuate GI complications and shorten the duration of the intubation period.
      Ivermectin has been shown to inhibit the viral replication of SARS-CoV-2 in vitro [
      • Caly L.
      • Druce J.D.
      • Catton M.G.
      • Jans D.A.
      • Wagstaff K.M.
      The FDA-approved drug ivermectin inhibits the replication of sars-cov-2 in vitro.
      ]. One of the presumed mechanisms is to be the inhibition of the enzyme importin α/β in the process of translocation into the cell nucleus [
      • Wehbe Z.
      • Wehbe M.
      • Iratni R.
      • Pintus G.
      • Zaraket H.
      • Yassine H.M.
      • et al.
      Repurposing ivermectin for covid-19: molecular aspects and therapeutic possibilities.
      ]. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2). A deficiency in murine ACE2, which encodes a key regulatory enzyme of the renin-angiotensin system, results in highly increased susceptibility to diarrhea and intestinal inflammation induced by dextran sulfate sodium [
      • Hashimoto T.
      • Perlot T.
      • Rehman A.
      • Trichereau J.
      • Ishiguro H.
      • Paolino M.
      • et al.
      Ace2 links amino acid malnutrition to microbial ecology and intestinal inflammation.
      ]. In a clinical study, fecal viral loads were detected [
      • Wu Y.
      • Cheng X.
      • Jiang G.
      • Tang H.
      • Ming S.
      • Tang L.
      • et al.
      Altered oral and gut microbiota and its association with sars-cov-2 viral load in covid-19 patients during hospitalization.
      ], and digestive histologic and immunofluorescent staining revealed GI infection in patients with COVID-19 [
      • Xiao F.
      • Tang M.
      • Zheng X.
      • Liu Y.
      • Li X.
      • Shan H.
      Evidence for gastrointestinal infection of sars-cov-2.
      ]. Previous reports showed that gastrointestinal complications occurred in about 15% of COVID-19 patients including mainly non-ventilated patients [
      • D'Amico F.
      • Baumgart D.C.
      • Danese S.
      • Peyrin-Biroulet L.
      Diarrhea during covid-19 infection: pathogenesis, epidemiology, prevention, and management.
      ]. In the present study, 51.2% of COVID-19 ventilated patients in the Control group experienced GI complications. The ventilated patients had a higher prevalence of GI complications than the non-ventilated patients, so the effect modification of ivermectin could be expected to be different. It may be difficult to detect the effect of ivermectin in non-ventilated patients because of the smaller incidences of GI complications. These results suggest that ivermectin could reduce SARS-CoV-2 infection in the intestine and attenuate the symptoms of regurgitation and diarrhea.
      Regarding with respiratory function, a s the gut has been proposed as the ‘‘motor’’ of multiple organ failure [
      • Clark J.A.
      • Coopersmith C.M.
      Intestinal crosstalk: a new paradigm for understanding the gut as the "motor" of critical illness.
      ], gut dysfunction is recognized as a causative factor in the progression of diseases such as sepsis, trauma, and infection. Intestinal injury by SARS-CoV-2 could cause intestinal inflammation and alteration of the gut microbiota, which might lead to progression of the respiratory disease seen with COVID-19. In the gut microbiota of COVID-19 patients, the diversity of normal gut microbiota bacteria is decreased and the number of opportunistic bacteria is increased [
      • Zuo T.
      • Zhang F.
      • Lui G.C.Y.
      • Yeoh Y.K.
      • Li A.Y.L.
      • Zhan H.
      • et al.
      Alterations in gut microbiota of patients with covid-19 during time of hospitalization.
      ,
      • Lv L.
      • Gu S.
      • Jiang H.
      • Yan R.
      • Chen Y.
      • Chen Y.
      • et al.
      Gut mycobiota alterations in patients with covid-19 and h1n1 infections and their associations with clinical features.
      ]. In the present study, GI complications were significantly decreased in the Ivermectin group. It is reported that the approved dose of ivermectin does not result in an adequate serum concentration to treat COVID-19 [
      • Schmith V.D.
      • Zhou J.J.
      • Lohmer L.R.L.
      The approved dose of ivermectin alone is not the ideal dose for the treatment of covid-19.
      ]. Ivermectin could have a direct effect in the intestine, and prevention of SARS-CoV-2-related GI complications might also be associated with the increase in VFD seen in the present study. The mortality in the whole ICU stay had significantly lower in this research, and we need further randomized controlled study to demonstrate that.
      Anti-inflammatory drugs are essential and effective, but dexamethasone, a glucocorticoid, affects immune cells [
      • Salem M.A.
      A response to the recommendations for using dexamethasone for the treatment of covid-19: the dark side of dexamethasone.
      ] and is a double-edge sword, especially in aged patients with lowered immunity who have difficulty in upregulating immunity under steroid therapy. As a result, such patients with COVID-19 have been reported to suffer from fungal disease [
      • White P.L.
      • Dhillon R.
      • Cordey A.
      • Hughes H.
      • Faggian F.
      • Soni S.
      • et al.
      A national strategy to diagnose covid-19 associated invasive fungal disease in the icu.
      ] and severe cytomegalovirus infection [
      • Amiya S.
      • Hirata H.
      • Shiroyama T.
      • Adachi Y.
      • Niitsu T.
      • Noda Y.
      • et al.
      Fatal cytomegalovirus pneumonia in a critically ill patient with covid-19.
      ,
      • Niitsu T.
      • Shiroyama T.
      • Hirata H.
      • Noda Y.
      • Adachi Y.
      • Enomoto T.
      • et al.
      Cytomegalovirus infection in critically ill patients with covid-19.
      ]. It may be important to combine both an antiviral drug and an anti-inflammatory drug for SARS-COV-2 virus in the early stage of infection to prevent prolonged respiratory failure and reduce the accumulated dose of steroids. Ivermectin might be one of the promising antiviral drugs in the treatment of COVID-19.
      This study has some limitations. An imbalance in the patients’ age between the treatment groups remained after weighting. The mutant variants may be different with time, but we could not identify this. Additional well-designed studies are needed to provide further elucidation. Second, we propose that the intestinal effect of ivermectin might influence COVID-19 infection, and thus, evaluation of intestinal viral load could be a next target to confirm this supposition.

