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Keiichiro Yoshioka,1 Mitsuhiro Abe,1 Yuki Shiko,2 Ken Koshikawa,1 Yohei Kawasaki,2 Shunichiro Iwasawa,1 Jiro Terada,1,3 Kenji Tsushima,3 Koichiro Tatsumi,1 Takuji Suzuki1 1Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan; 2Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan; 3Department of Pulmonary Medicine, International University of Health and Welfare, School of Medicine, Chiba, JapanCorrespondence: Mitsuhiro Abe, Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba, 260-8670, Japan, Tel +81 43 222 2576, Fax +81 43 226 2176, Email mthrsgnm@chiba-u.jpBackground/Aim: Nab-paclitaxel (Nab-PTX) has been widely used to treat several advanced cancers. Nab-PTX can cause drug-induced lung injury (DILI); however, its clinical and radiographic features have not been clarified. We aimed to assess the clinical characteristics of Nab-PTX-induced lung injury and identify its associated risk factors.Patients and Methods: We retrospectively investigated 304 patients who received Nab-PTX at Chiba University Hospital between November 2010 and November 2017. We obtained information regarding the clinical course, laboratory findings, and chest computed tomography findings from their medical records.Results: Forty-one patients (13%) developed DILI. Grade 1 lung injury occurred in 27 patients (8.8%), grade 2, 8 patients (2.6%); grade 3, 3 patients (0.9%); grade 4, 1 (0.3%); and grade 5, 2 (0.6%). Multivariate analysis revealed that age > 56 years (odds ratio [OR]: 3.0), pre-existing interstitial lung changes (OR: 3.2), and combined drugs with gemcitabine (OR: 2.7) were independent risk factors for DILI owing to Nab-PTX administration.Conclusion: Nab-PTX-induced lung injury is not rare; however, most cases are asymptomatic (grade 1). Older age, pre-existing interstitial lung changes, and combined drugs with gemcitabine could increase the incidence of Nab-PTX-induced lung injury; such patients should be treated with greater care.Keywords: drug-induced lung injury, gemcitabine, multivariate analysis, nab-paclitaxel, risk factor

Masashi Sakayori,1 Jiro Terada,1 Mitsuhiro Abe,1 Yasutaka Hirasawa,1 Kenichi Suzuki,1 Keiichiro Yoshioka,1 Kenji Tsushima,2 Koichiro Tatsumi11Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; 2Department of Pulmonary Medicine, International University of Health and Welfare, School of Medicine, Chiba 286-8686, JapanPurpose: Although pirfenidone (PFD) is a key drug for the treatment of idiopathic pulmonary fibrosis (IPF), differences in tolerability between elderly and young patients remain unclear. This study aimed to investigate age-related differences in adverse drug reactions to PFD and to evaluate whether patient age influences the safety and tolerability of PFD in clinical practice.Patients and method: One hundred fifty-four patients with IPF were treated with PFD in our institution between May 2009 and April 2017; these patients were classified into 2 groups on the basis of age: ≥75 years of age (elderly patients) and

Takuma Matsumura,1 Jiro Terada,1 Chikara Yoshimura,2 Ken Koshikawa,1 Taku Kinoshita,1 Misuzu Yahaba,1 Kengo Nagashima,3 Seiichiro Sakao,1 Koichiro Tatsumi1 1Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan; 2Department of Respiratory and Sleep Medicine, Fukuoka University School of Medicine, Fukuoka, Japan; 3Research Center for Medical and Health Data Science, The Institute of Statistical Mathematics, Tokyo, Japan Purpose: Although patients with suspected obstructive sleep apnea (OSA) might suffer difficulty in falling asleep during overnight polysomnography (PSG), standard hypnotics to obtain sleep during PSG have not been established. The aim of this study was to investigate the safety and efficacy of a new hypnotic agent, suvorexant, a dual orexin receptor antagonist, for insomnia in suspected OSA patients during in-laboratory PSG.Patients and methods: An observational study was conducted during PSG for 149 patients with suspected OSA who had no insomnia at home. Patients with difficulty in falling asleep during PSG were optionally permitted to take single-use suvorexant. Patients with residual severe insomnia (>1 hour) after taking suvorexant were permitted to take an add-on use zolpidem. Clinical data and sleep questionnaire results were analyzed between a no insomnia group (without hypnotics) and an insomnia group (treated with suvorexant).Results: Among 84 patients who experienced insomnia during PSG and required hypnotics (the insomnia group; treated with suvorexant), 44 (52.4%) achieved sufficient subjective sleep with single-use of suvorexant, while the other 40 (47.6%) required suvorexant plus zolpidem. An apnea hypopnea index (AHI) of ≥5 was observed in 144 out of 149 patients with predominantly obstructive respiratory events. Among those patients, 70.8% in the no insomnia group and 63.1% in the insomnia group had severe OSA. Regarding both subjective sleep time and morning mood, significant differences between the no insomnia group and the insomnia group were not observed. No patient taking suvorexant had an adverse event, such as delirium or falling.Conclusion: Single-use suvorexant seems to be a safe and effective (but mild) hypnotic agent for suspected OSA patients with insomnia during in-laboratory PSG. Keywords: insomnia, suvorexant, polysomnography, obstructive sleep apnea, zolpidem, natural sleep

