Background: Some novel anticancer agents are associated with drug-induced interstitial lung disease (ILD), a critical and potentially fatal adverse event. Lung cancer patients appear particularly susceptible, yet the risk and clinical characteristics remain incompletely analyzed. Objectives: To comprehensively evaluate ILD risk and characteristics induced by novel anticancer agents in non-small cell lung cancer (NSCLC) using large-scale real-world data. Design: A retrospective pharmacovigilance study based on spontaneous adverse event reports. Methods: Data from 2014 to 2024 were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). Reports of NSCLC patients who developed ILD during treatment with FDA-approved novel anticancer agents (immune checkpoint inhibitors, targeted therapies, antibody-drug conjugates). The reporting odds ratio (ROR) was used to assess the disproportionate reporting signals for each drug. Statistical significance was defined when the lower 95% confidence interval (CI) exceeded 1 with at least three reports. Results: A total of 4712 NSCLC cases were analyzed. Eight agents were identified with positive signals for ILD: ROR and 95% CI for nivolumab was 1.28 (1.20–1.38), pembrolizumab 1.47 (1.36–1.59), durvalumab 7.38 (6.90–7.89), atezolizumab 1.25 (1.12–1.39), ipilimumab 1.96 (1.74–2.21), tremelimumab 3.58 (1.97–6.50), trastuzumab-deruxtecan 3.14 (2.29–4.30), osimertinib 1.12 (1.03–1.23). The median onset time was 33 days, with 48.59% of ILD events occurring within the first month. The fatal cases experienced a significantly shorter onset time than non-fatal cases. Older age, male sex, and lower body weight were identified as factors affecting ILD, whereas lower body weight, male sex, and a higher number of concomitant drugs were linked to increased mortality. Conclusion: Our study identifies positive signals for ILD with eight novel antineoplastic agents in NSCLC, including nivolumab, pembrolizumab, durvalumab, atezolizumab, ipilimumab, tremelimumab, trastuzumab-deruxtecan, and osimertinib, highlights the importance of monitoring during the first month of therapy, and identifies older male patients with lower body weight as a high-risk group.

The persistent opening of the mitochondrial permeability transition pore (mPTP) plays a critical role in bronchial asthma pathogenesis. The ATP synthase c subunit (c subunit) constitutes a core component of mPTP. A novel c subunit inhibitor, 1,3,8-triazaspiro [4.5] decane derivatives (PP10), effectively suppresses pathological mPTP opening without impairing ATP synthesis. Although intraperitoneal PP10 administration mitigates airway inflammation in asthmatic mice, its hydrophobicity hinders inhaled delivery to airway epithelial mitochondria, requiring penetration of the mucus layer, cell membrane, and mitochondrial outer membrane. To overcome this, we developed inhalable human serum albumin-triphenylphosphine-polyethylene glycol-PP10 nanoparticles (HSA-TPP-PEG-PP10 NPs). These NPs demonstrated efficient mucus penetration, high drug loading, mitochondria-targeting capability, and biosafety. They suppressed house dust mite/lipopolysaccharide (HDM/LPS)-induced mPTP opening, inhibited the mitochondrial DNA (mtDNA)-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, reduced inflammation in human bronchial epithelial (HBE) cells, and alleviated airway inflammation in asthmatic mice upon inhalation.

Ferroptosis is an iron-dependent programmed cell death mechanism triggered by the accumulation of lipid-based reactive oxygen species (ROS). It is closely implicated in the pathogenesis of asthma. Liproxstatin-1 (LIP-1) is a ferroptosis inhibitor that is beneficial for treating neutrophilic asthma. However, low water solubility, limited blood concentration, and poor mucus permeability and biocompatibility limit the therapeutic efficacy of LIP-1. In this study, we successfully constructed polydopamine-polyethylene glycol-LIP-1 nanoparticles (PDA-PEG-LIP-1 NPs) for the treatment of neutrophilic asthma. Inhalation of PDA-PEG-LIP-1 NPs effectively inhibited lipopolysaccharide (LPS)- and interleukin (IL)-13-induced ferroptosis by alleviating lipid peroxidation and ROS production and chelating free ferrous ions (Fe2+). In addition, results from asthma mouse models demonstrated that inhalation of PDA-PEG-LIP-1 NPs could overcome the limitations of LIP-1 and effectively inhibit ferroptosis. This research suggests that PDA-PEG-LIP-1 NPs are an effective, practical, and safe option for treating neutrophilic asthma.