      5. 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.

      Authorship statement

      SK, NT, and MK reviewed the record and drafted the manuscript. HH and AU confirmed the clinical record as clinical attendants. DK, TJ and AS reviewed statistical parts and clinical application. YF and OH contributed to the discussion and managed this research. All authors read the draft and revised it critically and approved the final manuscript. All authors meet the ICMJE authorship criteria.

      Funding

      The study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 19H03760 and 19H03761 .

      Declaration of competing interest

      The authors declare that they have no conflict of interests.

      Acknowledgment

      The authors acknowledge the contributions made by all of the staff in Osaka University Hospital who aided in this research and are involved COVID-19 medical practice.

      References

        • Group R.C.
        • Horby P.
        • Lim W.S.
        • Emberson J.R.
        • Mafham M.
        • Bell J.L.
        • et al.
        Dexamethasone in hospitalized patients with covid-19.
        N Engl J Med. 2021; 384: 693-704
        • Salem M.A.
        A response to the recommendations for using dexamethasone for the treatment of covid-19: the dark side of dexamethasone.
        J Pharm Pract. 2021; 34: 179-180
        • Wang Y.
        • Zhang D.
        • Du G.
        • Du R.
        • Zhao J.
        • Jin Y.
        • et al.
        Remdesivir in adults with severe covid-19: a randomised, double-blind, placebo-controlled, multicentre trial.
        Lancet. 2020; 395: 1569-1578
        • Beigel J.H.
        What is the role of remdesivir in patients with covid-19?.
        Curr Opin Crit Care. 2021; https://doi.org/10.1097/MCC.0000000000000866
        • Yagisawa M.
        • Foster P.
        • Hanaki H.
        • Omura S.
        Global trends in clinical studies of ivermectin in covid-19.
        Jpn J Antibiot. 2021; 74: 44-95
        • Wehbe Z.
        • Wehbe M.
        • Iratni R.
        • Pintus G.
        • Zaraket H.
        • Yassine H.M.
        • et al.
        Repurposing ivermectin for covid-19: molecular aspects and therapeutic possibilities.
        Front Immunol. 2021; 12: 663586
        • Rajter J.C.
        • Sherman M.S.
        • Fatteh N.
        • Vogel F.
        • Sacks J.
        • Rajter J.J.
        Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the ivermectin in covid nineteen study.
        Chest. 2021; 159: 85-92
        • Lopez-Medina E.
        • Lopez P.
        • Hurtado I.C.
        • Davalos D.M.
        • Ramirez O.
        • Martinez E.
        • et al.
        Effect of ivermectin on time to resolution of symptoms among adults with mild covid-19: a randomized clinical trial.
        JAMA. 2021; 325: 1426-1435
        • Mao R.
        • Qiu Y.
        • He J.S.
        • Tan J.Y.
        • Li X.H.
        • Liang J.
        • et al.
        Manifestations and prognosis of gastrointestinal and liver involvement in patients with covid-19: a systematic review and meta-analysis.
        Lancet Gastroenterol Hepatol. 2020; 5: 667-678
        • D'Amico F.
        • Baumgart D.C.
        • Danese S.
        • Peyrin-Biroulet L.
        Diarrhea during covid-19 infection: pathogenesis, epidemiology, prevention, and management.
        Clin Gastroenterol Hepatol. 2020; 18: 1663-1672
        • Bone R.C.
        • Balk R.A.
        • Cerra F.B.
        • Dellinger R.P.
        • Fein A.M.
        • Knaus W.A.
        • 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. 1992; 101: 1644-1655
        • Shimizu K.
