Three Cases of the Early to Mid-stages of COVID-19 Pneumonia Improved by Inhalation of Ciclesonide[Note: This text is based on a machine translation of the original Japanese text.]Keisuke Iwabuchi, Koichiro Yoshie, Yuichi Kurakami, Kota Takahashi, Yoshio KatoKanagawa Prefectural Ashigarakami HospitalTsuneo MorishimaAichi Medical UniversityAs a Designated Medical Institution for Class II Infectious Diseases, our hospital has been accepting patients with confirmed SARS-CoV-2 since February 5, 2020, and as of February 28, 8 patients had been hospitalized (The infectious disease ward where inpatient treatment is carried out has an independent negative pressure ventilation environment that does not intersect with general practice). Inhalation of ciclesonide (Trade name: Alvesco), whose efficacy was introduced in the "Emergency meeting on measures against new coronavirus infections" conducted on February 19, was started in 3 patients with hypoxia and CT findings on February 20, and we report the favorable progress. In the case report, it was explained to all patients, and the consent was obtained.Case 1: A 73 year-old femaleShe boarded the Diamond Princess on 20 January 2020 and landed in Hong Kong on 25 January. Pharyngeal pain, malaise, and anorexia were observed on February 4, and pyrexia of 38 ° C developed on February 7. The specimen was submitted on February 8, and on February 10, it was determined to be positive for SARS-CoV-2 by a pharyngectomy PCR test. The ship disembarked on February 11 and was transported to our hospital. Clear consciousness, BP 105/65, pulse 103/min, respiratory rate 11/min, temperature 36.7 ° C, SpO2 94%/RAPhysical findings: No redness of pharynx, no swollen lymph nodes, and respiratory sound was fine crackles at the end of inspiration in both dorsal lower lung fields.Medical history: Collagen disease was pointed out, but no treatment was given and the patient is being followed up.Antinuclear antibody (discrete type) was 1,280 times in blood taken at the time of admission, and scleroderma was suspected due to poor color tone of fingers.・Laboratory findings (Table1)[omission]・Image findingChest X-ray (2/11): An infiltrative shadow was observed in the right lower lung field (Fig.1)CT (2/11): Bilateral mid- and lower lung fields with GGO along the pleura (Fig 2)Fig. 3: Day 9 of hospitalizationFig. 4: Day 18 of hospitalization The treatment was started with 1 L/min of nasal O2 to maintain SpO2 at 95% or more from the time of admission. The patient was feeling fatigued and was almost confined to bed with little food intake. Poor communication and disorientation were observed, and the patient had no memory before or after hospitalization. Maintenance fluid therapy and CTRX, AZM were started, but oxygenation gradually worsened. Pyrexia of 38 ° C or higher and poor oral intake continued. At 2/14, O2 of 4 L/min was required to maintain SpO2 of 95% or more, and 4 tablets of Lopinavir/Ritonavir (LPV/r) (800/200 mg) were started. After starting LPV/r, pyrexia tended to decrease and oxygenation improved, but O2 1 -2 L nasal was required to maintain SpO2 of 95 or more. SpO2 easily decreased to 80s by body motion.Her appetite did not improve, and her malaise was marked. A 2/19 CT scan showed an enhanced GGO shadow and an enlarged area (Fig 3). In addition, since diarrhea and liver enzyme elevation appeared, it was considered to be an adverse event of LPV/r together with anorexia, and LPV/r was stopped at 2/19. ciclesonide inhalation from 2/20 started (200 μg 2 times/day). Since poor oral intake reached 1 week, transnasal tube feeding was started.Approximately 2 days after starting ciclesonide, pyrexia of 37.5 ° C or higher was not observed, oxygenation was improved, SpO2 was maintained at 95% or higher in room air, and hypoxemia during body movement was improved. The appetite was remarkably recovered, and the tube feeding was stopped, since about 1,200 kcal could be taken orally in 2/22. The whole-body feeling of fatigue was also improved, and the indoor independent walking became possible. It was judged that the symptom was improved, and SARS-CoV-2 negative was confirmed by nasal cavity wiping liquid PCR on 2/25 and 2/26 day, and the patient left hospital on 2/28. The pneumonia image was obviously improved by CT (2/27) before