Given the current global challenges posed by antimicrobial resistance, the early and accurate identification of carbapenem-resistant Gram-negative bacilli (CR-GNB) is crucial for patient outcomes. This study evaluates the combined diagnostic performance of Xpert Carba-R and Loop-mediated isothermal amplification (LAMP) in the early detection of CR-GNB in patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) and investigates the effect of early treatment based on detection results on the prognosis of these patients. In this single-center prospective study, 250 HAP/VAP patients were enrolled. Respiratory specimens underwent bacterial culture, antimicrobial susceptibility testing, Xpert Carba-R, and LAMP. Diagnostic performance (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]) of the combined test to detect CR-GNB was assessed. Clinical utility in guiding early antibiotic therapy was evaluated. The combined method demonstrated 64.87% sensitivity (95% CI: 52.89%-75.61%) and 94.32% specificity (95% CI: 89.80%-97.24%), with perfect 100% sensitivity and specificity for detecting CR-GNB in Klebsiella pneumoniae. Patients testing positive were randomized to early or non-early treatment groups. For severe patients, the early treatment group showed significantly improved clinical outcomes, including lower acute physiology and chronic health evaluation-II (APACHE-II) scores (P < 0.05) and sequential organ failure assessment (SOFA) scores (P < 0.01) at 15 days post-treatment, along with reduced 30-day hospitalization costs (P < 0.05). Notably, among the critically ill patients, compared with the non-early treatment group, the early treatment group achieved a clinical improvement rate of 81.25% and a microbiological eradication rate of 56.25%, showing a clear advantage. IMPORTANCE:An urgent clinical need exists for rapid detection of carbapenem-resistant Gram-negative bacilli (CR-GNB) in respiratory specimens to facilitate early and precise antibiotic therapy. To address this gap, we developed an innovative dual-method assay: Xpert Carba-R to detect five major carbapenemases, and loop-mediated isothermal amplification (LAMP) to identify common Gram-negative respiratory pathogens. Integration of these methods enables simultaneous and early determination of bacterial species and their resistance profiles. We validated this assay against conventional culture-based antimicrobial susceptibility testing (AST) and assessed its clinical impact on patient outcomes. Results indicate that this integrated approach provides clinically actionable data, serving as a viable alternative to conventional diagnostic workflows.This study is registered with the Chinese Clinical Trial Registry as ChiCTR2400090694.

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The ATP synthase c subunit (c subunit) constitutes the mitochondrial permeability transition pore (mPTP). The extended opening of the mPTP is crucial in the development of various human illnesses. Nevertheless, it remains unclear whether the c subunit regulates the prolonged opening of the mPTP to attenuate inflammatory responses in asthma. This study sought to clarify the impact of the c subunit on inflammatory responses and to examine the therapeutic effects of 1,3,8-triazaspiro [4.5] decane derivatives (PP10), a c subunit inhibitor, in human bronchial epithelial (HBE) cells induced by house dust mite (HDM) and lipopolysaccharide (LPS), as well as in a mouse model. The findings indicated that the expression of the c subunit is elevated in asthmatic patients, HDM/LPS-induced HBE cells, and asthmatic mice. The inhibition of the c subunit by PP10 alleviated the prolonged opening of mPTP, then blocked the release of mitochondrial DNA (mtDNA) and cyclic GMP-AMP synthase (cGAS)-interferon response cGAMP interactor (STING) pathway activation in HDM/LPS-induced HBE cells. Furthermore, PP10 decreased the secretion of inflammatory cytokines and ameliorated airway inflammation in HDM/LPS-induced HBE cells and asthmatic animals, respectively. The data collectively suggest that the c subunit triggers an inflammatory response by promoting the sustained opening of mPTP, leading to the activation of the mtDNA-GAS-STING pathway in HDM/LPS-induced HBE cells. Inhibition of the c-subunit attenuates inflammatory responses in HDM/LPS-induced cells or mouse models. Clinical trial number Not applicable.

