Effectiveness of remdesivir-based therapy for moderate COVID-19: comparison of Omicron and other variant phases.

Remdesivir is an antiviral drug for the treatment of coronavirus disease 2019 (COVID-19), and the sustained antiviral activity against Omicron variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been reported. In this single-center retrospective study, we first compared the clinical effectiveness of remdesivir-based therapy between Omicron and other variant phases of moderate COVID-19 in a real-world setting. Between Dec 2020 and July 2022, a total of 406 patients with COVID-19 pneumonia were treated with remdesivir-based therapy on admission. The oxygen deterioration rate after initiation of treatment significantly decreased in the Omicron variant phase compared to the alpha and delta variant phases. In an adjusted multivariate Cox proportional hazards model, Omicron variant phase was significantly associated with delayed oxygen deterioration and early recovery from hypoxia. These favorable outcomes during the Omicron variant phase, compared to previous variant phases, might be due to the attenuation and the popularization of vaccination.

[DRUG-INDUCED LUNG INJURY DUE TO OTSU-JI-TO FOLLOWED BY DRUG-INDUCED LIVER INJURY: A CASE REPORT].

A 69-year-old woman who had been treated with Otsu-ji-to for fourteen days developed liver dysfunction. She continued to take Otsu-ji-to and was admitted to our hospital due to respiratory failure with extensive ground-glass opacities on chest computed tomography 22 days after starting to take Otsuji-to. Although she developed severe respiratory failure, her condition was improved by discontinuation of Otsu-ji-to and high-dose corticosteroid pulse therapy. The lymphocyte stimulation test was positive for Otsu-ji-to. Finally, we diagnosed drug-induced lung injury due to Otsu-ji-to. As in this case, severe herbal medicine-induced lung injury may be developed secondary to preceding liver injury. When a patient prescribed ou-gon-containing herbal medicines such as Otsu-ji-to develops liver dysfunction, due to herbal medicines containing ou-gon such as Otsu-ji-to, it is important to evaluate lung injury and discontinue the Kampo drug.

Subpleural fibrotic interstitial lung abnormalities are implicated in non-small cell lung cancer radiotherapy outcomes.

BACKGROUND: The relationship between interstitial lung abnormalities (ILAs) and the outcomes of lung cancer radiotherapy is unclear. This study investigated whether specific ILA subtypes are risk factors for radiation pneumonitis (RP). PATIENTS AND METHODS: This retrospective study analysed patients with non-small cell lung cancer treated with radical-intent or salvage radiotherapy. Patients were categorised into normal (no abnormalities), ILA, and interstitial lung disease (ILD) groups. The ILA group was further subclassified into non-subpleural (NS), subpleural non-fibrotic (SNF), and subpleural fibrotic (SF) types. The Kaplan-Meier and Cox regression methods were used to determine RP and survival rates and compare these outcomes between groups, respectively. RESULTS: Overall, 175 patients (normal, n = 105; ILA-NS, n = 5; ILA-SNF, n = 28; ILA-SF, n = 31; ILD, n = 6) were enrolled. Grade ≥2 RP was observed in 71 (41%) patients. ILAs (hazard ratio [HR]: 2.33, p = 0.008), intensity-modulated radiotherapy (HR: 0.38, p = 0.03), and lung volume receiving 20 Gy (HR: 54.8, p = 0.03) contributed to the cumulative incidence of RP. Eight patients with grade 5 RP were in the ILA group, seven of whom had ILA-SF. Among radically treated patients, the ILA group had worse 2-year overall survival (OS) than the normal group (35.3% vs 54.6%, p = 0.005). Multivariate analysis revealed that the ILA-SF group contributed to poor OS (HR: 3.07, p =0.02). CONCLUSIONS: ILAs, particularly ILA-SF, may be important risk factors for RP, which can worsen prognosis. These findings may aid in making decisions regarding radiotherapy.

A case of renal cell carcinoma with microscopic pulmonary tumor embolism proven by surgical lung biopsy.

Pulmonary tumor embolism (PTE) is difficult to diagnose before death. We report the case of a 75-year-old man with microscopic PTE of renal cell carcinoma who was diagnosed by surgical lung biopsy. He visited our hospital because of dyspnea on exertion. Chest computed tomography (CT) showed multiple micronodules and ground glass opacities. Steroid therapy was started as therapeutic diagnosis for IgG4-related pulmonary disease. However, he was admitted our hospital due to progressive respiratory failure. Pathological findings of a lung biopsy obtained by video-assisted thoracic surgery showed PTE of renal cell carcinoma without embolization of large pulmonary arteries. He received palliative medicine and died four months after the surgical lung biopsy. In cases of multiple micronodules in chest CT findings and worsened respiratory symptoms, PTE should be considered in the differential diagnosis.

