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.

A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study).

BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

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.

Favipiravir, camostat, and ciclesonide combination therapy in patients with moderate COVID-19 pneumonia with/without oxygen therapy: An open-label, single-center phase 3 randomized clinical trial.

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.

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.

Glucose levels between the anterior chamber of the eye and blood are correlated based on blood glucose dynamics.

Glycemic control is essential to manage metabolic diseases such as diabetes. Frequent measurements of systemic glucose levels with prompt managements can prevent organ damages. The eye is a glucose highly demanding organ in our body, and the anterior chamber (AC) in the eye has been suggested for a noninvasive blood glucose monitoring site. However, calculating blood glucose levels from measuring glucose levels in AC has been difficult and unclear. In this study, we aimed to examine glucose levels from AC and find a correlation with blood glucose levels. A total of 30 patients with cataracts (men and women, study 1; 7 and 3, study 2; 9 and 11) who visited Keio University Hospital from 2015 to 2018 and agreed to participate in this study were recruited. Glucose levels from AC and the blood were examined by a UV-hexokinase or H2O2-electrode method before/during the cataract surgery. These values were analyzed with regression analyses depending on the groups (blood glucose-ascending and descending groups). In the blood glucose-descending group, glucose levels from AC were strongly correlated with blood glucose levels (a high R2 value, 0.8636). However, the relatively moderate correlation was seen in the blood glucose-ascending group (a low R2 value, 0.5228). Taken together, we showed different correlation ratios on glucose levels between AC and the blood, based on blood glucose dynamics. Stacking data regarding this issue would enable establishing noninvasive blood glucose monitoring from measuring glucose levels in AC more correctly, which will be helpful for proper and prompt managements for glucose-mediated complications.

Coronary artery calcium score may be a novel predictor of COVID-19 prognosis: a retrospective study.

BACKGROUND: Although several studies have reported an association between atherosclerosis-related diseases and COVID-19, the relationship between COVID-19 severity and atherosclerosis progression remains unclear. The aim of this study is to determine the coronary artery calcium score (CACS) prognostic value in patients with COVID-19 using indices such as deterioration in oxygenation and CT images of the chest. METHODS: This was a single-centre retrospective study of 53 consecutive patients with COVID-19 in Narita who were admitted to our hospital between March 2020 and August 2020. CACS was calculated based on non-gated CT scans of the chest performed on admission day. The patients were divided into the following two groups based on CACS: group 1 (CACS ≥180, n=11) and group 2 (CACS <180, n=42). Following univariate analysis of the main variables, multivariate analysis of variables that may be associated with COVID-19 progression was performed. RESULTS: Multivariable logistic regression analysis of age, sex, smoking history, diabetes, hypertension, dyslipidaemia, number of days from symptom onset to hospitalisation and CACS of ≥180 was performed. It revealed that unlike CACS of <180, CACS of ≥180 is associated with exacerbation of oxygenation or CT images of the chest during hospitalisation (OR: 12.879, 95% CI: 1.399 to 380.401). Furthermore, this model of eight variables showed good calibration (Hosmer-Lemeshow p=0.119). CONCLUSION: CACS may be a prognosis marker of COVID-19 severity. Although coronary artery calcification is not typically assessed in pneumonia cases, it may provide a valuable clinical indicator for predicting severe COVID-19 outcomes.

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.

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.

Circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1): A potential biomarker for coronary artery disease in patients with obstructive sleep apnea.

OBJECTIVE: Although severe obstructive sleep apnea (OSA) is an important risk factor for atherosclerosis-related diseases including coronary artery disease (CAD), there is no reliable biomarker of CAD risks in patients with OSA. This study aimed to test our hypothesis that circulating autoantibodies against neuroblastoma suppressor of tumorigenicity 1 (NBL1-Abs) are associated with the prevalence of CAD in patients with OSA. METHODS: Eighty-two adults diagnosed with OSA by polysomnography, 96 patients with a diagnosis of acute coronary syndrome (ACS) and 64 healthy volunteers (HVs) were consecutively enrolled. Serum samples were collected from patients with OSA at diagnostic polysomnography and from patients with ACS at disease onset. Serum NBL1-Ab level was measured by amplified luminescence proximity homogeneous assay and its association with clinical variables related to atherosclerosis was evaluated. RESULTS: NBL1-Ab level was significantly elevated in patients with both OSA and ACS compared with HVs. Subgroup analyses showed that NBL1-Ab level was markedly higher in patients with severe OSA and OSA patients with a history of CAD. Weak associations were observed between NBL1-Ab level and apnea-hypopnea index, age, mean SpO2 and arousal index, whereas significantly higher NBL1-Ab levels were observed in OSA patients with a history of CAD than in those without a history of CAD. Sensitivity analysis using a logistic regression model also demonstrated that increased NBL1-Ab levels were associated with the previous history of CAD in patients with OSA. CONCLUSIONS: Elevated NBL1-Ab levels may be associated with the prevalence of CAD in patients with OSA, which needs to be confirmed further.