The pneumonia induced by carbapenem resistant Klebsiella pneumoniae (CRKP) has high morbidity and mortality. Among the antibiotics currently available, polymyxin B (PMB) is considered to be the last line of defense. Routine intravenous administration of PMB has many problems, such as severe neurotoxicity and nephrotoxicity. In this study, a novel inhaled PMB-loaded albumin nanoparticles (PEG-pHSA@PMB) capable of penetrating airway mucus and responding to the infection microenvironment is constructed. An acid-responsive functional molecule (PEBA) and NH2-PEG-SH are linked to the surface of human serum albumin (HSA) via the conjugation reaction. Subsequently, PMB is loaded through electrostatic interactions to yield PEG-pHSA@PMB. The sulfhydryl groups of PEG-pHSA@PMB interact with mucins to help penetrate mucus after inhaled. In an acidic environment, the protonation of the tertiary amino groups within PEG-pHSA@PMB causes the charge alteration, which leads to the release of PMB. It demonstrated excellent mucus permeability, potent bactericidal activity, and superior bacteriostatic effects compared to sole PMB. Inhalation of PEG-pHSA@PMB significantly reduced the bacterial load in the lungs of mice with CRKP pneumonia, alleviating inflammatory response. Moreover, PEG-pHSA@PMB exhibited good cytocompatibility and biosafety. The novel strategy of the inhalation drug delivery system is promising for the treatment of pneumonia caused by drug-resistant bacteria.

Background The bidirectional relationship between frailty and COPD is documented. However, longitudinal studies examining the combined effects of genetic predisposition and preserved ratio impaired spirometry (PRISm) on frailty in COPD development are lacking. Research Question What is the association between physical frailty and the incidence and mortality of COPD, and how do genetic predisposition and PRISm modify this association? Study Design and Methods We included 412,351 adults without COPD (mean age ± SD, 56.1 ± 8.1 years; 44.3% male) and 60,584 patients with COPD (mean age ± SD, 59.2 ± 7.4 years; 55.1% male) at baseline in the UK Biobank cohort. Frailty phenotypes were assessed using 5 components, including weight loss, exhaustion, low physical activity, slow gait speed, and low grip strength. Cox proportional hazards regression models were used to evaluate the association of genetic predisposition, PRISm, and frailty with COPD development. Life expectancy reductions due to frailty were estimated using life table methods in patients with COPD. Results During a median follow-up of 13.5 years, 10,695 incident COPD cases were recorded. In the multivariable-adjusted model, frailty and prefrailty were significantly associated with an increased risk of COPD (hazard ratio, 2.21; 95% CI, 2.06-2.37 for frailty; hazard ratio, 1.45; 95% CI, 1.39-1.51 for prefrailty). Significant interactions were observed between genetic predisposition and frailty (P for interaction = .0252), and between PRISm and frailty (P for interaction = .0027), in the development of COPD. Among patients with COPD at 45 years of age, frailty was associated with a reduction in life expectancy of 8.49 years for male individuals and 7.67 years for female individuals, whereas prefrailty was associated with reductions of 3.27 and 2.78 years, respectively, compared with their nonfrail counterparts. Interpretation The results of this study indicate that frailty and prefrailty increase COPD risk and are linked to reduced life expectancy in patients with COPD, highlighting the need for early detection and management of frailty in COPD risk reduction and treatment strategies.

