Combination therapy with predicted body weight-based dexamethasone, remdesivir, and baricitinib in patients with COVID-19 pneumonia: A single-center retrospective cohort study during 5th wave in Japan.

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.

Effects of the combination of atomoxetine and oxybutynin in Japanese patients with obstructive sleep apnoea: A randomized controlled crossover trial.

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 SpO2 , SpO2 drop time and sleep architecture, respectively. The safety endpoints included drug side effects and adverse events. RESULTS: The values of AHI, nadir SpO2 , 3% oxygen desaturation index (ODI), 4% ODI, and SpO2 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.

The relationship between CPAP and health literacy: A prospective observational study.

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.

Development of a novel score model to predict hyperinflammation in COVID-19 as a forecast of optimal steroid administration timing.

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, SpO2, 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 SpO2 ≤ 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.

Clinical Characteristics and Risk Factors of Lung Injury Induced by Nab-Paclitaxel.

Background/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.

Sleep-related hypoventilation and hypercapnia in multiple system atrophy detected by polysomnography with transcutaneous carbon dioxide monitoring.

PURPOSE: We aimed to evaluate sleep-related hypoventilation in multiple system atrophy (MSA) using polysomnography (PSG) with transcutaneous partial pressure of carbon dioxide (PtcCO2) monitoring. METHODS: This prospective study included 34 patients with MSA. Motor and autonomic function, neuropsychological tests, PSG with PtcCO2 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 PtcCO2 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.

High-flow nasal cannula oxygen therapy in hypoxic patients with COVID-19 pneumonia: A retrospective cohort study confirming the utility of respiratory rate index.

BACKGROUND: Although high-flow nasal cannula (HFNC) oxygen treatment has been frequently used in coronavirus disease 2019 (COVID-19) patients with acute respiratory failure after the 3rd wave of the pandemic in Japan, the usefulness of the indicators of ventilator avoidance, including respiratory rate-oxygenation (ROX) index and other parameters, namely oxygen saturation/fraction of inspired oxygen ratio and respiratory rate (RR), remain unclear. METHODS: Between January and May 2021, our institution treated 189 COVID-19 patients with respiratory failure requiring oxygen, among which 39 patients requiring HFNC treatment were retrospectively analyzed. The group that switched from HFNC treatment to conventional oxygen therapy (COT) was defined as the HFNC success group, and the group that switched from HFNC treatment to a ventilator was defined as the HFNC failure group. We followed the patients' oxygenation parameters for a maximum of 30 days. RESULTS: HFNC treatment success occurred in 24 of 39 patients (62%) treated with HFNC therapy. Compared with the HFNC failure group, the HFNC success group had a significantly higher degree of RR improvement in the univariate analysis. Logistic regression analysis of HFNC treatment success adjusting for age, respiratory improvement, and a ROX index ≥5.55 demonstrated that an improved RR was associated with HFNC treatment success. The total COT duration was significantly shorter in the HFNC success group than in the HFNC failure group. CONCLUSIONS: HFNC treatment can be useful for ventilator avoidance and allow the quick withdrawal of oxygen administration. RR improvement may be a convenient, useful, and simple indicator of HFNC treatment success.

Preliminary study regarding the predicted body weight-based dexamethasone therapy in patients with COVID-19 pneumonia.

BACKGROUND: The RECOVERY clinical trial reported that 6 mg of dexamethasone once daily for up to 10 days reduces the 28-day mortality in patients with coronavirus disease 2019 (COVID-19) receiving respiratory support. In our clinical setting, a fixed dose of dexamethasone has prompted the question of whether inflammatory modulation effects sufficiently reduce lung injury. Therefore, preliminary verification on the possibility of predicted body weight (PBW)-based dexamethasone therapy was conducted in patients with COVID-19 pneumonia. METHODS: This single-center retrospective study was conducted in a Japanese University Hospital to compare the treatment strategies/management in different periods. Consecutive patients (n = 90) with COVID-19 pneumonia requiring oxygen therapy and were treated with dexamethasone between June 2020 and May 2021 were analyzed. Initially, 60 patients administered a fixed dexamethasone dose of 6.6 mg/day were defined as the conventional group, and then, 30 patients were changed to PBW-based therapy. The 30-day discharged alive rate and duration of oxygen therapy were analyzed using the Kaplan-Meier method and compared using the log-rank test. The multivariable Cox regression was used to evaluate the effects of PBW-based dexamethasone therapy on high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), or mechanical ventilation (MV). RESULTS: In the PBW-based group, 9, 13, and 8 patients were administered 6.6, 9.9, and 13.2 mg/day of dexamethasone, respectively. Additional respiratory support including HFNC, NIV, or MV was significantly less frequently used in the PBW-based group (P = 0.0046), with significantly greater cumulative incidence of being discharged alive and shorter oxygen demand within 30 days (92 vs. 89%, log-rank P = 0.0094, 90 vs. 92%, log-rank P = 0.0002, respectively). Patients treated with PBW-based therapy significantly decreased the use of additional respiratory support after adjusting for baseline imbalances (adjusted odds ratio, 0.224; 95% confidence interval, 0.062-0.813, P = 0.023). Infection occurred in 13 (21%) and 2 (7%) patients in the conventional and PBW-based groups, respectively (P = 0.082). CONCLUSIONS: In patients with COVID-19 pneumonia requiring oxygen therapy, PBW-based dexamethasone therapy may potentially shorten the length of hospital stay and duration of oxygen therapy and risk of using HFNC, NPPV, or MV without increasing serious adverse events or 30-day mortality.