Mitsuhiro Abe,1 Kenji Tsushima,1,2 Masashi Sakayori,1 Kenichi Suzuki,1 Jun Ikari,1 Jiro Terada,1 Koichiro Tatsumi1 1Department of Respirology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba city, Chiba 260-8670, Japan; 2Department of Pulmonary Medicine, International University of Health and Welfare, School of Medicine, Narita city, Chiba 286-8686, Japan Introduction: The INPULSIS-ON trial demonstrated that nintedanib reduced decline in forced vital capacity (FVC) and low pulmonary function (%FVC < 50%) of patients with idiopathic pulmonary fibrosis (IPF). However, there is no sufficient evidence in real world.Objectives: Reveal the utility and adverse events of nintedanib for severe IPF patients.Methods: This was a single-center retrospective study. Patients who met the eligibility criteria of the INPULSIS trial (%FVC ≥ 50%; %DLCO [diffusing capacity of the lung carbon monoxide % predicted] ≥ 30%) were classified as Mild to Moderate Group (n = 34); patients who did not meet the criteria were classified as Severe Group (n=17).Results: The body mass index (24.7 ± 3.4 vs 22.4 ± 3.6 kg/m2; P = 0.021) were significantly low in Severe Group. Main adverse events (diarrhea, nausea, liver disorder, and acute exacerbation) tended to be more in Severe Group than in Mild to Moderate Group; however, the difference was not significant (P = 0.76, 0.14, 0.18, and 0.67, respectively). The continuation rates over 12 months tended to be higher in Mild to Moderate Group than in Severe Group (77% vs 44%; P = 0.027). Log-rank test revealed that the prognosis was significantly better in Mild to Moderate Group than in Severe Group (P = 0.014). In the Severe Group, patients who were able to continue nintedanib for more than 3 months had significantly better prognosis compared to those who could not (P = 0.007).Conclusion: The benefit from nintedanib was reduced in patients in Severe Group when compared to those in Mild to Moderate Group; however, the prognosis is expected to improve with control of side effects and long-term administration. It is more important to control the side effects in Severe Group. Keywords: idiopathic pulmonary fibrosis, nintedanib, triple tyrosine kinase inhibitor, INPULSIS trials, forced vital capacity

Abe M, Tsushima K, Sakayori M, et al. Drug Des Devel Ther. 2018;12:3369–3375.On page 3372, last paragraph of “Results” section should read from “In Severe Group, patients who were able to continue nintedanib for more than 3 months (n = 4) exhibited significantly better prognosis compared to those who could not (n = 13) (P = 0.007) (Figure 6).” to “In Severe Group, patients who were able to continue nintedanib for more than 3 months (n = 13) exhibited significantly better prognosis compared to those who could not (n = 4) (P = 0.007) (Figure 6).”Read the orginal article

Mitsuhiro Abe, Kenji Tsushima, Takuma Matsumura, Tsukasa Ishiwata, Yasunori Ichimura, Jun Ikari, Jiro Terada, Yuji Tada, Seiichirou Sakao, Nobuhiro Tanabe, Koichiro Tatsumi Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan Purpose: Acute exacerbation (AE) is an important outcome of idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). Recombinant human soluble thrombomodulin (rhTM) is a new drug for the treatment of disseminated intravascular coagulation in Japan. The objective of this study was to evaluate the efficacy of rhTM for AE of IPF/NSIP.Methods: Twenty-two patients with AE-idiopathic interstitial pneumonia (16 patients with IPF and six patients with NSIP) were enrolled in our study. Among them, eleven patients were treated with rhTM (rhTM group), and eleven patients were treated without rhTM (non-rhTM group). Patients admitted to our hospital prior to December 2013 were treated with rhTM, while those admitted after January 2014 were treated without rhTM. The primary endpoint was mortality at 90 days after AE treatment. The secondary endpoint was the safety of rhTM for AE-IPF/AE-NSIP. In addition, we examined prognostic factors of AE-IPF/AE-NSIP.Results: The mortality rate was significantly lower in the rhTM group than in the non-rhTM group (mortality rate at 90 days: 36% vs 90%, P=0.023; median survival time: not reached vs 15.0 days, P=0.019). A univariate analysis revealed the respiratory rate (hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.00–1.18, P=0.039) and rhTM administration (HR 0.21, 95% CI 0.06–0.77, P=0.013) as predictors of mortality at 90 days, and a multivariate analysis identified rhTM administration (HR 0.025, 95% CI 0.0006–0.94, P=0.046) as an independent predictor of mortality at 90 days. No serious adverse events were observed.Conclusion: The administration of rhTM is associated with reductions in mortality in patients with AE-IPF/NSIP, without causing adverse events. Keywords: recombinant human soluble thrombomoduline, acute exacerbation, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia

Daily acute intermittent hypoxia (dAIH) elicits respiratory plasticity, enhancing respiratory motor output and restoring breathing capacity after incomplete cervical spinal injuries (cSCI). We hypothesized that dAIH-induced functional recovery of breathing capacity would occur after both acute (2 weeks) and chronic (8 weeks) cSCI, but through distinct cellular mechanisms. Specifically, we hypothesized that dAIH-induced breathing recovery would occur through serotonin- independent mechanisms 2wks post C2 cervical hemisection (C2Hs), versus serotonin- dependent mechanisms 8wks post C2Hs. In two independent studies, dAIH or sham (normoxia) was initiated 1 week (Study 1) or 7 weeks (Study 2) post-C2Hs to test our hypothesis. Rats were pre-treated with intra-peritoneal vehicle or methysergide, a broad-spectrum serotonin receptor antagonist, to determine the role of serotonin signaling in dAIH-induced functional recovery. Our data support the hypothesis that dAIH-induced recovery of breathing capacity transitions from a serotonin- independent mechanism with acute C2Hs to a serotonin- dependent mechanism with chronic C2Hs. An understanding of shifting mechanisms giving rise to dAIH-induced respiratory motor plasticity is vital for clinical translation of dAIH as a therapeutic modality. [ABSTRACT FROM AUTHOR]

The relentless increase in network capacity is making it important to reduce power consumption. In optical access network systems, the buffer size in layer-2 switches, which aggregate multiple passive optical network systems, is expanding as the network speed increases, and the buffer is now significant in terms of power consumption. An effective way to reduce the buffer size is to adopt dynamic bandwidth allocation for a layer-2 switch; however, this leads to low bandwidth efficiency. In this paper, we propose a dynamic bandwidth allocation framework that is suitable for application to a layer-2 switch. The performance of the proposed scheme is evaluated by both computer simulations and experiments, and it is shown that the proposed scheme provides better performance than the conventional scheme with regard to buffer size with high bandwidth efficiency. [ABSTRACT FROM PUBLISHER]

Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Here, we tested four hypotheses in unanesthetized, spontaneously breathing rats using radiotelemetry for EEG and diaphragm electromyography (Dia EMG) activity: 1) AIH induces LTF in Dia EMG activity; 2) diaphragm LTF (Dia LTF) is more robust during sleep vs. wakefulness; 3) AIH (or repetitive AIH) disrupts natural sleep-wake architecture; and 4) preconditioning with daily AIH (dAIH) for 7 days enhances Dia LTF. Sleep-wake states and Dia EMG were monitored before (60 rain), during, and after (60 min) AIH (I0, 5-min hypoxic episodes, 5-min normoxic intervals; n = 9), time control (continuous normoxia, n = 8), and AIH following dAIH preconditioning for 7 days (n = 7). Dia EMG activities during quiet wakefulness (QW), rapid eye movement (REM), and non-REM (NREM) sleep were analyzed and normalized to pre-AIH values in the same state. During NREM sleep, diaphragm amplitude (25.1 ± 4.6%), frequency (16.4 ± 4.7%), and minute diaphragm activity (amplitude x frequency; 45.2 ± 6.6%) increased above baseline 0-60 min post-AIH (all P < 0.05). This Dia LTF was less robust during QW and insignificant during REM sleep, dAIH preconditioning had no effect on LTF (P > 0.05). We conclude that 1) AIH induces Dia LTF during NREM sleep and wakefulness; 2) Dia LTF is greater in NREM sleep vs. QW and is abolished during REM sleep; 3) AIH and repetitive AIH disrupt natural sleep patterns; and 4) Dia LTF is unaffected by dAIH. The capacity for plasticity in spinal pump muscles during sleep and wakefulness suggests an important role in the neural control of breathing. [ABSTRACT FROM AUTHOR]

Ventilatory long-term facilitation (vLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia (AIH). Although vLTF has been reported in unanesthetized animals, little is known concerning the effects of vigilance state on vLTF expression. We hypothesized that AIH-induced vLTF is preferentially expressed in sleeping vs. awake male Lewis rats. Vigilance state was assessed in unanesthetized rats with chronically implanted EEG and nuchal EMG electrodes, while tidal volume, frequency, minute ventilation (V̇/E), and CO2 production were measured via plethysmography, before, during, and after AIH (five 5-min episodes of 10.5% O2 separated by 5-min normoxic intervals), acute sustained hypoxia (25 min of 10.5% O2), or a sham protocol without hypoxia. Vigilance state was classified as quiet wakefulness (QW), light and deep non-rapid eye movement (NREM) sleep (1-NREM and d-NREM sleep, respectively), or rapid eye movement sleep. Ventilatory variables were normalized to pretreatment baseline values in the same vigilance state. During d-NREM sleep, vLTF was observed as a progressive increase in V̇E post-AIH (27 ± 5% average, 30-60 min post-AIH). In association, V̇E/V̇CO2 (36 ± 2%), tidal volume (14 ± 2%), and frequency (7 ± 2%) were increased 30-60 min post-AIH during d-NREM sleep, vLTF was significant but less robust during I-NREM sleep, was minimal during QW, and was not observed following acute sustained hypoxia or sham protocols in any vigilance state. Thus, vLTF is state-dependent and pattern-sensitive in unanesthetized Lewis rats, with the greatest effects during d-NREM sleep. Although the physiological significance of vLTF is not clear, its greatest significance to ventilatory control is most likely during sleep. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the appearance of microbubbles during radiofrequency ablation (RFA) of lung tumours. Eight consecutive patients (mean age, 73.1 years; 3 men and 5 women; 10 malignant lesions; mean lesion size, 24.8 mm) who underwent RFA of lung tumours using internally cooled single electrodes were enrolled. During the RFA procedure, the right internal carotid artery was continuously monitored by duplex ultrasound. High-intensity transient signals (HITS) that occurred in the Doppler blood flow waveform were taken to indicate microbubbles. 21 RFA applications were performed for the 10 lesions. HITS were observed in 19 of 21 RFA applications; the mean frequency in a single application was 10±13.3. A statistical correlation was seen between the duration of energy deposition and the number of HITS, and between tumour size and the number of HITS. Microbubbles were detected in all patients in the late phase of the first session of RFA. [ABSTRACT FROM AUTHOR]

The objective of the present study was to determine the frequency of gas retention in the renal vein following carbon dioxide intraosseous venography in the prone position and, while citing references, to examine its onset mechanisms. All percutaneous vertebroplasties performed at our hospital from January to December 2005 were registered and retrospectively analyzed. Of 43 registered procedures treating 79 vertebrae, 28 procedures treating 54 vertebrae were analyzed. Vertebral intraosseous venography was performed using carbon dioxide as a contrast agent in all percutaneous vertebroplasty procedures. In preoperative and postoperative vertebral CT, gas retention in the renal vein and other areas was assessed. Preoperative CT did not show gas retention (0/28 procedures; 0%). Postoperative CT confirmed gas retention in the renal vein in 10 of the 28 procedures (35.7%). Gas retention was seen in the right renal vein in 8 procedures (28.6%), in the left renal vein in 5 procedures (17.9%), in the left and right renal veins in 3 procedures (10.7%), in vertebrae in 22 procedures (78.6%), in the soft tissue around vertebrae in 14 procedures (50.0%), in the spinal canal in 12 procedures (42.9%), and in the subcutaneous tissue in 5 procedures (17.9%). In conclusion, in our study, carbon dioxide gas injected into the vertebra frequently reached and remained in the renal vein. [ABSTRACT FROM AUTHOR]

Background: Percutaneous vertebroplasty (PVP) improves back pain and corrects spinal misalignment to some extent, and thus may improve respiratory function. Purpose: To retrospectively investigate changes in respiratory function after PVP. Material and Methods: 41 patients (mean age 72.0 years, range 59-86 years; 39 women, two men) who had undergone PVP for vertebral compression fractures (37 thoracic vertebral bodies [Th6-Th12] and 50 lumbar vertebral bodies [L1-L5]) caused by osteoporosis visited our hospital for follow-up consultation between January and June 2005. At this follow-up consultation, respiratory function testing, including percent forced vital capacity (FVC%) and percent forced expiratory volume in 1 s (FEV1%), was performed. We retrospectively compared these values with those taken before PVP using a Wilcoxon signed-rank test. Results: FVC% was 85.2±30.3% before PVP and 91.5±16.8% at follow-up (mean 10 months after PVP), which represented a significant difference (P<0.003). No significant difference in FEV1% was detected. Regarding the number of treatment levels, that is, single vertebroplasty versus multiple vertebroplasty, no significant difference in improvement of FVC% was confirmed (P=0.1). FVC% was abnormally low (≤79%) before PVP in 16 patients and improved to within normal range postoperatively in six of these patients (38%). Conclusion: PVP improves preoperatively decreased lung function, but this improvement takes time. [ABSTRACT FROM AUTHOR]