Background:Cone-beam computed tomography (CBCT)-guided bronchoscopy is increasingly utilized for diagnosing peripheral pulmonary lesions (PPLs). We carried out the meta-analysis for assessing the efficacy and safety of CBCT-guided bronchoscopy for PPLs. Methods:An extensive search in several databases was conducted to identify relevant articles. We evaluated the quality of studies with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The pooled diagnostic yield (DY) and adverse event rate with the 95% confidence interval (CI) were computed. Subgroup analyses were performed according to additional use of navigation, use of radial endobronchial ultrasound (rEBUS), use of fixed or mobile CBCT, whether computed tomography (CT) spin was performed before biopsy to affirm tool-in-lesion, use of rapid onsite cytologic examination (ROSE), strictness of the definition of DY, and study design. Further analysis was performed to explore the association between odds of diagnosis with CBCT guided bronchoscopy and PPLs characteristics (>20 vs. ≤20 mm, non-upper lobe vs. upper lobe, with bronchus sign vs. without bronchus sign, and solid vs. non-solid) as well as sampling methods (forceps vs. fine needle aspiration, forceps vs. cryoprobe sampling). The pooled odds ratio (OR) and 95% CI were calculated. The significance level was set at 0.05. All analyses were performed by using meta package in R version 4.3.2. Results:We included 23 studies involving 1,769 patients and 1,863 PPLs in the meta-analysis. The overall pooled DY of CBCT-guided bronchoscopy was 80.2% (95% CI: 76.0-84.1%). Subgroup analysis showed that the DY was highest when CBCT was used with robotic-assisted navigation bronchoscopy (pooled DY 87.5%; 95% CI: 81.5-92.4%), the DY was 78.9% (95% CI: 70.8-85.9%) when CBCT was used alone without other navigation techniques. Lesion size >20 mm, presence of bronchus sign and solid lesions were associated with significant increase in the odds of diagnosis with CBCT-guided bronchoscopy. Pooled adverse event rate was 2.3% (95% CI: 1.2-3.6%). Conclusions:CBCT-guided bronchoscopy is a safe technique with high DY in diagnosing PPLs.

Background:Pulmonary cryptococcosis is a fungal infection of the lungs, particularly challenging to treat in patients with multiple comorbidities such as obesity, type 2 diabetes, and cirrhosis. Fluconazole is a first-line medication for the treatment of pulmonary cryptococcosis, but currently there is a lack of clinical medication experience in obese patients with multiple comorbidities, especially in dose adjustment after treatment failure. Case Introduction:This case report describes the experience of fluconazole in the treatment of pulmonary cryptococcal infection in a 45-year-old Chinese male with obesity, type 2 diabetes, and cirrhosis. The patient had a history of antifungal therapy for two weeks before admission, but the cough and hemoptysis were not improved. The treatment failed. After admission, it was recommended to use a conventional dose of fluconazole as an antifungal regimen according to the guidelines. However, the treatment effect was still unsatisfactory, due to the patients' cough, hemoptysis, and fever symptoms were not relieved. During this period, it was newly found that the patient had cirrhosis and type 2 diabetes and had not previously controlled blood glucose. Considering the above situation, combined with the pharmacokinetic characteristics of fluconazole and the patient's weight reaching 113 kg, the team readjusted the fluconazole medication regimen, and ultimately, the pulmonary infection improved without significant adverse reactions. Results:We found that it was more suitable for patients with obesity to calculate the dose of fluconazole by the lean weight. By estimation, the patient was finally given a loading dose of 800 mg fluconazole, and his condition improved significantly. After two weeks of medication, it was adjusted to a maintenance dose of 600 mg until the pulmonary infection in the patient disappeared. Conclusion:This case suggests that fluconazole antifungal therapy for pulmonary cryptococcal infection should fully consider the risk of comorbidities in patients. If necessary, medication dosage can be adjusted according to weight, and it is recommended to use lean bodyweight for evaluation and optimization. In addition, close attention should be paid to liver and kidney function.

