J. Respir., Volume 6, Issue 2 (June 2026) – 6 articles

Background: Medical thoracoscopy (MT) represents the gold standard for undiagnosed pleural effusions, traditionally performed in the presence of pleural fluid. Recent technical advances have enabled MT in “dry space” conditions (minimal or absent pleural effusion), raising questions about comparative diagnostic efficacy and safety profiles. Objective: This literature review aims to evaluate diagnostic yield and complication rates between traditional MT performed in patients with current pleural effusion and dry medical thoracoscopy (DMT). Results: MT demonstrates diagnostic sensitivity ranging from 80% to 96.3% and specificity close to 100% for malignant pleural disease, and the diagnostic accuracy is 99.1% for tuberculous pleuritis. DMT’s recent studies report optimal success rates in pleural access and tissue sampling, and diagnostic sensitivity for malignancy up to 100%, although a confirmation with larger cohorts for technique comparison is needed. Major complication rates are comparable between MT and DMT, with no significant differences in overall adverse events. Mortality rates remain exceptionally low (≤0.1%) for both approaches. Conclusions: MT remains a highly effective diagnostic tool for pleural diseases. DMT represents a valid and safe alternative in patients without significant pleural effusion, although technically more demanding, and further studies are required to validate the technique. Full article

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have dramatically transformed the clinical management of ALK-rearranged non-small cell lung cancer (NSCLC). Successive generations of ALK inhibitors have been developed to overcome resistance mediated by kinase domain mutations, culminating in the third-generation inhibitor lorlatinib. Despite these advances, resistance remains inevitable, and durable disease control is rarely achieved. While resistance driven by single ALK mutations has been extensively characterized and structurally classified, the emergence of compound ALK mutations under sequential TKI therapy represents a qualitatively distinct and insufficiently conceptualized resistance state. This issue is becoming more complex as lorlatinib is increasingly used in the first-line setting, where resistance may arise from an ALK TKI-naïve background rather than from tumors already shaped by sequential ALK inhibition. In this review, we propose a unified framework that integrates structural single ALK resistance mutations (Types 1–3) with compound ALK mutations (Type 4) as a distinct evolutionary entity. We argue that compound mutations mark a critical inflection point at which ALK dependency reaches its functional limit, explaining the failure of even highly potent inhibitors such as lorlatinib. Importantly, we discuss how certain compound mutations paradoxically restore sensitivity to earlier-generation TKIs, highlighting the value of structural interpretation over linear drug sequencing. Finally, we discuss the transition toward ALK-independent resistance and future strategies incorporating dynamic molecular monitoring and structure-agnostic therapies. This framework may help clinicians interpret resistance mechanisms and guide rational treatment selection in daily practice. Full article

Recurrent wheezing represents a significant cause of respiratory morbidity in preschool children. While viral infections in the context of immune dysregulation are primary drivers, gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are increasingly recognized as critical triggers. The link between GERD and respiratory symptoms has historically been controversial; however, recent advances necessitate a re-evaluation of this relationship. This review critically analyzes the pathophysiological nexus between reflux and airway hyperresponsiveness, emphasizing the dual mechanism of microaspiration and vagal reflex, while integrating the concept of reverse causality (where respiratory effort actively exacerbates reflux). We highlight that the “respiratory reflux” phenotype in preschoolers is often characterized by non-acid and proximal episodes, which standard pH-metry fails to detect. Consequently, we discuss the diagnostic shift towards multichannel intraluminal impedance-pH (MII-pH) monitoring and the incorporation of novel metrics defined by the Lyon Consensus 2.0 (MNBI, PSPW index), alongside specific biomarkers such as pepsin. Finally, we propose a phenotype-driven management algorithm, differentiating between acid-suppressive therapy and alginate-based interventions, to mitigate disease burden and improve clinical outcomes in refractory cases. Full article

Background/Objectives: COPD instability is heterogeneous; GOLD 2026 lowers the prior-year threshold to ≥1 moderate or severe exacerbation. We assessed whether this low-threshold criterion behaves as a high-sensitivity operational signal in primary-care EHRs. Methods: A retrospective multicenter same-window EHR pilot study in two Spanish primary-care centers (n = 106). Predictors and six binary endpoints were aggregated over the same 12-month window: any exacerbation, high-risk history, severe hospitalization, SABA dispensing, SAMA dispensing, and any rescue dispensing. We fitted Bayesian multi-outcome hierarchical logistic models with patient-level random intercepts, cross-endpoint partial pooling, regularizing priors, and missingness indicators. Robustness used prespecified scenarios, 10-fold ELPD cross-validation, and high-missingness exclusion. Results: Any exacerbation occurred in 53/106 patients; high-risk history in 25/106; hospitalization in 16/106; and any rescue dispensing in 65/106. Diagnostics were stable, and posterior predictive checks supported marginal adequacy. Heart failure showed the clearest positive pattern across exacerbation-defined endpoints; reliever-dispensing endpoints showed a distinct care-pathway-sensitive pattern. No scenario improved out-of-sample adequacy. High-missingness exclusion preserved directionality in 120/120 overlapping pairs; the median |ΔlogOR| was 0.061; and 119/120 remained within ±log(1.25). Conclusions: GOLD 2026 “any exacerbation” behaved as a high-sensitivity operational signal in an endpoint-operating-point sense, not as a homogeneous phenotype. Findings are within-window associations, not causal, medication-effect, or prospective prediction estimates; external validation is required. Full article

Alveolar–pleural or broncho-pleural fistulas, leading to persistent air leaks (PALs), are associated with prolonged hospitalization and substantial morbidity. While guidelines advocate surgical repair as the primary treatment, its efficacy is limited. For patients recently subjected to thoracic surgery or those for whom surgery is contraindicated due to severe illness, viable treatment alternatives have been lacking. This article reviews the newer and less invasive treatment options for PALs. Further research is crucial, including randomized controlled trials comparing these options, and long-term monitoring of intervention outcomes is warranted. Full article

Background: Proton pump inhibitors (PPIs) have been associated with lung dysbiosis and increased respiratory risk. Micro-aspiration is a proposed mechanism, but reliable biomarkers remain elusive. This study evaluates the potential of fluorescein as a biomarker of micro-aspiration and PPI-associated pulmonary risk. Methods: We conducted a retrospective analysis of 137 bronchial washing fluid samples from patients with pulmonary conditions to assess microbial colonization in relation to PPI use. Bacterial burden was determined by culture and PCR and categorized as 0, 1 or ≥2 pathogens. Micro-aspiration was evaluated by quantifying fluorescein-laden macrophages in bronchoalveolar lavage following oral fluorescein administration. Associations between PPI use, fluorescein levels and pathogen burden were analyzed using adjusted ordinal regression models. Results: PPI use was associated with higher odds of increased pathogen burden, though not statistically significant (OR = 1.40, 95% CI: 0.71–2.75, p = 0.33). Fluorescein-laden macrophages were higher in PPI users (41.5 versus 31.2 ng/mL), but showed no meaningful correlation with pathogen load (p = 0.09). Corticosteroid therapy was significantly associated with Gram stain results (OR = 2.37, 95% CI: 1.12–5.15, p = 0.03). Conclusions: These findings suggest a potential link between PPI use and airway colonization. Fluorescein shows promise as a biomarker for micro-aspiration, but its clinical utility requires further validation. Full article