The burst-mode 3R receiver using monolithic ICs for 10-Gbit/s-class optical access networks is reported. In a point-to-multipoint access system like a passive optical network (PON), the receiver at the optical line terminal (OLT) must be able to handle burst-mode optical packets with significantly different powers and phases. An OLT receiver with high sensitivity with instantaneous response to burst inputs is desired for widening the accommodation area and for high efficiency in PON uplinks. Currently, the diffusion of high-speed Internet connection services represented by fiber to the home services at 1.25 Gbit/s is remarkable and the standardization of the next-generation system operating at 10 Gbit/s has started in IEEE. We first discuss the issues in the implementation of 10-Gbit/s-class PON systems, focusing on securing the accommodation area and the quality of the service comparable with those of the deployed system. Against that background, we propose target specifications for sensitivity, a dynamic range and response speed of the 10-Gbit/s-class burst-mode receiver so as to secure the power budget and the upstream efficiency comparable with those of the already-installed systems. Our burst-mode 3R receiver was designed to meet the above requirements and developed using monolithic ICs of transimpedance amplifier, limiting amplifier, and clock and data recovery circuit fabricated by using SiGe BiCMOS technologies along with a p-i-n photodiode. High sensitivity of , a wide dynamic range of over 16.5 dB, and quick response time of 75 ns were confirmed for burst inputs with extremely different powers. [ABSTRACT FROM PUBLISHER]

Integrated dynamic bandwidth allocation with an overlap scheme that improves the bandwidth efficiency of aggregated access networks is implemented and demonstrated on the 10 G Ethernet passive optical network (EPON)‐based prototype system for the first time. Experiments revealed that the prototype system can achieve more than 99% bandwidth efficiency with only 150 kB aggregation buffers in each optical subscriber unit. [ABSTRACT FROM AUTHOR]

BACKGROUND Obesity-hypoventilation syndrome (OHS), also known as Pickwickian syndrome, is a respiratory consequence of morbid obesity, usually treated with non-invasive positive airway pressure (PAP) therapies and weight loss. This study reports a 53-year-old woman with a body mass index of 49 kg/m² who experienced acute hypercapnic respiratory failure due to OHS. Her treatment involved mechanical ventilation, home oxygen therapy, and long-term weight loss of >30 kg. CASE REPORT A 53-year-old woman (109 kg) presented with acute hypercapnic respiratory failure due to OHS, which improved with mechanical ventilation and diuretics. After discharge from the hospital, she was treated with nocturnal non-invasive positive-pressure ventilation (NPPV) and home oxygen therapy. Over a 5-year period, following loss of >30 kg, she was re-evaluated for the discontinuation of NPPV and oxygen therapy. She was evaluated with various NPPV settings and oxygen doses, monitored by transcutaneous pressure of carbon dioxide (PtcCO₂). On NPPV, PtcCO₂ levels ≥55 mmHg were maintained within 10 min, indicating that the durations of PtcCO₂ ≥50 mmHg were too prolonged for her to be switched to continuous PAP therapy. Nonetheless, oxygen therapy was discontinued because the duration of peripheral blood oxygen saturation <90% was brief. CONCLUSIONS For patients with OHS treated with NPPV and oxygen therapy, weight loss alone may not improve hypoventilation and wean the patient from NPPV. Besides obesity, various factors influence respiratory compromise in OHS; hence, a comprehensive assessment of hypoventilation, including PtcCO₂ monitoring, is essential to determine whether NPPV withdrawal is possible after body weight loss.

Background: This study aimed to develop and validate claims-based algorithms for identifying hospitalized patients with coronavirus disease 2019 (COVID-19) and disease severity., Methods: We used claims data including all patients at the National Center for Global and Medicine Hospital between January 1, 2020, and December 31, 2021. The claims-based algorithms for three statuses with COVID-19 (hospitalizations, moderate or higher status, and severe status) were developed using diagnosis codes (International Classification of Diseases, 10 th revision code: U07.1, B34.2) and relevant medical procedure code. True cases were determined using the COVID-19 inpatient registry and electronic health records. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each algorithm at 6-month intervals., Results: Of the 75,711 total patients, the number of true cases was 1,192 for hospitalizations, 622 for moderate or higher status, and 55 for severe status. The diagnosis code-only algorithm for hospitalization had sensitivities 90.4% to 94.9% and PPVs 9.3% to 19.4%. Among the algorithms consisting of both diagnosis codes and procedure codes, high sensitivity and PPV were observed during the following periods: 93.9% and 97.1% for hospitalization (January-June 2021), 90.4% and 87.5% for moderate or higher status (July-December 2021), and 92.3% and 85.7% for severe status (July-December 2020), respectively. Almost all algorithms had specificities and NPVs of approximately 99%., Conclusion: The diagnosis code-only algorithm for COVID-19 hospitalization showed low validity throughout the study period. The algorithms for hospitalizations, moderate or higher status, and severe status with COVID-19, consisting of both diagnosis codes and procedure codes, showed high validity in some periods.