Randomized phase II study of nintedanib with or without pirfenidone in patients with idiopathic pulmonary fibrosis who experienced disease progression during prior pirfenidone administration.

INTRODUCTION: A subgroup analysis of the CAPACITY and ASCEND trials showed that pirfenidone use beyond disease progression reduced the risk of subsequent forced vital capacity (FVC) decline and death. Our study aimed to compare the efficacy and safety of nintedanib with or without pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) who experienced disease progression during previous pirfenidone therapy. METHODS: In this randomized, open-label, selection design phase II trial, patients with IPF and a ≥5% relative decline in FVC within 6 months of the pirfenidone administration period were randomly assigned to nintedanib (switch group) or nintedanib plus pirfenidone (combination group). The primary endpoint was the incidence of a ≥5% relative decline in FVC or death during the first 6 months. RESULTS: Only 7 patients were enrolled (4 in the switch group and 3 in the combination group). Although the switch group continued with nintedanib for 1 year or more, 2 patients (66.7%) in the combination group discontinued nintedanib within 6 months due to severe adverse events. Given the slow case registration and safety concerns in the combination group, the trial was terminated without extending the registration. The incidence of a ≥5% relative decline in FVC during the first 6 months was 50.0% in the switch group and 66.7% in the combination group. There were no deaths during the observation period. CONCLUSIONS: Clinical trials verifying the use of pirfenidone after disease progression in IPF may be difficult to enroll patients. Definitive conclusions on both safety and efficacy cannot be drawn from the results of this study alone. TRIAL REGISTRATION: UMIN Clinical Trial Registry; registration number, UMIN000019436; date of first registration, 21/10/2015; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000022471.

A case of acute inhalation injury caused by premeditated chlorine gas exposure.

Chlorine is a toxic gas that causes severe inhalation injury. We report the case of a 43-year-old woman who inhaled chlorine gas generated by mixing household bleach and vinegar. She was referred to our hospital because she had developed respiratory failure. Chest computed tomography (CT) showed diffuse ground-glass opacity and the tree-in-bud pattern. We diagnosed acute inhalation injury compatible with that due to chlorine gas exposure. Six days after admission, her respiratory symptoms and abnormal CT findings fully resolved without the use of bronchodilators or corticosteroids. This is the first report of a patient with acute inhalation injury caused by intentional chlorine gas exposure. It is considered that chlorine gas reached her respiratory tract and induced widespread injury from bronchioles to alveoli.

Predictive factors for the long-term use of pirfenidone in patients with fibrosing interstitial lung disease.

BACKGROUND: Pirfenidone is an anti-fibrotic agent approved for idiopathic pulmonary fibrosis (IPF), and long-term treatment data and the effect of continuation after disease progression have been reported. The efficacy and safety of pirfenidone in fibrosing interstitial lung disease (ILD) patients without IPF have been recently reported in clinical trials; therefore, the benefits of long-term treatment are also expected. This study aims to analyze the long-term treatment data of pirfenidone and clarify the predictive factors for long-term use of pirfenidone in non-IPF patients. METHODS: We retrospectively reviewed the records of consecutive fibrosing ILD patients who started using pirfenidone between 2008 and 2014. RESULTS: Of the 266 fibrosing ILD patients, 167 patients had IPF, and 99 had non-IPF. Despite the non-significant differences in body size and pulmonary function between IPF and non-IPF patients, the non-IPF patients had better overall survival than the IPF patients (median 4.06 years vs. 2.09 years, p < 0.0001). In addition, the non-IPF patients had a significantly longer time to treatment discontinuation than the IPF patients (median 2.20 years vs. 1.20 years, p = 0.002). Multivariate logistic regression analysis for ≥2 years of use of pirfenidone showed that the percent predicted forced vital capacity (%FVC) and age were predictive factors common to both IPF and non-IPF patients. CONCLUSIONS: Our results indicate that non-IPF patients can continue using pirfenidone for longer durations than IPF patients. Initiation of pirfenidone for fibrosing ILD patients with higher %FVC and younger age would lead to long-term use of pirfenidone.

Tolerability and safety of nintedanib in elderly patients with idiopathic pulmonary fibrosis.