The efficacy and safety of omadacycline have been primarily documented through Phase III clinical trials; however, there are limited data from real-world clinical settings. This study aims to explore the real-world use of omadacycline in China and identify the factors associated with its efficacy. We conducted a retrospective review of medical records for patients treated with omadacycline at a single center from March 2022 to March 2024. We analyzed demographic characteristics, laboratory results, antibiotic regimens, and clinical outcomes. Logistic regression was employed to identify risk factors associated with clinical treatment failure or failure of microbial clearance. A total of 183 patients were included in the final analysis. Clinical success was achieved in 71.0

Mycoplasma penumoniae (MP) is a common etiological agent of community-acquired pneumonia. However, there has been an increasing incidence of macrolide-unresponsive Mycoplasma penumoniae pneumonia (MUMPP) in recent years. The treatment of MUMPP requires further investigation. In this report, we describe a case of MUMPP complicated by secondary spontaneous pneumothorax. The patient was unresponsive to initial macrolide treatment and his pneumonia worsened with increasing hypoxemic respiratory failure. However, after receiving a novel tetracycline and a carbapenem antibiotic as anti-infective agents, glucocorticoid for anti-inflammatory and bronchoscopic interventions to clear the bronchial casts, his fever and hypoxia resolved, and his lung lesions had significantly improved. Symptomatic supportive measures, including supplemental oxygen, was provided for the management of spontaneous pneumothorax developed twenty days after discharge. At follow-up, he did not experience any more initial symptoms. All indexes remained normal for half a year. This study represents the initial investigation into the utilization of tigecycline in conjunction with bronchoscopic interventions including bronchoalveolar lavage (BAL) and bronchoscopic cryotherapy (BC) in the treatment of MUMPP, glucocorticoid can be considered for anti-inflammatory purposes, especially for patients with severe pneumonia. The findings from this case offer valuable insights into a potential therapeutic approach for individuals afflicted with MUMPP.

Abstract Background Patients with COPD are prone to be accompanied by frailty, whether frailty poses a burden of developing COPD in in the general population remains unknown. The purpose of this study is to explore whether prefrailty and frailty increase the risk of COPD, and whether the risk of COPD is significantly increased in the preserved ratio impaired spirometry population with frailty. Methods We included 412,351 adults without COPD at baseline in UK Biobank study. Frailty phenotypes were assessed using five components (weight loss, exhaustion, low physical activity, slow gait speed, and low grip strength). Cox proportional hazard regression models were used to analyze the association between frailty and the incidence of COPD, as well as the impact of frailty in conjunction with preserved ratio impaired spirometry on the incidence of COPD. Results Among all participants, 243,777 (59.1%) were nonfrailty, 155,114 (37.6%) were prefrailty, and 13,460 (3.3%) were frailty. During a median follow-up of 13.5 years, 10,695 COPD cases were recorded. In the multivariable-adjusted model, frailty and prefrailty significantly increased the risk of COPD (HR 2.22, 95%CI: [2.07, 2.38] for frailty and HR 1.45, 95%CI: [1.39, 1.51] for prefrailty). The hazard ratio for the incidence of COPD in individuals with both frailty and preserved ratio impaired spirometry was 4.34 (95%CI: 3.69, 5.12). Conclusions Prefrailty and frailty were associated with an increased risk of COPD. Such association was independent of socioeconomic factors, lifestyles, morbidities, and genetic susceptibility, and modified by preserved ratio impaired spirometry status.