discharge (Fig.4). At present, inhalation of 400 μg 2 times a day is continued until the completion of the kit, and outpatient follow-up is planned.Case 2: A 78 year-old maleOn January 20, 2020, he boarded the Diamond Princess. On February 6, he developed dry cough, malaise, anorexia, and diarrhea, and was almost unable to eat solid food. The exothermic reaction of 37.4 ° C was also recognized. The pharynx wiping PCR performed on February 16 was positive, and the patient was hospitalized in our hospital at 21 on February 16. The patient was lucid but had significant malaise, blood pressure 146/83, pulse rate 75/min, respiratory rate 16/min, body temperature 37.5 ° C, SpO2 99%/RAPhysical findings: no redness of pharynx, no lymphadenopathy, no abnormal murmur in lung sounds.Medical history: noneSmoking history: Previously smoking 80 cigarettes/day, but now quitting smoking・Laboratory findings (Table 2)・image findingChest X-ray (2/17): An infiltrative shadow was observed in the right lower lung field (Fig.5).CT (2/18): Bilateral middle and lower lung field GGO (Right > Left) (Fig. 6) The patient's body temperature was 37.2 ° C at the time of admission, but pyrexia of 38 ° C was observed from the next day. Oxygenation was also good at the time of admission, but SpO2 decreased from 2/19 to 90 ~ 88%, and 1 L/min of nasal O2 was started. The goal was to maintain the SO2 at 95% or more, but 2/20 required an increase to O2 2L. Information was obtained in 2/19, and ciclesonide (200 μg 2 times/day) was started in 2/20.The patient had persistent watery stools and had almost no food from the time of admission. However, his appetite gradually improved from 2/21, and his diarrhea also recovered and he passed normal stools. Oxygen can be discontinued in 2/22, and fatigue improved. He ate almost all of his meals and recovered to the extent that he performed daily squats indoors.Throat wiping PCR was positive in 2/25 of the patients and was positive in 2/27 of the patients. The dose of ciclesonide was increased to 1,200 μg/day (400 μg 3 times/day) and the treatment is being continued.Case 3: A 67 year-old femaleOn January 20, 2020, she boarded the Diamond Princess. A dry cough developed on February 6, malaise and arthralgia developed on February 8, and a fever of 38.9 ° C developed on February 9, followed by anorexia and diarrhea, and almost no food was consumed. SARS-CoV-2 PCR performed on February 16 was positive. The patient was transferred to our hospital and hospitalized on February 16. Clear consciousness, BP 125/86, pulse 88/min, respiratory rate 18/min, temperature 36.4 ° C, SpO2 99%/RAPhysical findings: no redness of pharynx, no lymphadenopathy, no abnormal murmur in lung sounds.Medical history: An abnormal shadow on an X-ray was pointed out by a medical examination and is being followed up by CT.・Laboratory findings (Table3)・Image findingChest X-ray (2/17): Infiltrative shadow was found in hilar region of right middle lung field (Fig. 7).CT (2/21): Bilateral middle and lower lung fields showed GGO. Cavitary lesion with bronchiectasis and calcification was found in the right lung (Fig.8). The patient had a history of pulmonary cavitary lesions in other hospitals and was being followed up without any signs of exacerbation. The patient had difficulty in expectorating sputum at the time of admission, so no mycobacterial test was performed. The patient's body temperature was 36.4 ° C and oxygenation was good. He had fatigue and was often lying in bed. Meals are about half. Ciclesonide was started in 2/20 for the purpose of prevention of aggravation, fine crackles were heard from the dorsal side by chest auscultation in 2/21, and GGO was recognized in the bilateral dorsal lower lung fields by CT. Since SpO2 decreased to less than 90% during body movement on the same day, administration of O2 1 L/min nasal was started. When the patient was followed up only with ciclesonide administration, oxygenation was improved in 2/22, and oxygen administration could be discontinued. Appetite tended to improve in the afternoon on 2/20, and total intake became possible on 2/22, and general malaise rapidly improved.The pharyngectomy PCR test was positive in 2/25 and 2/27. Therefore, the inhalation dose was increased to 1,200 μg/day 3, and the treatment is being