Werner's syndrome is a rare progressive disorder that is characterized by a variety of clinical manifestations which mimic features of advanced ageing. Malignancy is one of the most problematic complications of Werner's syndrome. Lung cancer associated with Werner's syndrome is rare. A 54-year-old woman with Werner's syndrome was referred to our department because an abnormal shadow had been detected on routine chest radiography. Chest computed tomography revealed an abnormal nodule in the left upper lobe. Bronchoscopic examination revealed the presence of squamous cell carcinoma. Other imaging studies showed no metastatic lesions; therefore, the patient was diagnosed with stage IA3 squamous cell carcinoma. She underwent left upper lobectomy and lymph node dissection without major complications, and no recurrence was found for 2 years postoperatively., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Background: The Guidelines for the Management of Cough and Sputum (2019) of the Japanese Respiratory Society (JRS) were the first internationally published guidelines for the management of sputum. However, the data used to determine the causative diseases of bloody sputum and hemoptysis in these guidelines were not obtained in Japan., Methods: A retrospective analysis was performed using the clinical information of patients with bloody sputum or hemoptysis who visited the department of respiratory medicine at a university or core hospital in Japan., Results: Included in the study were 556 patients (median age, 73 years; age range, 21-98 years; 302 males (54.3%)). The main causative diseases were bronchiectasis (102 patients (18.3%)), lung cancer (97 patients (17.4%)), and non-tuberculous mycobacterial disease (89 patients (16%)). Sex and age differences were observed in the frequency of causative diseases of bloody sputum and hemoptysis. The most common cause was lung cancer in males (26%), bronchiectasis in females (29%), lung cancer in patients aged <65 years (19%), and bronchiectasis in those aged >65 years (20%)., Conclusions: The present study is the first to investigate the causative diseases of bloody sputum and hemoptysis using data obtained in Japan. When investigating the causative diseases of bloody sputum and hemoptysis, it is important to take the sex and age of the patients into account., Competing Interests: Declaration of competing interest KT received Grants-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare (Nos. 20K08545). The other authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

BACKGROUND: Vaccination against mpox (formerly known as monkeypox), an infectious disease caused by the monkeypox virus (MPXV), is needed to prevent outbreaks and consequent public health concerns. The LC16m8 vaccine, a dried cell-cultured proliferative live attenuated vaccinia virus–based vaccine, was approved in Japan against smallpox and mpox. However, its immunogenicity and efficacy against MPXV have not been fully assessed. We assessed the safety and immunogenicity of LC16m8 against MPXV in healthy adults. METHODS: We conducted a single-arm study that included 50 participants who were followed up for 168 days postvaccination. The primary end point was the neutralizing antibody seroconversion rate against MPXVs, including the Zr599 and Liberia strains, on day 28. The secondary end points included the vaccine “take” (major cutaneous reaction) rate, neutralizing titer kinetics against MPXV and vaccinia virus (LC16m8) strains, and safety outcomes. RESULTS: Seroconversion rates on day 28 were 72% (36 of 50), 70% (35 of 50), and 88% (44 of 50) against the Zr599 strain, the Liberia strain, and LC16m8, respectively. On day 168, seroconversion rates decreased to 30% (15 of 50) against the Zr599 and Liberia strains and to 76% (38 of 50) against LC16m8. The vaccine “take” (broad definition) rate on day 14 was 94% (46 of 49). Adverse events (AEs), including common solicited cutaneous reactions, occurred in 98% (45 of 48) of participants; grade 3 severity AEs occurred in 16% (8 of 50). No deaths, serious AEs, or mpox onset incidences were observed up to day 168. CONCLUSIONS: The LC16m8 vaccine generated neutralizing antibody responses against MPXV in healthy adults. No serious safety concerns occurred with LC16m8 use. (Funded by the Ministry of Health, Labour and Welfare of Japan; Japan Registry of Clinical Trials number, jRCTs031220171.)

Background: Autoantibodies develop in autoimmune diseases, cancer, diabetes mellitus (DM), and atherosclerosis-related diseases. However, autoantibody biomarkers have not been successfully examined for diagnosis and therapy., Methods: Serological identification of antigens through recombinant cDNA expression cloning (SEREX) was used for primary screening of antigens. The cDNA product was expressed in bacteria and purified. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) was used to evaluate antibody levels in serum samples., Results: Phosphoenolpyruvate carboxykinase 1 (PCK1) was recognized as an antigen by serum IgG antibodies in the sera of patients with atherosclerosis. AlphaLISA showed significantly higher serum antibody levels against recombinant PCK1 protein in patients with DM and cardiovascular disease than in healthy donors, but not in those with acute ischemic stroke, transient ischemic attack, or obstructive sleep apnea syndrome. The area under the receiver operating characteristic curve for anti-PCK1 antibodies was 0.7024 for DM. The serum anti-PCK1 antibody levels were associated with age, platelet count, and blood pressure. Anti-PCK1-antibody-positive patients showed significantly lower overall survival than the negative patients., Conclusions: Serum anti-PCK1 antibody levels were found to be associated with DM. The anti-PCK1 antibody marker is useful for predicting the overall survival of patients with DM., (© 2023. The Author(s).)

