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〈Case Report〉

Treatment of two cases of COVID-19 with ciclesonide
resulted in amelioration of pneumonia symptoms
Tomoya Tsuchida1, Yukitaka Yamasaki2, Hiroyuki Kunishima2,
Kentaro Sato3, Minoru Kanazawa3, Asami Moriuchi3,
Daiki Morikawa3, Mumon Takita3, Yoshiyuki Naito1, Shuichi Fujii3,
Shigeki Fujitani3 and Takahide Matsuda1
1

Division of General Internal Medicine, Department of Internal Medicine,
St. Marianna University School of Medicine, Kanagawa, Japan2
Department of Infectious Diseases, St. Marianna University School of Medicine,
Kanagawa, Japan3
Department of Emergency and Critical Care Medicine, St. Marianna
University School of Medicine, Kanagawa, Japan(Received for publication April 15, 2020)

We have observed two cases in which ciclesonide, an inhaled steroid drug forbronchial asthma, had a possibly useful eﬀect on novel coronavirus disease(coronavirus disease 2019: COVID-19) pneumonia. Our observations suggest thatciclesonide treatment may ameliorate the clinical symptoms of COVID-19; however,further studies on a larger number of cases are required to conﬁrm the therapeutic
eﬀects of ciclesonide.

Introduction
The novel coronavirus disease (coronavirus disease 2019: COVID-19), which originated in
Wuhan City, Hubei Province, China in December 2019, is rapidly spreading worldwide1). On the
Diamond Princess ship (a cruise ship), which docked in Japan, 3,711 passengers and crew were
tested for COVID-19 using the reverse transcription polymerase chain reaction (RT-PCR) test forsevere acute respiratory syndrome coronavirus (SARS-CoV-2) and 712 tested positive2). This infection is highly contagious and could be aggravated. Drugs used for treating cases of hepatitis B,
human immunodeﬁciency virus (HIV), Ebola hemorrhagic fever, and malaria have been considered for treatment of COVID-193); however, their eﬀectiveness remains unknown and no treatCorresponding author: Tomoya Tsuchida, Tel: ＋81–44–977–8111, E-mail: t2tsuchida@marianna-u.ac.jp

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ment methods have been established yet. Previously, ciclesonide was shown to inhibit the replication of Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 in vitro4,5),
and it exerted a similar eﬀect on COVID-19 cases in Japan6). Although there is basic and eﬀective
data available for ciclesonide and some studies have reported its potential clinical eﬀectiveness asa medicine, to date, only one study is available in Japanese on the eﬀectiveness of the drug intreatment of COVID-196). Here, we have detailed our observations of two patients admitted toour hospital with COVID-19 who showed improvement in their symptoms upon treatment withciclesonide.

Case Studies
Case 1Case 1 is a 34-year-old Thai man without a preexisting disease or history of smoking. A
waiter on the cruise ship had a fever of 39°C four days before admission and a cough with dyspnea on exertion three days before admission. He complained of right lower quadrant abdominal
pain two days before admission. His nasopharyngeal COVID-19 RT-PCR test was found to bepositive, and he was transferred to our hospital. On admission, his vital signs were blood pressure(BP) 130/85 mmHg, pulse rate (PR) 96/min, respiratory rate (RR) 22/min, temperature (T)38.6°C, and SPO2 97% at rest on room air and 92% during exertion. Analysis of breath sound revealed crackles in the lower zones of both the lungs and tenderness in the right lower area of theabdomen. On the same day, oxygen treatment was started at a rate of 2 L/min. Blood testing results were: WBC, 4,900×103/µL (neutrophils, 70.9%; lymphocytes, 20.7%; monocytes, 7.8%;
and eosinophils, 0.3%); Hb, 13.6 g/dL; platelets, 246×103/µL; LDH, 390 U/L; CRP, 5.33 mg/dL;
procalcitonin, 0.21 ng/mL; and NT-proBNP, 23 pg/mL; no abnormalities in the liver or kidney
function were observed (Table 1). Chest X-ray and computed tomography (CT) revealed inﬁltrative shadows and ground-glass opacities (GGOs) in the bilateral lung ﬁelds (Figures 1a, 1b). Further, moderate enlargement of the appendix was noted. After obtaining various culture specimens,
we began to administer 500 mg azithromycin and 2 g ceftriaxone intravenously once daily. We
began 500 mg metronidazole orally thrice daily in consideration of the risk of concomitant appendicitis, too. The tests for blood culture, Streptococcus pneumoniae and Legionella urinary antigens, Mycoplasma pneumoniae antibodies, Chlamydia IgA and β-D glucan, and other pneumonia-causing pathogens were negative, and no unusual bacteria were detected in the sputum
culture. On day 2, the vital signs were BP 120/76 mmHg, PR 104/min, RR 25/min, and T 39.4°C,
and oxygen treatment at the rate of 4 L/min was occasionally required. After obtaining consent,
we administered ciclesonide at 200 µg per dose, with two inhalations daily. On day 5, his fever
subsided, and on day 6, his SPO2 on room air was found to be 97%. Chest X-ray and CT on day 6
showed remarkable improvement in the GGOs in the lung ﬁelds (Figures 1c, 1d). His abdominal