continued.Knowledge and Discussion up to the Present(1) Knowledge of ciclesonideCiclesonide (Product name: Alvesco), an existing inhalant for the treatment of bronchial asthma, has been reported to have strong antiviral activity against this virus from the Coronavirus Laboratory at the National Institute of Infectious Diseases' Murayama Branch.Ciclesonide is a safe inhalation steroid widely used from premature infants and newborns to the elderly, and is effective in suppressing chronic inflammation of the respiratory tract. The pathology of COVID-19 lung injury has not yet been clarified. However, it is assumed from MERS and SARS that the virus proliferates in alveolar epithelial cells, causing lung injury, and at the same time infects alveolar macrophages and other organs, causing local inflammation. The antiviral and anti-inflammatory properties of ciclesonide are expected to be effective in the treatment of lung injury during the transition to severe disease. Inhaled steroids other than ciclesonide do not currently demonstrate antiviral activity of COVID-19.It has been reported that steroid therapy for COVID-19 is not recommended due to the possibility of prolongation of viremia and complications such as diabetes 1), but it refers to systemic steroid administration with hydrocortisone, methylprednisolone, dexamethasone, and prednisolone. Ciclesonide is an inhaled prodrug that remains on the surface of the lungs with minimal increase in blood levels. It is desirable to administer the drug in the early to middle stage of infection or in the early stage of pneumonia before it becomes serious, and it is expected to be effective for the early negative conversion of the virus and the prevention of progress to severe pneumonia.(2) Clinical application studiesThe insured adult dosage is 400 μg/day (400 μg once/day) and the maximum dosage is 800 μg/day (400 μg 2 times/day). Professor Morishima's opinion is that (1) frequent administration is recommended based on the time of viral amplification (6 -8 hr), and high doses are recommended in order to achieve a sufficient amount in the alveoli. (2) In order to avoid reactivation of residual virus and emergence of resistant virus, it is desirable to continue for about 14 days or more after initiation. (3) Since the virus is proliferating in alveolar epithelial cells, it is considered that inhalation should be performed as deeply as possible to enhance the effectiveness. Based on the above findings, considering the dosage form, the following dosage should be used as the standard at present.―――――Adhibition: Pneumonia in confirmed COVID-19 positive patients (Asymptomatic long-term positive patients may require further investigation)Dosage and Administration:(i) Ciclesonide (Alvesco) 200 μg Inhaler 56Inhalation 2 times/day, 2 at one time → 14 days(ii) Ciclesonide (Alvesco) 200 μg Inhaler 56Inhalation 3 times/day, 2 at one time → about 9 days(i) is a basic plan. For severe or ineffective cases, (ii) should be examined. We consider that "a deep inhalation" is currently the most reasonable method for delivering drugs to the infected area.―――――Concomitant use with LPV/r is cautioned in the package insert. Since only bronchial asthma is covered by insurance, additional disease names are used. The contrivance of the administration to the elderly with weak inhalation power and patients with respiratory diseases, etc. is under examination. It can be administered using a spacer even during endotracheal intubation.(3) Adverse effectAdverse reactions to this drug were reported in 45 (7.7%) of 588 patients evaluated for safety up to the time of approval. These included subjective and objective adverse reactions in 35 patients (6.0%) and abnormal laboratory values in 12 patients (2.0%). The major adverse reactions were dyspnoea in 5 patients (0.9%), hoarseness in 5 patients (0.9%), and rash in 3 patients (0.5%). Abnormal laboratory values as adverse reactions included urinary protein in 4 cases (0.7%), increased AST (GOT) in 3 cases (0.5%), and increased ALT (GPT) in 3 cases (0.5%) (Cited from the package insert). Inhalation of ciclesonide at 1,200 μg/day in our hospital, although only a few days old, has not resulted in adverse events at this time.