Background: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19). Despite its use for treating several viral infections, we lack comprehensive data on its efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Methods: We conducted a multicenter, open-label, randomized controlled trial of convalescent plasma therapy with high neutralizing activity against SARS-CoV-2 in high-risk patients within five days after the onset of COVID-19 symptoms. The primary endpoint was the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs from days 0-5., Results: Between February 24, 2021, and November 30, 2021, 25 patients were randomly assigned to either convalescent plasma (n = 14) or standard of care (n = 11) groups. Four patients discontinued their allocated convalescent plasma, and 21 were included in the modified intention-to-treat analysis. The median interval between the symptom onset and plasma administration was 4.5 days (interquartile range, 3-5 days). The primary outcome of the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs did not significantly differ between days 0-5 (1.2 log 10 copies/mL in the convalescent plasma vs. 1.2 log 10 copies/mL in the standard of care (effect estimate, 0.0 [95% confidence interval, -0.8-0.7]; P = 0.94)). No deaths were observed in either group., Conclusions: The early administration of convalescent plasma with high neutralizing activity did not contribute to a decrease in the viral load within five days compared with the standard of care alone., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Dexamethasone, remdesivir, and baricitinib reduce mortality in patients with coronavirus disease 2019 (COVID-19). A single-arm study using combination therapy with all three drugs reported low mortality in patients with severe COVID-19. In this clinical setting, whether dexamethasone administered as a fixed dose of 6 mg has sufficient inflammatory modulation effects of reducing lung injury has been debated., Methods: This single-center retrospective study was conducted to compare the treatment strategies/management in different time periods. A total of 152 patients admitted with COVID-19 pneumonia who required oxygen therapy were included in this study. A predicted body weight (PBW)-based dose of dexamethasone with remdesivir and baricitinib was administered between May and June 2021. After this period, patients were administered a fixed dose of dexamethasone at 6.6 mg/day between July and August 2021. The additional respiratory support frequency of high-flow nasal cannula, noninvasive ventilation, and mechanical ventilation was analyzed. Moreover, the Kaplan-Meier method was used to analyze the duration of oxygen therapy and the 30-day discharge alive rate, and they were compared using the log-rank test., Results: Intervention and prognostic comparisons were performed in 64 patients with PBW-based and 88 with fixed-dose groups. The frequency of infection or additional respiratory support did not differ statistically. The cumulative incidence of being discharged alive or oxygen-free rate within 30 days did not differ between the groups., Conclusions: In patients with COVID-19 pneumonia who required oxygen therapy, combination therapy with PBW-based dexamethasone, remdesivir, and baricitinib might not shorten the hospital stay's length or oxygen therapy's duration., Competing Interests: Conflict of Interest Koichiro Tatsumi received honoraria from Boehringer Ingelheim Japan, Tsumura, AstraZeneca, and Jannsen Pharmaceutical, research funding from Boehringer Ingelheim Japan and Tsumura, and endowed departments by Kyorin pharmaceutical and Fukuda Denshi; Jiro Terada received research funding from Teijin Pharma Ltd; other authors have no competing interests., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Pulmonary tumor thrombotic microangiopathy is a rapidly progressive and fatal disease in which tumor cells embolize to the pulmonary microvasculature. This condition is characterized by severe dyspnea and right heart failure. Although pulmonary tumor thrombotic microangiopathy typically occurs in patients with untreated and/or advanced cancer, its occurrence in patients who are responding well to medical therapy is poorly documented., Case Presentation: A 68-year-old Japanese woman who had received four cycles of immuno-chemotherapy (pembrolizumab, carboplatin, and pemetrexed) followed by three cycles of maintenance therapy (pembrolizumab and pemetrexed) for advanced non-small cell lung cancer and had achieved a partial response with a stable clinical course was admitted to the emergency ward because of worsening breathlessness and general fatigue for 1 week. Chest computed tomography showed no evidence of tumor progression or any new lung lesion. Two-dimensional transthoracic echocardiography demonstrated right atrial and ventricular dilatation, tricuspid regurgitation, and a high trans-tricuspid pressure gradient of 65 mmHg. Despite her percutaneous oxygen saturation being 96% on room air at the time of admission, it worsened rapidly; the patient requiring 8 L/min of oxygen within 4 h. Repeat computed tomography with contrast medium revealed no evidence of pulmonary embolism. The patient developed progressive respiratory failure that was unresponsive to optimal cardio-pulmonary supportive therapy. An autopsy revealed tumorous clusters in pre-capillary lung vessels, whereas the primary lesion had shrunk to the point of almost complete resolution., Conclusion: Pulmonary tumor thrombotic microangiopathy occurs not only in patients with advanced and/or uncontrolled cancer but also in those whose primary lesion seems to have been well controlled by medical treatment., (© 2023. The Author(s).)

Background and Objective: The possibility of combination therapy with atomoxetine (ATO) and oxybutynin (OXY) has been suggested for obstructive sleep apnoea (OSA). However, the effectiveness of this treatment remains uninvestigated in Japanese OSA patients. Therefore, we performed a randomized, crossover, phase II, single-centre prospective trial to examine the effects of ATO-OXY therapy in Japanese OSA patients., Methods: In total, 17 OSA patients participated in this study. The effects of one night of 80-mg ATO plus 5-mg OXY administration were compared with those of no medication administered before sleep. The primary and secondary outcomes comprised the apnoea-hypopnoea index (AHI) and nadir SpO 2 , SpO 2 drop time and sleep architecture, respectively. The safety endpoints included drug side effects and adverse events., Results: The values of AHI, nadir SpO 2 , 3% oxygen desaturation index (ODI), 4% ODI, and SpO 2 drop time of <90% did not significantly differ between patients receiving ATO-OXY administration and no medication. Sleep architecture exhibited a significant change: ATO-OXY increased sleep stage N1 (p < 0.0001) and decreased stage N2 (p = 0.03), rapid eye movement (p < 0.0001) and sleep efficiency (p = 0.02). However, the subanalysis demonstrated an obvious decrease in AHI in five responder patients. Total sleep time and basal sleep efficiency tended to be lower in the responders compared with nonresponders (p = 0.065). No patients experienced severe adverse events or side effects., Conclusion: Overall, ATO-OXY therapy does not reduce AHI in Japanese OSA patients, although AHI was decreased in a proportion of patients. Future studies for identifying treatment response group characteristics are warranted., (© 2022 Asian Pacific Society of Respirology.)

Background: The 6-min walk test (6MWT) is a common assessment of exercise-induced hypoxemia and exercise capacity used in patients with chronic fibrosing interstitial pneumonia (CFIP). However, whether the dynamic changes in S pO 2 and heart rate during the 6MWT are associated with mortality in patients with CFIP has been undefined., Methods: This retrospective study enrolled 63 subjects with mild to severe CFIP who underwent the 6MWT. Subjects with CFIP were divided into 2 groups according to disease severity: mild, diffusing capacity of the lungs for carbon monoxide percentage predicted (%D LCO ) > 55% and %FVC > 75%; and severe, %D LCO ≤ 55% and/or %FVC ≤ 75%. This study aimed to evaluate dynamic changes in the 6MWT including 6-min walk distance, change in S pO 2 (ΔS pO 2 ), S pO 2 reduction time, S pO 2 recovery time, change in heart rate (Δ heart rate), heart rate acceleration time, slope of heart rate acceleration, heart rate recovery at 1 min of rest after the 6MWT (HR-recovery), and dyspnea on exertion that are reflected by static pulmonary function and are related to exacerbation of CFIP and mortality., Results: Compared with subjects with mild CFIP, subjects with severe CFIP had significantly larger ΔS pO 2 and longer S pO 2 reduction time and recovery time. The slope of heart rate, heart rate immediately after the 6MWT, and HR-recovery were lower in subjects with severe CFIP than in those with mild CFIP. In multiple regression analysis, percent vital capacity was significantly associated with S pO 2 reduction time, and %D LCO was significantly associated with ΔS pO 2 and S pO 2 recovery time. Subjects with ΔS pO 2 of > 10% and S pO 2 recovery time of > 79 s had a significantly higher risk for exacerbation and mortality., Conclusions: Dynamic changes in S pO 2 and heart rate during the 6MWT were associated with risk for exacerbation and mortality in subjects with CFIP. Impaired dynamic response of S pO 2 could reflect likelihood of exacerbation and increased mortality in CFIP., Competing Interests: Dr Nagashima reports relationships with Pfizer R&D Japan, Fujimoto Pharmaceutical Corporation, SENJU Pharmaceutical, and Toray Industries. The other authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