        • Hibino S.
        • Biros M.H.
        • Irisawa T.
        • Shimazu T.
        Emergency medicine in Japan: past, present, and future.
        Int J Emerg Med. 2021; 14: 2
        • Mikasa K.
        • Aoki N.
        • Aoki Y.
        • Abe S.
        • Iwata S.
        • Ouchi K.
        • 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 Chemother. 2016; 22: S1-S65
        • Schoenfeld D.A.
        • Bernard G.R.
        • Network A.
        Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
        Crit Care Med. 2002; 30: 1772-1777
        • Zein A.
        • Sulistiyana C.S.
        • Raffaelo W.M.
        • Pranata R.
        Ivermectin and mortality in patients with covid-19: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.
        Diabetes Metab Syndr. 2021; 15: 102186
        • Caly L.
        • Druce J.D.
        • Catton M.G.
        • Jans D.A.
        • Wagstaff K.M.
        The FDA-approved drug ivermectin inhibits the replication of sars-cov-2 in vitro.
        Antivir Res. 2020; 178: 104787
        • Hashimoto T.
        • Perlot T.
        • Rehman A.
        • Trichereau J.
        • Ishiguro H.
        • Paolino M.
        • et al.
        Ace2 links amino acid malnutrition to microbial ecology and intestinal inflammation.
        Nature. 2012; 487: 477-481
        • Wu Y.
        • Cheng X.
        • Jiang G.
        • Tang H.
        • Ming S.
        • Tang L.
        • et al.
        Altered oral and gut microbiota and its association with sars-cov-2 viral load in covid-19 patients during hospitalization.
        NPJ Biofilms Microbiomes. 2021; 7: 61
        • Xiao F.
        • Tang M.
        • Zheng X.
        • Liu Y.
        • Li X.
        • Shan H.
        Evidence for gastrointestinal infection of sars-cov-2.
        Gastroenterology. 2020; 158: 1831-18333 e3
        • Clark J.A.
        • Coopersmith C.M.
        Intestinal crosstalk: a new paradigm for understanding the gut as the "motor" of critical illness.
        Shock. 2007; 28: 384-393
        • Zuo T.
        • Zhang F.
        • Lui G.C.Y.
        • Yeoh Y.K.
        • Li A.Y.L.
        • Zhan H.
        • et al.
        Alterations in gut microbiota of patients with covid-19 during time of hospitalization.
        Gastroenterology. 2020; 159: 944-955 e8
        • Lv L.
        • Gu S.
        • Jiang H.
        • Yan R.
        • Chen Y.
        • Chen Y.
        • et al.
        Gut mycobiota alterations in patients with covid-19 and h1n1 infections and their associations with clinical features.
        Commun Biol. 2021; 4: 480
        • Schmith V.D.
        • Zhou J.J.
        • Lohmer L.R.L.
        The approved dose of ivermectin alone is not the ideal dose for the treatment of covid-19.
        Clin Pharmacol Ther. 2020; 108: 762-765
        • White P.L.
        • Dhillon R.
        • Cordey A.
        • Hughes H.
        • Faggian F.
        • Soni S.
        • et al.
        A national strategy to diagnose covid-19 associated invasive fungal disease in the icu.
        Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa1298
        • Amiya S.
        • Hirata H.
        • Shiroyama T.
        • Adachi Y.
        • Niitsu T.
        • Noda Y.
        • et al.
        Fatal cytomegalovirus pneumonia in a critically ill patient with covid-19.
        Respirol Case Rep. 2021; 9e00801
        • Niitsu T.
        • Shiroyama T.
        • Hirata H.
        • Noda Y.
        • Adachi Y.
        • Enomoto T.
        • et al.
        Cytomegalovirus infection in critically ill patients with covid-19.
        J Infect. 2021; https://doi.org/10.1016/j.jinf.2021.07.004