Impact of Arterial Stiffness on WatchPAT Variables in Patients With Obstructive Sleep Apnea.

STUDY OBJECTIVES: The WatchPAT is a wrist-worn portable device that creates integration data regarding peripheral arterial tone (PAT), oxyhemoglobin saturation, heart rate, and actigraphy to diagnose or screen for obstructive sleep apnea (OSA). Previous studies have demonstrated the efficacy and validity of respiratory variables measured by the WatchPAT compared to those using polysomnography (PSG). However, the effects of arterial stiffness or atherosclerosis on WatchPAT parameters remain to be elucidated. METHODS: Sixty-one consecutive patients with suspected OSA who underwent home-based testing with the WatchPAT 200, standard in-laboratory overnight polysomnography (PSG), and pulse wave velocity (PWV) as an index of arterial stiffness were studied. All PSG recordings were scored manually using the American Academy of Sleep Medicine criteria, whereas WatchPAT data were analyzed by an automatic algorithm. We evaluated how arterial stiffness affected respiratory event index data in WatchPAT (WP-AHI), because WP-AHI could be partly influenced by PAT, comparing WP-AHI and the apneahypopnea index measured by PSG (PSG-AHI) in consideration of PWV result. RESULTS: Overall, WP-AHI was moderately correlated to PSG-AHI, but WP-AHI was significantly lower than PSG-AHI (28.4 ± 19.2 versus 53.6 ± 30.2 events/h, P < .0001). For the lower PWV group, there was a significant correlation and good agreement between the WP-AHI and PSG-AHI, but as the PWV increased, there was low correlation between the WP-AHI and PSG-AHI. CONCLUSIONS: Arterial stiffness may affect the respiratory variables measured by WatchPAT in patients with OSA. COMMENTARY: A commentary on this article appears in this issue on page 301.

Circulating Anti-Coatomer Protein Complex Subunit Epsilon (COPE) Autoantibodies as a Potential Biomarker for Cardiovascular and Cerebrovascular Events in Patients with Obstructive Sleep Apnea.

STUDY OBJECTIVES: Although moderate to severe obstructive sleep apnea (OSA) is an independent risk factor for severe arteriosclerotic diseases such as cardiovascular disease (CVD) and stroke, the development of atherosclerosis-related diseases cannot yet be predicted in patients with OSA. In a pilot study, we identified autoantibodies against the coatomer protein complex, subunit epsilon [circulating anti-coatomer protein complex subunit epsilon autoantibody (COPE-Ab)], a cytosolic complex that mediates protein transport in the Golgi compartment, as a potential novel biomarker of atherosclerosis. This study aimed to evaluate whether COPE-Ab levels had an association with cardiovascular and cerebrovascular events in patients with OSA. METHODS: Eighty-two adult patients with a diagnosis of OSA via polysomnography and 64 healthy donors were studied. Serum COPE-Ab levels were measured using an amplified luminescence proximity homogeneous assay. Then, clinical factors related to atherosclerosis were evaluated with respect to COPE-Ab levels. RESULTS: Significant differences in COPE-Ab levels were observed in terms of OSA severity. COPE-Ab levels were significantly higher in patients with OSA and also CVD and/or stroke, hypertension, and a high body mass index. Univariate and multivariate logistic regression analyses of patients with OSA identified elevated COPE-Ab level as a significant predictor of CVD and/or stroke. CONCLUSIONS: An elevated COPE-Ab level may be a potential predictor of the risks of cardiovascular and cerebrovascular events in patients with OSA. Therefore, patients with higher COPE-Ab levels may require more careful and intensive treatment. COMMENTARY: A commentary on this article appears in this issue on page 361.

Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype.

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

Living Donor Lung Transplantation for Pleuroparenchymal Fibroelastosis.

We report the first patient with pleuroparenchymal fibroelastosis (PPFE) to undergo living donor bilateral lobar lung transplantation. The patient was diagnosed with secondary PPFE as a late complication of chemotherapy that included high-dose cyclophosphamide for mature B-cell lymphocytic leukemia. Although the patient maintained complete remission, dry cough and back pain appeared 8 years after the chemotherapy. He had repeated bilateral pneumothoraces, and his respiratory condition gradually deteriorated because of progressive pleural thickening and parenchymal fibrosis. He underwent living-donor bilateral lobar lung transplantation with an inverse transplant on the left side.