High-flow nasal cannula (HFNC) can be effective in treating type 1 respiratory failure by reducing the severity of coronavirus disease 2019 (COVID-19). The purpose of this study was to assess the reduction of disease severity and safety of HFNC treatment in patients with severe COVID-19. We retrospectively observed 513 consecutive patients with COVID-19 admitted to our hospital from January 2020 to January 2021. We included patients with severe COVID-19 who received HFNC for their deteriorating respiratory status. HFNC success was defined as improvement in respiratory status after HFNC and transfer to conventional oxygen therapy, while HFNC failure was defined as transfer to non-invasive positive pressure ventilation or ventilator, or death after HFNC. Predictive factors associated with failure to prevent severe disease were identified. Thirty-eight patients received HFNC. Twenty-five (65.8%) patients were classified in the HFNC success group. In the univariate analysis, age, history of chronic kidney disease (CKD), non-respiratory sequential organ failure assessment (SOFA) ≥ 1, oxygen saturation to fraction of inspired oxygen ratio (SpO 2 /FiO 2 ) before HFNC ≤ 169.2, were significant predictors of HFNC failure. Multivariate analysis revealed that SpO 2 /FiO 2 value before HFNC ≤ 169.2 was an independent predictor of HFNC failure. No apparent nosocomial infection occurred during the study period. Appropriate use of HFNC for acute respiratory failure caused by COVID-19 can reduce the severity of severe disease without causing nosocomial infection. Age, history of CKD, non-respiratory SOFA before HFNC ≤ 1, and SpO 2 /FiO 2 before HFNC ≤ 169.2 were associated with HFNC failure., Competing Interests: The authors have no conflicts of interest to disclose., (2023, National Center for Global Health and Medicine.)

Purpose: We aimed to evaluate sleep-related hypoventilation in multiple system atrophy (MSA) using polysomnography (PSG) with transcutaneous partial pressure of carbon dioxide (PtcCO 2 ) monitoring., Methods: This prospective study included 34 patients with MSA. Motor and autonomic function, neuropsychological tests, PSG with PtcCO 2 monitoring, and pulmonary function tests were performed. Sleep-related hypoventilation disorder (SRHD) was defined according to the International Classification of Sleep Disorders, third edition., Results: Nine (27%) of the 34 patients met the diagnostic criteria of SRHD. Twenty-nine (85%) patients had sleep-related breathing disorders based on an Apnea-Hypopnea Index of ≥ 5/h. The patients with MSA and SRHD had a higher arousal index (p = 0.017) and obstructive apnea index (p = 0.041) than those without SRHD. There was no difference in the daytime partial pressure of carbon dioxide in arterial blood or respiratory function between MSA patients with and without SRHD., Conclusion: Sleep-related hypoventilation may occur in patients with MSA even with a normal daytime partial pressure of carbon dioxide. This can be noninvasively detected by PSG with PtcCO 2 monitoring. SRBD and sleep-related hypoventilation are common among patients with MSA, and clinicians should take this into consideration while evaluating and treating this population., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Rationale: The long-term effects of using a high-flow nasal cannula for chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease remain unclear. Objectives: To assess whether long-term high-flow nasal cannula use reduces the number of exacerbations and improves other physiological parameters in patients with chronic hypercapnic respiratory failure caused by chronic obstructive pulmonary disease. Methods: We enrolled 104 participants (aged ⩾40 yr) with daytime hypercapnia (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) receiving long-term oxygen therapy (⩾16 h/d for ⩾1 mo) and randomly assigned them to high-flow nasal cannula/long-term oxygen therapy and long-term oxygen therapy groups. The primary endpoint was the moderate or severe exacerbation rate. We compared changes from baseline in arterial blood gas values, peripheral oxygen saturation, pulmonary function, health-related quality-of-life scores, and the 6-minute-walk test. Measurements and Main Results: High-flow nasal cannula use significantly reduced the rate of moderate/severe exacerbations (unadjusted mean count 1.0 vs. 2.5, a ratio of the adjusted mean count between groups [95% confidence interval] of 2.85 [1.48-5.47]) and prolonged the duration without moderate or severe exacerbations. The median time to first moderate or severe exacerbation in the long-term oxygen therapy group was 25 (14.1-47.4) weeks; this was not reached in the high-flow nasal cannula/long-term oxygen therapy group. High-flow nasal cannula use significantly improved health-related quality of life scores, peripheral oxygen saturation, and specific pulmonary function parameters. No safety concerns were identified. Conclusions: A high-flow nasal cannula is a reasonable therapeutic option for patients with stable hypercapnic chronic obstructive pulmonary disease and a history of exacerbations. Clinical trial registered with www.umin/ac.jp (UMIN000028581) and www.clinicaltrials.gov (NCT03282019).