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Table 1. Vital sings and biochemistry date of a 34-year-old man and a72-year-old man with pneumonia caused by COVID-19 on day ofadmission

pain was resolved. The nasopharyngeal RT-PCR test was negative on days 8 and 10 and he wasdischarged with full recovery on day 11. No side eﬀects of ciclesonide were observed. Figure 2
shows the treatment response course of the patient after admission to the hospital.

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Figure 1. Chest X-ray and computed tomography ﬁndings of Case 1

a. Upon admission of the patient, shadows accompanying changes due to shrinkage were conﬁrmed over wide
areas of the bilateral lung ﬁelds, with the overall lung volume being slightly reduced.
The heart shadow was also slightly enlarged.
b. High-density areas of ground-glass opacities and high-density areas accompanying changes due to shrinkage
were conﬁrmed across multiple lobes bilaterally.
The increase in heart size and a small amount of pleural eﬀusion in bilateral lung ﬁelds were also conﬁrmed.
c. On hospital day 6, improvements were observed in the overall shadows of the lung ﬁelds and in the lung volume
and size of the heart shadow.
d. The conﬁrmed shadows showed overall improvement, and lung volume was also improved. The bilateral pleural
eﬀusion was also reduced.

Case 2
A 73-year-old Japanese man, also a passenger on the same cruise ship, had cough and feverof 37.5°C four days before admission and his nasopharyngeal swabs were found to be positive for
COVID-19 using RT-PCR two days before admission. One day prior to admission, he was transferred to a diﬀerent hospital, where CT scan revealed GGOs and he required O2 at 2 L/min. Later,
he was transferred to our hospital. He had no history of smoking. His only known medical history
was hypertension, for which he was taking amlodipine at 2.5 mg/day. On admission, his vital
signs were BP 125/76 mmHg, PR 75/min, RR 22/min, T 37.5°C, and SPO2 99% following O2
treatment at a rate of 4 L, which was administered via a face mask. Blood testing results were:
WBC, 4,600×103/µL; Hb, 14.7 g/dL; platelets, 141×103/µL; T bil, 1.0 mg/dL; AST 66 U/L; ALT
95 U/L; LDH 330 U/L; ALP 549 U/L; γ-GTP 370 U/L; CRP 5.33 mg/dL; and procalcitonin

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Figure 2. Hospital course of Case 1

AZM, azithromycin; CTRX, ceftriaxone; MNZ, metronidazole
The X-axis indicates the treatment period. The left Y-axis indicates body temperature and required amount ofoxygen. The right Y-axis indicates respiratory rate.
Dotted lines and straight lines indicate respiratory rates and fever, respectively.
The rectangles indicate the administration period of drugs. Open triangles indicate the days on which the RT-PCR
test was negative for COVID-19.