BACKGROUND: In the phase III trial of nintedanib, only 10.8% of participants were aged ≥75 years. Here, we aimed to evaluate the tolerability and safety of nintedanib in elderly patients with idiopathic pulmonary fibrosis (IPF). METHODS: In total, 71 consecutive patients with (1) IPF, (2) age ≥75 years, and (3) newly prescribed nintedanib from September 2015 to April 2018 (elderly group) were retrospectively reviewed. Patient characteristics, treatment status, and adverse events (AEs) were compared between the elderly group and 126 patients with IPF, aged <75 years, with newly prescribed nintedanib during the same period (non-elderly group). RESULTS: In the elderly group, 32 patients (46.4%) discontinued nintedanib within 6 months. Body size was significantly smaller, the incidence rates of anorexia and nausea were significantly higher, and early termination within 6 months were more common in the elderly than in the non-elderly group. In elderly patients, a univariate logistic regression analysis showed that body mass index (BMI) and percentage forced vital capacity (FVC) were risk factors for early termination (p = 0.02 and 0.03, respectively). A low initial nintedanib dose did not reduce the incidence of AEs and early termination rate in the elderly group. CONCLUSIONS: In elderly patients with IPF, the incidence of early nintedanib termination was higher, and anorexia and nausea were common AEs compared with those in non-elderly IPF patients. Treatment was frequently discontinued in elderly patients with low BMI and FVC, and chest physicians should be aware that nintedanib therapy may result in early termination in these patients.

Relationship of flow-volume curve pattern on pulmonary function test with clinical and radiological features in idiopathic pulmonary fibrosis.

BACKGROUND: The flow-volume (FV) curve pattern in the pulmonary function test (PFT) for obstructive lung diseases is widely recognized. However, there are few reports on FV curve pattern in idiopathic pulmonary fibrosis (IPF). In this study, we investigated the relationship between FV curve pattern and clinical or radiological features in IPF. METHODS: The FV curves on PFTs and chest high-resolution computed tomography (HRCT) images of 130 patients with IPF were retrospectively evaluated. The FV curves were divided into four groups based on the presence or absence of the convex and concave patterns: convex/concave, non-convex/concave, convex/non-concave, and non-convex/non-concave. Using a computer-aided system, CT honeycombing area (%HA) and subtracted low attenuation area (%sLAA) were quantitatively measured. To assess the distribution of CT findings, the lung area was divided into upper, lower, central, and peripheral areas. The relationships of FV curve patterns with patient characteristics, spirometry results, and quantitative CT findings were evaluated. RESULTS: The patients with convex pattern was identified in 93 (71.5%) and concave pattern in 72 (55.4%). Among the four groups, patients with the convex/non-concave pattern had significantly lower forced vital capacity (FVC) and higher %HA of the upper/peripheral lung area (p = 0.018, and p = 0.005, respectively). The convex/non-concave pattern was a significant predictor of mortality for IPF (hazard ratio, 2.19; p = 0.032). CONCLUSIONS: Patients with convex/non-concave pattern in FV curve have lower FVC and poorer prognosis with distinct distribution of fibrosis. Hence, FV curve pattern might be a useful predictor of mortality in IPF.

Five cases of BRAF V600E-mutant lung adenocarcinoma with high expression of programmed death ligand 1.

We reported consecutive five patients with BRAF V600E-mutant recurrent or advanced non-small cell lung cancer who were identified between April 2016 and June 2019. All five patients had high programmed death ligand 1 (PD-L1) tumor proportion scores (50, 55, 75, 95 and 100%). Four of the five patients received regimens including pembrolizumab. Of them, one patient experienced a partial response, but two patients experienced progressive disease and one patient was not evaluable. Three of the four patients received regimens including pemetrexed were able to continue long-term treatment. The presence of a BRAF mutation may be associated with higher levels of PD-L1 expression. The effect of immune checkpoint inhibitors therapy in patients with BRAF mutation was similar to the previous reports in patients with previously treated advanced non-small cell lung cancer with PD-L1 tumor proportion score ≥50%. Chemotherapy regimens including pemetrexed may have a positive effect in patients with BRAF V600E-mutant lung adenocarcinoma. Accumulation of additional Case series is necessary to confirm our results.

Miliary lung metastases from ROS1-rearranged lung adenocarcinoma: A case report.

Miliary lung metastases are a rare form of metastasis of non-small-cell lung carcinoma. Miliary lung metastases commonly develop in lung adenocarcinoma with epidermal growth factor receptor mutation. In the present study, we present a case of miliary lung metastases from lung adenocarcinoma with ROS1 rearrangement. The patient, who had a history of surgery for stage IIIA lung adenocarcinoma, presented to our hospital with cough, dyspnea, and severe hypoxia. Chest computed tomography showed numerous tiny, randomly distributed nodules throughout both lungs. No metastases were observed in other organs. Molecular profiling of the surgical specimens was positive for ROS1 rearrangement. The results suggest that chest physicians should be aware that miliary lung metastases can develop in patients with lung adenocarcinoma with ROS1 rearrangement.