Background Multidrug-resistant (MDR) bacteria-induced VAP often has high lethality. We present this systematic review and meta-analysis to assess the risk factors for MDR bacterial infection in patients with VAP. Methods PubMed, EMBASE, Web of Science, and Cochrane Library were searched for studies regarding MDR bacterial infection in VAP patients, from Jan 1996 to Aug 2022. Study selection, data extraction, and quality assessment of included studies were conducted by two reviewers independently, and potential risk factors for MDR bacterial infection were identified. Results Meta-analysis showed that the score of the Acute Physiology and Chronic Health Evaluation II (APACHE-II) [OR = 1.009, 95% (CI 0.732, 1.287)], Simplified Acute Physiology Score II (SAPS-II) [OR = 2.805, 95%CI (0.854, 4.755)], length of hospital-stay before VAP onset (days) [OR = 2.639, 95%CI (0.387, 4.892)], in-ICU duration [OR = 3.958, 95%CI (0.894, 7.021)], Charlson index [OR = 1.000, 95%CI (0.889, 1.111)], overall hospital-stay [OR = 20.742, 95%CI (18.894, 22.591)], Medication of Quinolones [OR = 2.017, 95%CI (1.339, 3.038)], medication of carbapenems [OR = 3.527, 95%CI (2.476, 5.024)], combination of more than 2 prior antibiotics [OR = 3.181, 95%CI (2.102, 4.812)], and prior use of antibiotics [OR 2.971, 95%CI (2.001, 4.412)] were independent risk factors of MDR bacterial infection in VAP patients. Diabetes and mechanical ventilation duration before VAP onset showed no association with risk for MDR bacterial infection. Conclusions This study has identified 10 risk factors associated with MDR bacterial infection in VAP patients. Identification of these factors would be able to facilitate the treatment and prevention of MDR bacterial infection in clinical practice.

Multidrug-resistant Klebsiella pneumoniae (MDR-Kp) poses a looming health threat to humans. Clinicians find difficulties in treating MDR-Kp infections in patients with severe pneumonia. Various effective therapeutic regimes are now available to clinicians. Through new methods of administration or combinations of other antibiotics, repurposing old drugs such as polymyxins or fosfomycin may be effective against MDR-Kp. Furthermore, many new antibiotics and inhibitors that potentially treat MDR-Kp infections have been recently approved. Concurrently, bacteriophage-based therapy is heading for clinical practice and demonstrating a remarkable ability to kill MDR-Kp. Researchers are working feverishly on nanotechnology-based drug delivery systems (DDSs) or antimicrobial polymers nowadays, which offer more possibilities for treating pneumonia caused by MDR-Kp. The use of photodynamic (PDT), photothermal therapy (PTT), and sonodynamic therapy (SDT) is also gaining popularity as novel antimicrobial methods. This review discusses the promising strategies for MDR-Kp pulmonary infections, including new tricks of older drugs, recently approved antibiotics, bacteriophage-based therapies, innovative DDSs, novel compounds, and alternative nondrug therapies. In particular, this review highlights the potential of inhalation administration. Although none of the aforementioned strategies is a panacea, these advances may provide solutions for specific MDR-Kp pneumonia.

Rationale: Pneumocystis pneumonia (PCP) is an opportunistic infection of patients with congenital or acquired immunodeficiency. It is most frequently occurred in human immunodeficiency virus (HIV) infection, organ transplantation, leukemia, and immunosuppressive therapy. Here we describe the rare case of PCP in a non-HIV-infected diabetic patient and find possible reasons for the association through a literature review. Patient concerns: A 65-years-old male was admitted to our hospital due to a 10-year history of abnormal blood glucose levels and edema of both lower extremities for half a month. However, the patient developed a high fever and progressive dyspnea during hospitalization. Diagnoses: The patient had elevated blood sugar levels, a low white blood cell count within normal limits, and severe lymphopenia. His blood G test and lactate dehydrogenase levels increased significantly. Multiple sputa and bronchoalveolar lavage fluid specimens for Pneumocystis jirovecii (PJ) nucleic acid detection were positive. Chest computed tomography scan demonstrated hazy patchy shadows in the lungs suspected to be pulmonary infections. No tumor, transplantation, or an autoimmune disease was found in the examinations. The patient was diagnosed with PCP finally. Interventions: A combination of oral trimethoprim-sulfamethoxazole and intravenous caspofungin was administered immediately against PJ. The patient was also treated with noninvasive ventilator-assisted ventilation, subcutaneous insulin, and hemodialysis therapy. Outcomes: The patient was discharged home finally with a fair general condition and was followed up without respiratory symptoms. Lessons: The compromised immunity in HIV-negative patients with diabetes may be related to lymphocyte decrease and dysfunction, which may cause diabetic patients prone to PJ. Although PCP is rare in diabetes, it should be paid attention to the high rate of misdiagnosis and missed diagnosis.