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〈Case Report〉

Three cases of COVID-19 pneumonia treated withivermectin monotherapy
Kosuke Jo1, Hironori Goto2, Tsunetoshi Mogi2,Kenji Kono1 and Takafumi Ueno3
1

Department of Infectious Diseases, Fukuoka Kinen Hospital, Fukuoka, Japan
2
General Medical Department, Fukuoka Kinen Hospital, Fukuoka, Japan3
Department of Cardiovascular Medicine, Fukuoka Kinen Hospital, Fukuoka, Japan(Received for publication Mmmm dd, 2021)

We report three cases of coronavirus disease 2019 (COVID-19) pneumonia treatedwith ivermectin monotherapy. The patients included two men (aged 40 and 49 years)
and a woman (aged 53 years), all of whom had high fever and bilateral pneumonia.
We administered 0.2 mg/kg of ivermectin orally every alternate day. Theydefervesced soon after, the blood inﬂammatory markers and chest radiographic
ﬁndings improved and the patients were discharged. There was no need for
additional therapy. These three patients improved following ivermectin
administration. Oral ivermectin may have a role to play in the home treatment ofCOVID-19 patients.

Introduction
Ivermectin, a Nobel Prize-winning drug, has been used worldwide since 1987 for the treatment of river blindness, lymphatic ﬁlariasis, strongyloidiasis, and scabies1). It is a well-tolerated,
low-cost medication. The coronavirus disease 2019 (COVID-19) pandemic began in Wuhan,
China, in December 2019 and subsequently spread worldwide. In April 2020, Caly et al. foundthat ivermectin suppresses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro2), and it has been clinically used for the treatment and prevention of COVID-19
worldwide. Numerous clinical trials have been performed in various countries to conﬁrm the eﬃcacy and safety of ivermectin for COVID-19. In Japan, Kitasato University is currently conducting a doctor-initiated clinical trial1).
Corresponding author: Kosuke Jo, Department of Infectious Diseases, Fukuoka Kinen Hospital; 1–1–35 Nishijin, Sawara-ku,
Fukuoka-city, Fukuoka 814–8525, Japan, Tel: ＋81–92–821–4731, Fax: ＋81–92–821–6449, E-mail: kousuke-j@oita-u.ac.jp

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74―3211（ 31 ）Fukuoka Kinen Hospital is an acute-care hospital consisted of 239 beds. Since April 2020,
three to twenty COVID-19 patients have been hospitalized at any time in dedicated isolation
wards. In April 2021, oﬀ-label use of ivermectin for COVID-19 was approved by ethics committee in our hospital, and we have begun to use it for inpatients with mild or moderate disease, after
obtaining informed consent. The severity of COVID-19 was deﬁned as follows: mild: oxygen saturation (SpO2)≧96% on room air and no respiratory symptom (coughing only, no shortness ofbreath), moderate I: 93%＜SpO2＜96%, (shortness of breath and pneumonia ﬁndings), moderate
II: SpO2≤93% oxygen administration required, and severe: admission to ICU or mechanical ventilator required, according to the Severity Classiﬁcation of COVID-19 in our country3).
We administered oral ivermectin (0.2 mg/kg/day) on Days 1, 3 and 5 (where Day 1 is the ﬁrst
day of admission) to patients (Niaee MS, manuscript in preparation). We decided to add steroids
or tocilizumab if there were persistent high fever and inﬂammatory markers worsened. Glycyrrhizin preparations were added if liver damage occurred.

Case Studies
Case 1
A 40-year-old man presented with a 10-days history of fever and a several-day history of diarrhea before hospitalization. A nasopharyngeal swab tested positive for SARS-CoV-2 using
polymerase chain reaction (PCR) in another hospital, three days before admission to our hospital.
He had no signiﬁcant medical history but had been a long-time smoker (current smoker). Findings on physical examination included: SpO2 on room air 97%, body temperature 39.3°C, bloodpressure 138/98 mmHg, heart rate 100 beats/min, his height 171 cm, weight 69 kg, and body massindex (BMI) 23.6 kg/m2. Laboratory ﬁndings included: white blood cell (WBC) count of 5,940/μL,platelet (PLT) count of 20.3×104/μL, mildly elevated liver enzyme levels (aspartate aminotransferase (AST) 44 IU/L, alanine aminotransferase (ALT) 55 IU/L), elevated lactate dehydrogenase(LDH) levels 389 U/L, and C-reactive protein (CRP) levels 5.67 mg/dL. Blood urea nitrogen(BUN) 12 mg/dL, creatinine (Cr) 0.95 mg/dL, D-dimer 1.80 μg/mL, ferritin 472 ng/mL, and sialylated carbohydrate antigen KL-6 251 U/mL. Chest computed tomography (CT) showed peripheral predominant, multiple ground-glass opacities (Fig. 1A). He received 15 mg ivermectin
three times every other day from the date of admission (Day 1, Day 3, and Day 5). From Day 4
onwards, defervescence below 37°C was observed along with improvement of LDH and CRPlevels (Fig. 2). On Day 8, computed tomography (CT) after treatment with ivermectin showed animprovement of the pneumonia (Fig. 1B). No adverse eﬀects of ivermectin were observed. Thepatient was discharged on Day 8.

