Therapeutic Advances in Respiratory Disease最新文献

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT), as a rare and highly malignant neoplasm associated with a high mortality risk, is easily confused with SMARCA4-deficient nonsmall-cell lung cancer (NSCLC). To date, no standard and effective protocol for thoracic SMARCA4-UT has been established. Immunotherapy has demonstrated efficacy in advanced NSCLC, achieving unprecedented survival benefits. However, immune-related adverse events (irAEs) remain a significant clinical challenge. Here, we reported the first case of thoracic SMARCA4-UT with immune-related cystitis and hypothyroidism, in which the patient benefited from first-line immune checkpoint inhibitor (ICI)-based combination therapy, achieving a remarkable overall survival of over 100 weeks. Furthermore, we performed a review and analysis of the diagnosis, differential diagnosis, immunotherapy, and prognosis of thoracic SMARCA4-UT, proposing that first-line therapy combining immunotherapy with platinum-based chemotherapy (induction and maintenance phases) with or without radiotherapy, may improve the prognosis of such patients. Additionally, we hypothesized a potential role of macrophages in the pathogenesis of immune-related cystitis for the first time and detailed the clinicopathological characteristics and evidence-based management of this irAE.

Background: Females with cystic fibrosis (fwCF) are at increased risk of urinary incontinence (UI), likely due to chronic coughing and elevated intra-abdominal pressure. Prevalence rates reported in the literature vary widely, and no large multicenter study has been carried out to date.

Objective: To estimate the prevalence and severity of UI in fwCF and to investigate clinical variables associated with UI.

Design: A multicenter, cross-sectional study conducted across 21 Italian CF centers.

Methods: UI prevalence and severity were assessed using two validated questionnaires. A multivariable fractional polynomial approach was used to select variables for inclusion in the final logistic regression model to identify relevant associations with UI.

Results: UI was present in 218/542 females (40.2%, 95% Confidence Interval (CI): 36.1-44.5). Among children and adolescents, the prevalence was 12/160 (7.5%, 95% CI: 4.1-13), whereas among adults it was 206/382 (53.9%, 95% CI: 48.8-59). FwCF with UI showed a BMI of 0.2 Z score higher (95% CI: 0.1-0.4) than fwCF without UI; however, the overall prevalence of UI in fwCF overweight was 41% (95% CI: 30.2-52.7) compared to 40.1% (95%CI: 35.6-44.7) in fwCF with normal weight. Age (interquartile range-odds ratio (IQR-OR) 4.19, 95% CI: 2.80-6.28), days of hospitalization (IQR-OR 1.72, 95% CI: 1.42-2.08), and physical activity (OR 0.66, 95% CI: 0.53-0.82) were the only factors statistically associated with UI.

Conclusion: UI affects mostly adult fwCF and is associated with older age and longer hospitalization. Physical activity of ⩾150 min per week was also associated with a reduced probability of UI.

Background: There is uncertainty regarding the optimal next imaging modality for identifying likely malignant pulmonary lesions in patients with abnormal chest radiography, with or without respiratory symptoms.

Objectives: We compared the diagnostic accuracy of chest contrast-enhanced computed tomography (CECT) and positron emission tomography or positron emission tomography-computed tomography (PET/PET-CT) for identifying malignant pulmonary lesions.

Design: Systematic review and meta-analysisData sources and methods:We searched the PubMed, Embase, Scopus, and Cochrane CENTRAL databases to identify head-to-head diagnostic accuracy studies comparing CECT and PET/PET-CT for their ability to differentiate between benign and malignant pulmonary lesions. The risk of bias of included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies - Comparative (QUADAS-C) tool. Meta-analysis was performed using the bivariate random effects model.