Elevated TAT in COVID-19 Patients with Normal D-Dimer as a Predictor of Severe Respiratory Failure: A Retrospective Analysis of 797 Patients.

Although previous studies have revealed that elevated D-dimer in the early stage of coronavirus 2019 (COVID-19) indicates pulmonary intravascular coagulation, the state of coagulation/fibrinolysis disorder with normal D-dimer is unknown. The study aimed to investigate how coagulation/fibrinolysis markers affect severe respiratory failure in the early stage of COVID-19. Among 1043 patients with COVID-19, 797 patients were included in our single-center retrospective study. These 797 patients were divided into two groups, the normal D-dimer and elevated D-dimer groups and analyzed for each group. A logistic regression model was fitted for age, sex, body mass index (BMI) ≥ 30 kg/m2, fibrinogen ≥ 617 mg/dL, thrombin-antithrombin complex (TAT) ≥ 4.0 ng/mL, and plasmin-alpha2-plasmin inhibitor-complex (PIC) > 0.8 µg/mL. A multivariate analysis of the normal D-dimer group demonstrated that being male and TAT ≥ 4.0 ng/mL significantly affected severe respiratory failure. In a multivariate analysis of the elevated D-dimer group, BMI ≥ 30 kg/m2 and fibrinogen ≥ 617 mg/dL significantly affected severe respiratory failure. The elevated PIC did not affect severe respiratory failure in any group. Our study demonstrated that hypercoagulation due to SARS-CoV-2 infection may occur even during a normal D-dimer level, causing severe respiratory failure in COVID-19.

Clinical characteristics and risk factors of drug-induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis.

BACKGROUND: If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice. METHODS: The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group. RESULTS: A total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute. CONCLUSIONS: Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern. KEY POINTS: Significant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern. WHAT THIS STUDY ADDS: The same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.

Circulating Anti-Sorting Nexins 16 Antibodies as an Emerging Biomarker of Coronary Artery Disease in Patients with Obstructive Sleep Apnea.

Biomarkers are not available for monitoring the onset and progression of coronary artery disease (CAD) in patients with obstructive sleep apnea (OSA), a major risk factor for arteriosclerotic cardiovascular diseases. This study aimed to test for correlation between circulating anti-Sorting Nexins 16 antibody (SNX16-Ab) levels, CAD history and clinical parameters of patients with OSA. Sixty-four healthy donors, 82 adults with OSA, and 96 with acute coronary syndrome (ACS) were studied. Serum samples were collected at diagnostic polysomnography in the OSA group or at the disease onset in the ACS group. Serum SNX16-Ab levels were measured by amplified luminescence proximity homogeneous assay (AlphaLISA), and correlation between SNX16-Ab levels and clinical parameters was analyzed. SNX16-Ab levels and apnea-hypopnea index (AHI) were weakly correlated. Additionally, logistic regression analyses of OSA group identified that elevated SNX16-Ab level associated with the history of CAD. Circulating SNX16-Ab could increase during CAD pathogenesis in patients with OSA. Further prospective studies are required to prove the predictive potential of SNX16-Ab level in CAD onset of patients with OSA.

Characteristics of Japanese elderly patients with pulmonary arterial hypertension.

Previous nationwide Japanese data suggested that pulmonary arterial hypertension (PAH) predominantly affects young women. However, the number of elderly patients diagnosed with PAH has been increasing in western countries. There have been no reports on elderly PAH patients in Asian countries. This study aimed to investigate the clinical characteristics of elderly PAH patients in a Japanese cohort. Idiopathic/heritable PAH (I/H-PAH) was included in the national research project on intractable diseases. The patients were required to submit a clinical research form completed by their attending physicians. We analyzed the characteristics of Japanese I/H-PAH using the newly registered forms in 2013 (Study 1, n = 148). Also, we did a retrospective, observational cohort study at Chiba University Hospital (Study 2, n = 42). We compared the characteristics of elderly PAH patients (≥65 years old) with younger patients (<65) in both studies. Study 1 revealed a predominance of males (51% male), better hemodynamics and poorer exercise capacity in the elderly group (n = 72), compared with the younger group (n = 76) in study 1. In Study 2, elderly patients showed a male predominance (63% male), a higher ratio of smokers, a lower % carbon monoxide diffusing capacity, and poorer exercise tolerance. Elderly patients in Study 2 showed less improvement in hemodynamics with therapy. There was no significant difference in disease-specific survival between elderly and younger patients. Japanese elderly patients with I/H-PAH showed poorer exercise capacity and impaired gas exchange, but better pulmonary hemodynamics than younger patients.

Single-use suvorexant for treating insomnia during overnight polysomnography in patients with suspected obstructive sleep apnea: a single-center experience.

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.

The Development of Marked Collateral Circulation due to Inferior Vena Cava Filter Occlusion in a Patient with Chronic Thromboembolic Pulmonary Hypertension Complicated with Anti-phospholipid Syndrome.

A 30-year-old Japanese man was diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) with lupus anticoagulants (LAs) in 2003. He underwent pulmonary endarterectomy after the placement of an inferior vena cava filter (IVCF) in 2004, and treatment with warfarin was continued. In 2014, IVCF occlusion and marked collateral circulation were noted during an examination for transient dyspnea; however, his warfarin level was within the therapeutic range for 88.9% of the time from 2003 to 2014. We herein report a rare case of CTEPH and LAs with IVCF occlusion; in such cases, intense treatment may be required.