Suvorexant (Belsomra(R)), a dual orexin receptor antagonist widely used in the treatment of insomnia, inhibits the arousal system in the brain. However, the drug's ventilatory effects have not been fully explored. This study aims to investigate the expression of orexin receptors in respiratory neurons and the effects of suvorexant on ventilation. Immunohistology of brainstem orexin receptor OX2R expression was performed in adult mice (n = 4) in (1) rostral ventral respiratory group (rVRG) neurons projecting to the phrenic nucleus (PhN) retrogradely labeled by Fluoro-Gold (FG) tracer, (2) neurons immunoreactive for paired like homeobox 2b (Phox2b) in the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), and (3) neurons immunoreactive for neurokinin 1 receptor (NK1R) and somatostatin (SST) in the preBötzinger complex (preBötC). Additionally, we measured in vivo ventilatory responses to hyperoxic hypercapnia (5% CO 2 ) and hypoxia (10% O 2 ) before and after suvorexant pretreatment (10 and cumulative 100 mg/kg) in unrestrained mice (n = 10) in a body plethysmograph. We found the OX2R immunoreactive materials in pFRG/RTN Phox2b and preBötC NK1R/SST immunoreactive neurons but not in FG-labeled rVRG neurons, which suggests the involvement of orexin in respiratory control. Further, suvorexant expressly suppressed the hypercapnic ventilatory augmentation, otherwise unaffecting ventilation. Central orexin is involved in shaping the hypercapnic ventilatory chemosensitivity. Suppression of hypercapnic ventilatory augmentation by the orexin receptor antagonist suvorexant calls for caution in its use in pathologies that may progress to hypercapnic respiratory failure, or sleep-disordered breathing. Clinical trials are required to explore the role of targeted pharmacological inhibition of orexin in ventilatory pathologies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: This study aims to create and validate a useful score system predicting the hyper-inflammatory conditions of COVID-19, by comparing it with the modified H-score., Methods: A total of 98 patients with pneumonia (without oxygen therapy) who received initial administration of casirivimab/imdevimab or remdesivir were included in the study. The enrolled patients were divided into two groups: patients who required corticosteroid due to deterioration of pneumonia, assessed by chest X-ray or CT or respiratory failure, and those who did not, and clinical parameters were compared., Results: Significant differences were detected in respiratory rate, breaths/min, SpO 2 , body temperature, AST, LDH, ferritin, and IFN-λ3 between the two groups. Based on the data, we created a corticosteroid requirement score: (1) the duration of symptom onset to treatment initiation ≥ 7 d, (2) the respiratory rate ≥ 22 breaths/min, (3) the SpO 2 ≤ 95%, (4) BT ≥ 38.5°C, (5) AST levels ≥ 40 U/L, (6) LDH levels ≥ 340 U/L, (7) ferritin levels ≥ 800 ng/mL, and (8) IFN-λ3 levels ≥ 20 pg/mL. These were set as parameters of the steroid predicting score. Results showed that the area under the curve (AUC) of the steroid predicting score (AUC: 0.792, 95%CI: 0.698-0.886) was significantly higher than that of the modified H-score (AUC: 0.633, 95%CI: 0.502-0.764)., Conclusion: The steroid predicting score may be useful to predict the requirement of corticosteroid therapy in patients with COVID-19. The data may provide important information to facilitate a prospective study on a larger scale in this field., Competing Interests: JT received research funding from Teijin Pharma Ltd (a collaborative research project with Chiba University and Teijin Pharma Ltd). YTo received lecture fees from GlaxoSmithKline, AstraZeneca, and Novartis Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takeshita, Terada, Hirasawa, Kinoshita, Tajima, Koshikawa, Kinouchi, Isaka, Shionoya, Fujikawa, Kato, To, Tada and Tsushima.)

Background: We aimed to assess differences in health literacy between those who improved CPAP non-adherent and those who remained non-adherent., Methods: We included patients newly diagnosed with sleep apnea syndrome who had started CPAP therapy between February 2019 and October 2020 with ≥6 follow-up months or who self-interrupted CPAP therapy <6 months. We recorded the CPAP wearing time after 3 and 6 months. Patients were divided into the CPAP adherent (using CPAP for ≥4 h per night) and non-adherent (self-interrupted CPAP therapy/using CPAP for <4 h per night) groups. We compared the European Health Literacy Survey Questionnaire 47 (HLS-EU-Q47) score between those who were CPAP non-adherent after 3 months and become CPAP adherent after 6 months, and those who remained non-adherent after 6 months., Results: At 3 months, 34 patients were CPAP non-adherent. After 6 months, there were 7 and 27 patients in the CPAP adherent and non-adherent groups, respectively. There was a significant difference in the HLS-EU-Q47 score between the patients who became adherent to CPAP and who remained non-adherent after 6 months., Conclusion: Previously non-adherent patients who subsequently became adherent tended to have higher health literacy., Competing Interests: There are no conflicts of interest to declare for either the lead author or co‐authors., (© 2022 The Authors. Journal of General and Family Medicine published by John Wiley & Sons Australia, Ltd on behalf of Japan Primary Care Association.)

Background: The effectiveness of combination therapy for COVID-19 pneumonia remains unclear. We evaluated favipiravir, camostat, and ciclesonide combination therapy in patients with moderate COVID-19 pneumonia., Methods: In this open-label phase 3 study, hospitalized adults who were positive for SARS-CoV-2 and had COVID-19 pneumonia were enrolled prior to official vaccination drive in Japan. Participants were randomly assigned to favipiravir monotherapy or favipiravir + camostat + ciclesonide combination therapy. The primary outcome was the length of hospitalization due to COVID-19 infection after study treatment. The hospitalization period was calculated from the time of admission to the time of patient discharge using the clinical management guide of COVID-19 for front-line healthcare workers developed by the Japanese Ministry of Health, Labour, and Welfare (Version 3). Cases were registered between November 11, 2020, and May 31, 2021. Japan Registry of Clinical Trials registration: jRCTs031200196., Findings: Of 121 enrolled patients, 56 received monotherapy and 61 received combination therapy. Baseline characteristics were balanced between the groups. The median time of hospitalization was 10 days for the combination and 11 days for the monotherapy group. The median time to discharge was statistically significantly lower in the combination therapy vs monotherapy group (HR, 1·67 (95% CI 1·03-2·7; P = 0·035). The hospital discharge rate was statistically significantly higher in the combination therapy vs monotherapy group in patients with less severe COVID-19 infections and those who were ≤60 years. There were no significant differences in clinical findings between the groups at 4, 8, 11, 15, and 29 days. Adverse events were comparable between the groups. There were two deaths, with one in each group., Interpretation: Combination oral favipiravir, camostat and, ciclesonide therapy could decrease the length of hospitalization stays without safety concerns in patients with moderate COVID-19 pneumonia. However, lack of hard clinical primary outcome is one of the major limitations of the study., Funding: This research was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number 20fk0108261h0001., Competing Interests: J.T has received funding from Teijin Pharma Ltd as part of a collaborative research project with Chiba University and Teijin Pharma Ltd. Other authors declare that they have no conflict of interest., (© 2022 The Author(s).)