Results: We included eight studies, comprising a total of 873 subjects. The pooled sensitivity and specificity of CECT (850 lesions) were 0.93 (95% CI, 0.89-0.96; I² = 24.99%) and 0.54 (95% CI, 0.32-0.75; I² = 84.00%). The pooled sensitivity and specificity of PET/PET-CT (851 lesions) were 0.87 (95% CI, 0.78-0.93; I² = 65.15%) and 0.83 (95% CI, 0.63-0.94; I² = 73.23%). Compared to CECT, PET/PET-CT had a lower relative sensitivity (relative ratio [RR], 0.93; 95% CI, 0.89-0.97; p < 0.01) and a higher relative specificity (RR, 1.69; 95% CI, 1.18-2.41; p < 0.01). After excluding the study with the largest sample size, PET/PET-CT was not less sensitive than CECT (RR, 0.99; 95% CI, 0.94-1.04; p = 0.73). There was a high/unclear risk of bias and applicability concerns in the population domain in six out of eight studies.

Conclusions: Based on limited evidence with applicability concerns, CECT of the chest may have a higher sensitivity but lower specificity than PET/PET-CT for identifying malignant lesions among patients with suspected lung cancer.

Trial registration: The protocol for the systematic review was prospectively registered on PROSPERO (CRD42024590904).

Background: Pulmonary function tests offer crucial parameters for evaluating lung health and predicting clinical outcomes. Hyperlipidemia, a prevalent metabolic disorder, has been linked to declining pulmonary function. Statins are an essential therapy for lowering lipid levels in hyperlipidemia.

Objectives: This study aims to investigate the therapeutic potential of statins in mitigating the decline in pulmonary function.

Design: This is a retrospective cohort study.

Methods: Out of 8286 patients who underwent spirometry testing from January 2018 to December 2020, 492 patients were included in the final analysis. The relationship between statin usage, dosage, along with other biometric indices and spirometry parameters were evaluated. Multivariate logistic regression analyses were employed to assess the association between statin use and the decline in pulmonary function.

Results: In patients with persistent hyperlipidemia, the use of statins was associated with a higher predicted percentage of forced expiratory volume in 1 second (FEV1) compared to non-users (84.0% vs 78.0%, p = 0.015). Logistic regression models further revealed that statin use independently prevented FEV1 decline, irrespective of dosage (adjusted OR 0.036, 95% CI: 0.002-0.618 in lower statins dose group and adjusted OR 0.170, 95% CI: 0.019-1.552 in higher statins dose group).

Conclusion: The findings suggested that statin usage, regardless of dosage, independently mitigated the decline in pulmonary function among patients with persistent hyperlipidemia. Early initiation of statin therapy may hold promise for individuals experiencing hyperlipidemia and declining pulmonary function.

Background: Malignant pleural effusion (MPE) affects approximately 150,000 patients in the United States each year and usually signifies advanced-stage cancer. The optimal treatment remains a challenge but indwelling pleural catheters (IPC) offer several advantages and may help achieve spontaneous pleurodesis (SP) in some patients.

Objectives: We aim to investigate the predictors of SP among patients with MPE, particularly in a resource-limited community-based safety net hospital.

Design: This is a retrospective cohort study done at a community-based safety net hospital.

Methods: Adults diagnosed with or suspected of having MPE between January 2015 and December 2023 who underwent IPC placement were included. Data was collected retrospectively from December 2023 to June 2024. Data encompassed demographics, imaging, post-procedural complications, pleural fluid analysis, oncology treatment history, and utilization of medical thoracoscopy without chemical pleurodesis (MTWCP) for diagnosis.

Results: A total of 173 patients underwent IPC insertion. Most of our patients were women (64.2%), and Latin American (65.9%), with a mean age of 55.3 years. The most common type of primary cancer was breast (28.9%) followed by lung (23.1%) and lymphoma (6.9%). Pleural fluid characteristics such as glucose, eosinophils, Lactate Dehydrogenase (LDH), and protein concentration were not significantly associated with SP. Most patients had low Eastern Cooperative Oncology Group scores of 0-2 (64.6%) and low LENT (Lactate Dehydrogenase (L), Eastern Cooperative Oncology Group (E) Performance Score, Neutrophil-to-Lymphocyte Ratio (N), and Tumor type (T) score) scores of 0-4 (59%). Lower scores (better functional status) were significantly associated with SP. Post-IPC chemotherapy and/or radiotherapy and immunotherapy were significantly associated with SP, adjusted odds ratio (OR) 7.295 (95% CI: 3.05-17.4, p = 0.001) and adjusted OR 6.261 (95% CI: 2.73-14.36, p = 0.001) respectively. MTWCP was also a predictor of SP with an adjusted OR of 4.031 (95% CI: 1.452-11.19, p = 0.007).