(4) The situation in our hospitalOur hospital accepted 8 positive cases from the cruise ship, all of whom were over 65 years old. Two patients were asymptomatic on admission and had no symptoms thereafter. They became negative and were discharged. Pneumonia with poor oxygenation and ground-glass opacity on chest CT were observed in 6 patients. Four patients had pneumonia on admission, and two were considered to have developed it after admission. In addition, 3 of the 6 patients were transferred to a higher medical institution because of severe symptoms, and 2 of them (Onset after hospitalization: 1 person) were managed by mechanical ventilation.Immediately after the acceptance, the patients who developed pneumonia were in a situation where they became almost severe, and as many reports mentioned, even if the initial symptoms were mild, they seemed to worsen rapidly 7 to -10 days after the onset. At that time, our hospital was unable to establish a system for ventilator management in the infectious disease ward, and as there was a strong sense of crisis with pneumonia patients at risk of worsening, administration of ciclesonide was started immediately upon receiving information on February 19. In particular, case 1 developed pneumonia from the time of admission, and although LPV/r was started and the acute phase of inflammation was overcome, poor oxygenation persisted, and anorexia prolonged, but LPV/r could not be stopped. The patient's physical strength was markedly decreased, and acute aggravation was feared, and CT findings showed a tendency of aggravation, so we considered changing hospitals, but we had to lower the order of transportation because there were other critically ill patients, and it was difficult to select a new hospital. It is an impressive case in which the patient rapidly recovered after the start of administration based on the information.(5) Consideration of the effectOf the 6 patients with pneumonia, 2 out of 3 required ventilator management before the introduction of ciclesonide, and 3 recovered after the introduction of ciclesonide. Of course, the background of the disease is different, and the effectiveness cannot be discussed based on this marginal result. In the future, the progress of other 3 disease cases will be summarized and reported additionally. At present, LPV/r is widely used in patients with COVID-19 , which is considered to be serious. However, adverse reactions such as diarrhea, queasy, vomiting, and abdominal pain have occurred, and pharmacokinetics in elderly patients have not been sufficiently investigated (Cited from the attached document). In in vitro result, ciclesonide is as effective as or better than lopinavir in preventing viral growth, and its effects have been compared at the same concentration, although tissue concentrations of ciclesonide aerosol reaching the alveoli are thought to be several tens of times higher. In COVID-19, it was mainly elderly patients who became more severe. For elderly patients such as Case 1, who showed frailty due to pneumonia, early administration of ciclesonide, which is safe, simple, and inexpensive (2,169 yen/kit., LPV/r = 1,289.6 yen/day), is considered to have a great advantage if an effect is established. Accumulation and examination of future use cases are desired.(6) Please cooperate in providing case accumulationWith the cooperation of Professor Morishima and other doctors, we are currently developing a protocol for a multi-site collaborative study to accumulate cases of ciclesonide use. Because of the low risk, high versatility, and urgency of ciclesonide use, it will be treated as an observational study rather than a randomized controlled trial, and will be republished after a certain number of cases have been accumulated.Currently, the use of ciclesonide for "Patients with infections or deep mycosis in the absence of effective antibiotics" is contraindicated in the package insert of Alvesco. Therefore, each medical institution should consult the Ethics Committee before using the product. If ciclesonide is used in patients with COVID -19, we ask for your cooperation in a multicenter study to evaluate its efficacy. Keisuke Iwabuchi, Kanagawa Prefectural Ashigarakami Hospitaliwabuchi@ashigarakami-hospital.jpTsuneo Morishima, Aichi Medical Universitytmorishima@aichi-med-u.ac.jpCOVID-19 肺炎初期～中期にシクレソニド吸入を使用し改善した 3 例 (Japanese)