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Fig. 1. (A) Chest computed tomography on admission showed multiple ground glass opacities inboth lung ﬁelds. (B) On Day 8, chest computed tomography showed improvement of thepneumonia

Fig. 2. Clinical course of Case 1** glycyrrhizin preparation

Abbreviations: AST, aspartate transaminase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CRP,C-reactive protein; BT, body temperature; SpO2, oxygen saturation

Case 2A 49-year-old man presented with fever persisting for nine days. He was referred to our hospital and was admitted immediately. On admission, a nasopharyngeal swab tested positive for
SARS-CoV-2 using reverse transcription-loop-mediated isothermal ampliﬁcation (LAMP). His
medical history included hypertension, myocardial infarction, and borderline diabetes. Findingson physical examination included: SpO2 on room air 93%, body temperature 38.8°C, blood pressure 129/84 mmHg, heart rate 86 beats/min, his height 174 cm, weight 91.0 kg, and BMI 30 kg/

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74―3213（ 33 ）Fig. 3. (A) Chest computed tomography on admission showed multiple ground glass opacities
around bronchovascular bundles bilaterally. (B) On Day 8, chest computed tomography
showed improvement of the pneumonia

Fig. 4. Clinical course of Case 2** glycyrrhizin preparation

Abbreviations: AST, aspartate transaminase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CRP,C-reactive protein; BT, body temperature; SpO2, oxygen saturation

m2. Laboratory ﬁndings included: WBC count of 4,400/μL, decrease in PLT 9.8×104/μL, elevated liver enzyme AST 64 U/L, ALT 66 U/L, LDH 416 U/L, BUN 9 mg/dL, Cr 0.97 mg/dL, CRP
5.63 mg/dL, D-dimer 1.70 μg/mL, ferritin 406 ng/mL. Chest CT showed multiple ground-glass
opacities around bilateral bronchovascular bundles (Fig. 3A). He received 18 mg ivermectin threetimes every other day and oxygen inhalation at 1 L/min from the date of admission. From Day 4
onwards, defervescence was observed along with improvement of LDH and CRP levels. Oxygeninhalation was discontinued on Day 6 (Fig. 4). On Day 8, chest CT showed improvement in thepneumonia (Fig. 3B).

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Fig. 5. Chest computed tomography on admission showed wide ground glass opacity withinterlobular septal thickening in the right middle lobe

Fig. 6. Clinical course of Case 3** glycyrrhizin preparation

Abbreviations: AST, aspartate transaminase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CRP,C-reactive protein; BT, body temperature; SpO2, oxygen saturation

Case 3A 53-year-old woman presented with a sore throat and cough for six days prior to hospital admission. She had a fever of 40°C the day before admission. A nasopharyngeal swab tested positivefor SARS-CoV-2 using PCR in a clinic, one day prior to admission to our hospital. She had no signiﬁcant past medical history. Findings on physical examination included; SpO2 on room air 98%,

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74―3215（ 35 ）body temperature 38.7°C, blood pressure 112/82 mmHg, heart rate 113 beats/min, her height
165 cm, weight 72 kg, and BMI 26.4 kg/m2. Laboratory ﬁndings included: WBC count of 5,220/μL,
PLT 20.3×104/μL, elevated liver enzyme AST 55 U/L, ALT 59 U/L, LDH 380 U/L, BUN 10 mg/dL,
Cr 0.71 mg/dL, marked increase of CRP levels 15.52 mg/dL, D-dimer 2.0 μg/mL, KL-6 208 U/mL,
ferritin 962 ng/mL. Chest CT showed multiple subpleural ground-glass opacities and widespread
opacity with thickening of alveolar septum in the right middle lobe (Fig. 5). She received 15 mg
ivermectin three times every other day. From Day 4 onwards, defervescence below 37°C was obtained, and CRP levels decreased until discharge on Day 10. Chest radiography on discharge
showed improvement of the inﬁltrative shadow in the right lung (Fig. 6).