Conclusion: Our study is the first to assess predictors of SP in a resource-limited safety net hospital representing under-represented and underserved patients. We identify several factors associated with higher rates of SP such as higher functional status, MTWCP, chemotherapy, immunotherapy, and radiation post-IPC placement. The study findings can help clinicians consider IPC placement and guide them regarding the duration and possible complications of IPC. MTWCP appears to improve the success of SP. Further studies are needed to assess these findings further.

Background: Prevention of lung attacks (LAs)/exacerbation is an important treatment goal in both asthma and chronic obstructive pulmonary disease (COPD). However, LAs are often not registered as such in medical records.

Objectives: Development and evaluation of CodeX Asthma and COPD.

Design: An electronic medical record-based algorithm to identify LAs in Dutch primary care patients with asthma or COPD was developed. The algorithms were evaluated in nine general practices in the Netherlands.

Results: A total of 479 LAs (in 1164 patients) were identified with CodeX Asthma in the past year, of which only 16% were registered. CodeX COPD identified 321 LAs (in 242 patients) in the past 3 years, of which two were registered.

Conclusion: CodeX algorithms are capable of identifying unrecorded LAs and high-risk/uncontrolled patients in an easy way. This offers primary care providers a simple solution to easily identify and closely manage high-risk patients with asthma or COPD by identifying LAs' frequency and potential under- or overtreatment.

This review focuses on the advancements in the treatment of pulmonary hypertension (PH), especially after the Food and Drug Administration (FDA) approval of sotatercept and the advances in treatment recommendations after seven World Symposia on PH. PH, a complex and progressive condition defined hemodynamically by a mean pulmonary artery pressure >20 mmHg, encompasses multiple PH groups, each with distinct pathophysiological characteristics and treatment implications. Diagnosing PH can be challenging because symptoms like shortness of breath, fatigue, and chest pain are nonspecific. Contemporary treatment of pulmonary arterial hypertension aims to improve outcomes, symptoms, and overall quality of life, with a primary focus on preventing and treating right ventricular failure. Comprehensive risk stratification remains crucial, aiding in personalized therapy adjustments that improve patients' outcomes. This review also touches upon the limited treatment options for other PH groups, like PH associated with left heart disease, parenchymal lung diseases, and chronic thromboembolic PH, underscoring the need for expanded therapeutic options. Despite advances, challenges remain: diagnostic delays, misdiagnosis, absence of head-to-head clinical trials, and the timing of introducing newer treatments such as sotatercept are discussed, emphasizing an integrated approach that transcends vasodilation to target underlying disease mechanisms. Future directions envision a comprehensive risk stratification incorporating right ventricular function and a mechanism-based treatment paradigm, encouraging a tailored therapeutic approach in PH management.

Background: The role of the gut-lung axis in respiratory disease is increasingly recognised. Much emphasis has been placed on gastro-oesophageal reflux disease; however, oesophageal dysmotility may also play a significant role. Azithromycin, a known prokinetic, has been shown to be of major benefit in a number of respiratory diseases, but the relationship between oesophageal function and the lung has not been examined.

Objectives: We assessed the feasibility of performing continuous cough monitoring and repeated high-resolution oesophageal manometry (HROM) in patients with chronic respiratory disease.

Design: We conducted an open-label, single-arm, feasibility trial.

Methods: Azithromycin 250 mg once daily was given to patients with chronic respiratory disease who reported a chronic cough. All participants were monitored continually for at least 1 week prior to and 4 weeks after azithromycin with the Hyfe Cough Tracker. Participants also had HROM performed at two time-points, immediately before and 4 weeks after initiation of azithromycin. Feasibility outcomes pertaining to recruitment, data quality, and acceptability of trial processes were assessed. Exploratory outcome data for metrics of oesophageal function were also analysed.