A case of intrathoracic desmoid tumor with pulmonary Mycobacterium abscessus disease.

A 68-year-old man who was on treatment for pulmonary Mycobacterium avium complex complained a worsening of sputum. Although he archived negative sputum culture two months ago, sputum culture tests revealed the newly isolation of Mycobacterium abscessus repeatedly. Chest computed tomography showed newly-appeared extra-pulmonary mass lesion in contact with a cyst at the bottom of his right lung. From the results of contrast-enhanced magnetic resonance imaging, we first suspected loculated pleural effusion due to Mycobacterium abscessus infection. A thoracoscopic examination was performed as the right pneumothorax developed, and the pleural lesion was successfully resected and diagnosed as an intrathoracic desmoid tumor. Intrathoracic desmoid tumor is very rare, and this is the first report of a case with pulmonary Mycobacterium abscessus disease.

Pemetrexed-induced Interstitial Lung Disease Mimicking Hypersensitivity Pneumonia: A Pathologically Proven Case.

We herein report a 45-year-old woman with lung adenocarcinoma stage IV (cT4N3M1a). She was treated with pemetrexed (PEM) monotherapy following four cycles of first-line treatment with carboplatin, paclitaxel, and veliparib. After three cycles of PEM treatment, she presented with dyspnea, and chest computed tomography showed diffuse ground-glass attenuation (GGA), suggesting hypersensitivity pneumonia (HP). Bronchoalveolar lavage revealed a marked increase in lymphocytes (90.5%), and a transbronchial lung biopsy confirmed lymphocytic alveolitis with granuloma. Because her symptoms and diffuse GGA were spontaneously resolved with PEM discontinuation alone, PEM-induced interstitial lung disease was diagnosed. Chest physicians should be aware that PEM can induce HP-type interstitial lung disease.

Negative impact of anorexia and weight loss during prior pirfenidone administration on subsequent nintedanib treatment in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Current clinical practice guidelines for idiopathic pulmonary fibrosis (IPF) conditionally recommend use of pirfenidone and nintedanib. However, an optimal treatment sequence has not been established, and the data of treatment sequence from pirfenidone to nintedanib are limited. This study aimed to evaluate safety, tolerability and efficacy of nintedanib switched from pirfenidone in patients with IPF. METHODS: Thirty consecutive IPF cases, which discontinued pirfenidone because of a decline in forced vital capacity (FVC) or intolerable adverse event (AE), and newly started nintedanib (150 mg twice daily) from September 2015 to August 2017 (switch-group) were retrospectively reviewed. Subsequently, we compared the characteristics, treatment status, and AEs between the switch-group and other 64 IPF patients newly started nintedanib during the same period without any prior anti-fibrotic treatment (pirfenidone-naïve group). RESULTS: In the switch group, median age, body weight, body mass index (BMI), and %FVC were 72 years old, 54.9 kg, 21.0 kg/m2, and 52.9%, respectively. Most common AE of nintedanib was aspartate aminotransferase/alanine aminotransferase elevation (71.9%), followed by anorexia (46.7%) and diarrhea (46.7%); whereas, anorexia (63.3%) and ≥ 5% weight loss from baseline (56.7%) were common during pirfenidone administration. Sixteen patients (53.3%) discontinued nintedanib within 6 months (early termination). Multivariate logistic regression analysis revealed a significant association between low BMI and early nintedanib termination in the switch-group (p = 0.0239). Nintedanib suppressed FVC decline as compared with that during administration period of pirfenidone in 70% of the patients who could undergo lung function before and after switching to nintedanib. The incidence of early termination of nintedanib was higher in the switch-group than in the pirfenidone-naïve group, whereas body-weight, BMI, absolute FVC values, and %FVC were significantly lower in the switch-group (just before nintedanib initiation) than in the pirfenidone-naïve group. Nintedanib-induced anorexia was more frequent and severer in the switch-group than in the pirfenidone-naïve group, but no significant differences were observed in terms of other AEs. CONCLUSIONS: A high incidence of early termination of nintedanib was noted when patients were switched from pirfenidone. Anorexia and weight loss during prior pirfenidone administration may increase the rate of the early termination of subsequent nintedanib treatment.

Anti-Ku antibody-positive desquamative interstitial pneumonia.