0.1 ng/mL; no abnormalities in kidney function were observed (Table 1). Chest X-ray and CT revealed inﬁltrative shadows and GGOs in bilateral lung ﬁelds (Figures 3a, 3b). After obtaining
various culture specimens, we began to administer 500 mg azithromycin and 2 g ceftriaxone intravenously once daily and 400 mg/100 mg lopinavir/ritonavir orally twice daily. We performed anevaluation similar to that in Case 1 and observed that the test for pneumonia due to other pathogens was negative. On day 4, O2 treatment at a rate of 6 L/min was necessary on exertion, butthereafter, the condition of the patient improved. On day 11, he required O2 treatment at the rate

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Figure 3. Chest X-ray and computed tomography ﬁndings of Case 2

a. On admission, light shadows were found in the bilateral lung ﬁelds, but they were primarily peripheral and more
towards the right side.
b. High-density areas of ground-glass opacities and irregular high-density areas were conﬁrmed, primarily
peripherally, in the bilateral lung ﬁelds along with changes due to shrinkage.
c. On hospital day 16, the shadows were somewhat enlarged bilaterally, and changes due to shrinkage were also
noticeable. The lung volume was slightly reduced overall.
d. Irregular high-density areas of the main body were apparent in the posterior region of the bilateral lower lobes,
and the changes due to shrinkage had also increased and were accompanied by mildly dilated peripheral bronchi
within the lesions.
e. On hospital day 23, both the shadows within the lung ﬁelds and the lung volume were improved.
f. Absorbance of the lesions in the lung ﬁelds was reduced overall, and the changes due to shrinkage were also
improved. Fibrous network structures thought to represent ﬁbrous changes and areas of bronchial dilation
remained.

of 1 L/min at rest and 3 L/min on exertion, but the nasopharyngeal RT-PCR test remained positive(40 copies/5 μL). Chest X-ray and CT scan on day 16 showed partial reduction of the inﬁltrative
shadows in his lungs (Figures 3c, 3d), and the nasopharyngeal RT-PCR test remained positive (50copies/5 µL). After obtaining consent, we began to administer ciclesonide at 200 µg per dose,with two inhalations per day. On day 19, oxygenation at rest was deemed unnecessary, and on
day 20, his nasopharyngeal RT-PCR test was found to be negative. The following day, oxygenation on exertion was also deemed unnecessary. On day 22, his nasopharyngeal RT-PCR test remained negative, and chest X-ray and CT on day 23 showed signiﬁcant improvement in the shadows in both lung ﬁelds (Figures 3e, 3f). He was discharged with full recovery on hospital day 25.
No side eﬀects of ciclesonide were observed. Figure 4 shows the treatment response course of theJune 2020

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Figure 4. Hospital course of Case 2

AZM, azithromycin; CTRX, ceftriaxone; LPV/r, lopinavir/ritonavir.
On the X-axis, treatment period is indicated. The left Y-axis indicates body temperature and required amount ofoxygen. The right Y-axis indicates respiratory rate. Dotted lines and straight lines indicate respiratory rates andfever, respectively. Rectangles indicate the administration period of drugs. Filled triangles indicate days on which
RT-PCR test was positive for COVID-19. Open triangles indicate days on which RT-PCR was negative for COVID19.

patient after admission to the hospital.