Discussion
Ivermectin is a potent inhibitor of SARS-CoV-2 in vitro2). Many small-sized clinical trials of
ivermectin have been conducted worldwide, and they reveal the eﬃcacy of ivermectin at various
end points, such as on length of hospital stay, mortality, and symptom improvement4,5). Thus,ivermectin is a candidate for the treatment of COVID-19, although it has not been formally approved in Japan. We referred to a randomized phase II clinical trial conducted in Iran, in which
there was signiﬁcant diﬀerence between Ivermectin groups and Control groups in improvementof inﬂammatory marker and mortality. Administration of 0.2 mg/kg ivermectin three times every
other day was one of four regimens in Ivermectin groups. The administered dose of 0.2 mg/kg is
the dose for indication disease of ivermectin in Japan, so we thought this regimen would be safer
than high dose regimens.
The mechanism of ivermectinʼs antiviral action is thought to be due to inhibition of importin
α/β1-mediated nuclear import of viral proteins, resulting in the reduction of viral RNA replication2, 5, 6). One of the prominent features of severe COVID-19 is cytokine release syndrome (CRS)
which activates monocytes and macrophages resulting in the secretion of various cytokines suchas IL-65,7). Fortunately, ivermectin has antiviral and anti-inﬂammatory properties, which decreases the production of TNF-α, IL-1, and IL-6 in vivo and in vitro5,8). Therefore, ivermectin administration may not only be eﬀective in the early stages of infection, but also could have a rolein the later stages because of its anti-cytokine properties9,10). Indeed, in our cases the durationfrom disease onset to ivermectin administration was 6 to 10 days, suggesting that they may nothave been in the early stages of disease. Re-ascent of CRP, suggestive of CRS, was not observedin all cases, and clinical symptoms, physical examination, and clinical parameters improved concurrently after administration of ivermectin.
In Japan, the COVID-19 pandemic has rapidly reduced the number of available hospital
beds. Moreover, there are currently no therapeutic agents available for outpatients. Remdesivir is
not suitable for home treatment because it is administered intravenously and is not recommended

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for mild disease3). To solve these problems, a home treatment plan for outpatients with mild
COVID-19 must be established immediately11). Case 1 and 3 were healthy adults who did nothave any signiﬁcant past medical history and did not require oxygen inhalation. If it were possible to prescribe ivermectin for the treatment of COVID-19 out of hospital, they could recover athome. Outpatient ivermectin use may lead to an increased availability of hospital beds. Case 2
had underlying diseases that were risk factors for severe infection12). In addition, the demand forinhaled oxygen made us consider the administration of steroids13). However, ivermectin monotherapy was followed by an improvement in the patientʼs overall status. Ivermectin monotherapy
without steroid administration, could bring a signiﬁcant beneﬁt to patients who have underlying
diseases which get worse by administering steroids, such as diabetes mellitus and immunocompromised state.
In conclusion, oral ivermectin monotherapy has the potential to be a therapeutic agent, especially for patients with mild COVID-19. A large randomized controlled trial of ivermectin hometreatment is needed to validate its eﬃcacy and safety. If successful, this could prevent a shortageof hospital beds for COVID-19 patients in our country.
Conﬂicts of interest
The authors have no conﬂicts of interest to declare.
Ethical statement
Consent to publish the details of their case was obtained from the patient.

References
1) Yagisawa M, Foster PJ, Hanaki H, Omura S: Global trends in clinical studies of ivermectin in
COVID-19. Jpn J Antibiot. 2021; 74: 44–95.
2) Caly L, Druce JD, Catton MG, Jans DA, Wagstaﬀ KM: The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020; 178: 104787.
3) The Ministry of Health, Labour and Welfare: Clinical management of patients with COVID-19. A
guide for front-line healthcare workers Version 5 (in Japanese). 2021.5.26. https://www.mhlw.
go.jp/content/000785119.pdf
4) Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ: Use of ivermectin is associatedwith lower mortality in hospitalized patients with Coronavirus disease 2019: the ivermectin in
COVID nineteen study. Chest. 2021; 159: 85–92.
5) Kory, P, Meduri, GU, Varon, J, Iglesias J, Marik, PE: Review of the emerging evidence demonstrating the eﬃcacy of ivermectin in the prophylaxis and treatment of COVID-19. Am J Ther.
2021; 28: e299–e318.
6) Martin AJ, Jans DA: Antivirals that target the host IMPα/β1-virus interface. Biochem Soc Trans.
2021; 49: 281–95.
7) Subbarao K, Mahanty S: Respiratory virus infections: understanding COVID-19. Immunity. 2020;

Sept. 2021

8)
9)
10)
11)
12)
13)

THE JAPANESE JOURNAL OF ANTIBIOTICS

74―3217（ 37 ）52: 905–9.
Zhang X, Song Y, Ci X, et al.: Ivermectin inhibits LPS-induced production of inﬂammatory cytokines and improves LPS-induced survival in mice. Inﬂamm Res. 2008; 57: 524–9.
Heidary F, Gharebaghi R: Ivermectin: a systematic review from antiviral eﬀects to COVID-19
complementary regimen. J Antibiotics. 2020; 73: 593–602.
DiNicolantonio JJ, Barroso-Arranda J, McCarty M: Ivermectin may be a clinically useful anti-inﬂammatory agent for late-stage COVID-19. Open Heart. 7: e001350, 2020.
Ayaz CM, Dizman GT, Metan G, Alp A, Unal S: Out-patient management of patients with
COVID-19 on home isolation. Infez Med. 2020; 28: 351–6.
Gandhi RT, Lynch JB, Del Rio C: Mild or moderate Covid-19. N Engl J Med. 2020; 383: 1757–66.
Recovery Collaborative Group, Horby S, Lim WS, et al.: Dexamethasone in hospitalized patientswith Covid-19. N Engl J Med. 2021; 384: 693–704.