Results: A total of 30 participants (57% female, mean age 65.2 (SD = 11.3)) were recruited over a 10-month period, giving a recruitment rate of three patients per month in a single centre. A total of 87% (n = 26) of participants completed all three study visits. All pre-specified data quality outcomes met their 'green' traffic light stop-go criteria. HROM demonstrated that the majority (52%) of participants had abnormal oesophageal function, as defined by the Chicago Classification, at baseline. Changes in oesophageal function were not significantly associated with changes in objective or subjective cough measures, except for a weakly negative correlation with the Hull Airway Reflux Questionnaire score.

Conclusion: A large-scale trial examining the effect of azithromycin on the relationship between oesophageal function and cough in respiratory disease is feasible and acceptable to patients.

Trial registration: This trial was prospectively registered ClinicalTrials.gov ID: NCT05469555.

Background: Joubert syndrome (JS) is an autosomal recessive disorder with a distinctive mid-hindbrain malformation known as the "molar tooth sign" which involves the breathing control center and its connections with other structures. Literature has reported significant respiratory abnormalities which included hyperpnea interspersed with apneic episodes during wakefulness. Larger-scale studies looking at polysomnographic findings or subjective reports of sleep problems in this population have not yet been published.

Objectives: The primary objectives were (1) compare a large group of children with JS and their unaffected siblings for caregiver-reported sleep difficulties. Secondary objectives were (1) present new polysomnography (PSG) data on our JS cohort; (2) review sleep disordered breathing (SDB) in other rare congenital hindbrain anatomic abnormalities.

Design: We conducted a cross-sectional study on a cohort of 109 families affected by JS.

Methods: Pediatric Sleep Questionnaire (PSQ) and the Children's Sleep Habits Questionnaire (CSHQ) along with general medical health information focused on respiratory and sleep problems were mailed to all patients and families. Caregivers were asked to complete the survey for both children with JS and unaffected siblings, if any. Baseline diagnostic PSG was retrospectively reviewed for those with available studies, and the sleep parameters were compared to a referent cohort.

Results: Study participants with JS were older than their unaffected siblings (p = 0.02). Genetic mutations were available for 41 out of 118 individuals, with the most common mutation being MKS3 (31.4%). Patients with JS had higher scores in the PSQ compared to their unaffected siblings (p < 0.001). PSG data showed severe SDB with apnea-hypopnea index (AHI) of 23 ± 15 events/h in patients with JS. Events were primarily obstructive (obstructive AHI 18 ± 15 events/h vs central AHI 4 ± 4 events/h). Abnormal sleep architecture with increased arousal indices, decreased efficiency, and more time awake and in light sleep or wakefulness when compared to the referent data.

Conclusion: SDB is common and severe in patients with JS, and the significantly greater obstructive component reported in this cohort makes it necessary to perform complete PSG studies to address or prevent clinical manifestations in this at-risk population. PSQ could represent a viable method to screen for SDB in JS.

Over the past decade, major clinical advances have been made in the healthcare and therapeutic development for cystic fibrosis (CF), a lethal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. CFTR modulators represent innovative treatments that directly target the primary defects in the mutated CFTR protein and have demonstrated significant clinical benefits for many people with CF (pwCF) who are eligible for these treatments. In particular, the triple combination therapy composed of elexacaftor, tezacaftor, and ivacaftor (ETI) has changed the CF therapeutic landscape by significantly improving lung function, quality of life, and predicted survival rates. Here, we provided a comprehensive summary of the impact of ETI on clinical outcomes and the need for further research on long-term efficacy, side effects, pregnancy, possible drug-drug interactions, and extra-pulmonary manifestations. Moreover, a significant number of pwCF are unresponsive to these drugs or cannot afford their high costs. We, therefore, discussed health inequity issues and alternative therapeutic strategies under development aiming to obtain effective therapies for all pwCF.