Discussion
Various drugs have been considered for the treatment of COVID-193). Some have not been
eﬀective, as reported in a randomized clinical trial of a drug used for treating HIV (lopinavir/ritonavir and arbidol) in China7), while clinical trials for others are ongoing, e.g., remdesivir in the
United States8) and favipiravir in Japan. The US Center for Disease Control and Prevention currently does not recommend the use of steroids for treatment of COVID-19, except in case of
acute exacerbation of chronic obstructive pulmonary disease and septic shock9).
Ko et al. (2020) reported that ciclesonide suppresses the growth of a clinically isolated strainof the MERS-CoV4) and Matsuyama et al. (2020) conﬁrmed that ciclesonide blocks the replication of coronavirus RNA by targeting the viral NSP155). Iwabuchi et al. (2020) reported to theJapanese Association for Infectious Diseases that they have obtained tentatively positive results
after administering ciclesonide in patients with COVID-196). After inhalation, esterases in the42（ 8 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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lungs convert ciclesonide into active metabolites with strong glucocorticoid aﬃnity that act locally within the lungs, resulting in reduced ciclesonide migration into the peripheral blood andfewer side eﬀects10). In the attached document of their paper, side eﬀects (including abnormal
laboratory ﬁndings) were reported in 45 out of 588 (7.7%) ciclesonide-treated cases. The breakdown was 35 cases (6.0%) with subjective/objective side eﬀects and 12 cases (2.0%) with abnormal laboratory ﬁndings. Main subjective/objective side eﬀects included 5 cases of dyspnea(0.9%), 5 cases of hoarseness (0.9%), and 3 cases with skin rash (0.5%). According to them, abnormal laboratory ﬁndings as side eﬀects included 4 cases with urine protein (0.7%), 3 cases withincreased AST (GOT) (0.5%), and 3 cases with increased ALT (GPT)11). Ciclesonide has been
available since 2007. In fact, it is a safe drug that is widely used in asthmatic patients, including
the elderly.
As for Case 1, lopinavir/ritonavir were used previously for three other critically ill patientsin our hospital. However, no eﬀects were observed upon administration of the drugs, and thus, we
had been considering the use of other eﬀective agents. We then decided to use ciclesonide, whoseeﬀectiveness was reported in a crisis-response expansion meeting for measures against SARSCoV-2, organized by the Novel Coronavirus Response Headquarters and held at the National Institute of Infectious Diseases on February 19.
The dosage recommended in this meeting was used. Ciclesonide was administered in response to progressive hypoxemia. As a result, oxygenation was deemed unnecessary, despite theneed for O2 administration at the rate of 4 L/min four days earlier. Although it is unclear whether
this was the natural course of the disease, the improved treatment progress in this patient lends
support to the eﬃcacy of ciclesonide.
The eﬀectiveness of lopinavir/ritonavir against severe acute respiratory syndrome (SARS)
and Middle East Respiratory Syndrome (MERS) have been suggested in the past12,13). In Case 2,
lopinavir/ritonavir were used since the admission of the patient to our hospital, but his nasopharyngeal swabs remained RT-PCR-positive. His samples continued to be RT-PCR-positive and noprospective treatment strategy was determined. The introduction of Home oxygen therapy (HOT)
following hospital discharge was considered. Case 1 suggested the possible eﬃcacy of ciclesonide, we started administering it for Case 2. As a result, three days after starting ciclesonide
treatment, the nasopharyngeal swab samples of the patient were found to be RT-PCR-negative,
and his lung shadows were improved. Oxygenation at the rate of 1 L/min at rest and 3 L/min on
exertion became unnecessary 5 days after the initiation of ciclesonide treatment. In both cases,
ciclesonide appeared not only to have an anti-inﬂammatory eﬀect on COVID-19, but also an antiviral eﬀect, and such an eﬀect may be expected in both acute and sub-acute stages of COVID-19.
After these cases, the Japanese Society of Infectious Diseases announced the concept of drug
treatment for COVID-1914). It also mentioned ciclesonide.
More COVID-19 cases must be studied to verify the eﬃcacy of ciclesonide. Although theJune 2020

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harmful eﬀects of long-term administration of inhaled corticosteroids must be considered, no
proven eﬀective treatments to curb this explosive expansion of the COVID-19 pandemic havebeen reported thus far. Thus, we have reported our ﬁndings observed in these two cases.

Conclusion
Ciclesonide appeared to be useful in the treatment of two cases of COVID-19. It may be apotential drug for the treatment of COVID-19 in the future; thus, its eﬃcacy has to be ascertained
through more studies.
Acknowledgements
The authors thank Takafumi Ono and Shoichiro Matsushita, Department of Radiology, St.
Marianna University School of Medicine, for their advice. The authors also thank Tina Tajima,
Research Institute for Medical Education, St. Marianna University School of Medicine, for her
assistance with English editing.
Funding
No ﬁnancial support was received for this study.
Conﬂict of interest
There is no conﬂict of interest.

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