A 66-year-old man, an ex-smoker, was referred to our hospital for slightly progressive respiratory symptoms of cough and dyspnea on exertion and chest abnormal shadow. Chest high-resolution computed tomography showed wide-ranging ground-glass attenuation and reticulation with lower lobe predominance. Bronchoalveolar lavage (BAL) fluid revealed a marked increase in lymphocytes (53.0%), and a surgical lung biopsy revealed a pattern of desquamative interstitial pneumonia (DIP) with hyperplasia of the lymphoid follicles. His serum was positive for anti-Ku and anti-SS-A antibodies, and he had signs (such as Raynaud's phenomenon, joint pain, and mechanic's hand) suspicious of connective tissue disease (CTD) although a definitive diagnosis of CTD had not been established. On the basis of the findings in our patient obtained from the serologic domain, BAL, and pathological examination, clinicians should consider the important correlation of DIP with CTD as well as with smoking.

Newly defined acute exacerbation of idiopathic pulmonary fibrosis with surgically-proven usual interstitial pneumonia: risk factors and outcome.

BACKGROUND: In 2016, the diagnostic criteria for the acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) were revised. However, there have been published few clinical reports on AE-IPF published using the new criteria. The aim of this study was to investigate the incidence of, risk factors for, and mortality due to newly defined AE. Moreover, differences between triggered AE and idiopathic AE were investigated. METHODS: The retrospective study was conducted including all IPF patients diagnosed with surgically-proven usual interstitial pneumonia through multi-disciplinary discussion between January 2006 and December 2015. Data were retrieved from a clinical chart review. RESULTS: A total of 107 patients with newly diagnosed 107 IPF patients were included. The cumulative incidence of initial AE were 9.6% at 1 year, 16.8% at 2 years, 23.9% at 3 years, and 37.3% at 4 years after diagnosis. Three risk factors for AE-IPF development were identified: 1) the minimum peripheral ozygen saturation level of ≤88% during the 6-minute walk test at the time of diagnosis; 2) forced vital capacity (FVC) decreasing by ≥10% in 1 year; and 3) diffusion capacity of the lungs for carbon monoxide (DLco) decreasing by ≥15% in 1 year. There were no significant differences in background (excluding C-reactive protein), survival and treatment between patients with triggered AE and those with idiopathic AE. CONCLUSIONS: The 6-minute walk test and an annual decline in FVC and DLco were predictive factors for AE incidence. The causes of AE-IPF did not affect the prognosis or treatment options in clinical practice.

Miliary lung metastases from non-small cell lung cancer with Exon 20 insertion: A dismal prognostic entity: A case report.

Miliary lung metastases have been reported to be frequently observed in nοn-small cell lung cancer (NSCLC) with major EGFR mutations, which consist of exon 19 deletion and exon 21 L858R. However, it remains undetermined whether NSCLC with minor EGFR mutations possesses characteristics similar to those with major EGFR mutations. In the present study, two cases of miliary lung metastases from NSCLC with exon 20 insertion were reported. Both the patients visited our hospital because of cough and/or dyspnea and were treated with chemotherapeutic agents, including platinum-doublet regimen. In addition, 1 patient received afatinib during the clinical course. However, all therapeutic regimens did not result in the desired outcome, and the respiratory condition rapidly deteriorated. Both the patients succumbed to disease within 3 months from the beginning of the 1st-line treatment due to disease progression. To conclude, chest physicians should be aware that miliary lung metastases could develop in NSCLC patients with exon 20 insertion and present a dismal prognosis.

Secondary pulmonary alveolar proteinosis predominant in the transplanted lung in patients with idiopathic interstitial pneumonia: an autopsy case.

A man in his 40 s with idiopathic interstitial pneumonia underwent cadaveric left single-lung transplantation from a brain-dead donor in October 2014. In October 2015, chest high-resolution computed tomography revealed centrilobular ground-glass opacities (GGOs) predominantly in the transplanted left lung, and subsequently, the shadows progressed to a geographic GGO without crazy paving. Bronchoalveolar lavage fluid analysis revealed an opaque and milky appearance, and cytopathology demonstrated foamy alveolar macrophages and abundant granular, acellular, eosinophilic, and amorphous material in the background. There was no evidence of infection. Serum anti-granulocyte-macrophage colony-stimulating factor antibody testing was negative. We diagnosed the patient with secondary pulmonary alveolar proteinosis (PAP) following lung transplantation. Autopsy revealed PAP findings predominant in the transplanted left lung, which also had dilated lymphatic vessels. In addition to defects in alveolar macrophage function from immunosuppressive therapy, impaired lymphatic drainage due to transplantation would contribute to the onset of secondary PAP in the transplanted lung.