PURPOSE:Given limited treatments for advanced interstitial lung disease (ILD), this updated study focuses strictly on phosphodiesterase 5 inhibitors (PDE5Is) efficacy exclusively in a clinically high-risk ILD subgroup, unlike prior meta-analyses that pooled diverse lung diseases or mixed vasodilator classes. METHODS:We systematically searched PubMed, Embase, and the Cochrane Library from inception to February 2026 to identify randomized controlled trials (RCTs) and observational cohort studies evaluating PDE5Is in advanced ILD. The primary outcome was all-cause mortality. The secondary outcomes were the St. George's Respiratory Questionnaire (SGRQ) score, forced vital capacity (FVC), B-type natriuretic peptide (BNP) levels, and serious adverse events. Effect sizes were pooled using random-effects models, and between-study heterogeneity was assessed using the I² and τ² statistics. FINDINGS:Six studies (including 3 RCTs) with a total of 1,800 patients were analyzed (759 patients in the PDE5Is group and 1,041 patients in the control group; 4 IPF and 2 generalized ILD studies). Overall, PDE5I therapy was not associated with a significant reduction in all-cause mortality, and substantial between-study heterogeneity was observed (HR 0.76, 95% CI 0.31-1.90; p = 0.56; I² = 96%). However, a subgroup analyses suggested a lower mortality point estimate in the clinically suspected or hemodynamically confirmed PH-targeted population (HR 0.51, 95% CI 0.37-0.71; p < 0.01; I² = 23%), whereas no significant mortality benefit was observed in the untargeted advanced ILD population (HR 1.11, 95% CI 0.33-3.72; p = 0.86; I² = 91%), though the subgroup interaction was statistically insignificant (p(interaction) = 0.23). Additionally, PDE5I therapy significantly improved SGRQ scores (-3.48; 95% CI -5.41 to -1.55; p < 0.001; I² = 0%) without significantly affecting FVC, BNP or serious adverse events (RR= 0.84; 95% CI 0.62-1.14; p = 0.27). IMPLICATIONS:Our findings show that PDE5I therapy was not associated with a statistically significant overall survival benefit in advanced ILD, although a favorable survival trend is observed within the clinically suspected or hemodynamically confirmed PH-targeted population. (HR 0.51, 95% CI 0.37-0.71). However, the absence of a statistically significant subgroup interaction indicates that this finding should be interpreted with caution.
PURPOSE:Identifying clinical phenotypes that may exhibit heterogeneous associations with treatment exposure is an important focus of sepsis research. Sepsis phenotyping mainly relies on static variables, which fail to fully capture early hemodynamic evolution. This study utilized longitudinal mean arterial pressure (MAP)/norepinephrine equivalent dose (NEQ) trajectories to characterize hemodynamic phenotypes in patients with septic shock and to explore phenotype-specific associations between albumin exposure and ICU mortality. METHODS:Adult patients diagnosed with septic shock within 24 h of ICU admission and with at least four MAP/NEQ measurements during the 72 h following initiation of the first vasopressor after ICU admission were identified from the MIMIC-IV database. The trajectory time origin was defined as initiation of the first vasopressor after ICU admission. Hourly MAP/NEQ values during the subsequent 72 h were used to identify phenotypes by group-based trajectory modeling. Associations between MAP/NEQ-trajectory phenotypes and ICU mortality were analyzed using doubly robust estimation. Subsequently, parametric G-formula was employed to estimate the cumulative mortality risk under hypothetical daily albumin infusion regimens within each phenotype. External validation was performed using the eICU-CRD. FINDINGS:A total of 3152 patients with septic shock were included in this study. Four distinct MAP/NEQ trajectory phenotypes were identified: phenotype A (low-level stable, 29.8%), phenotype B (ascending, 26.1%), phenotype C (descending, 24.0%), and phenotype D (high-level stable, 20.1%). Phenotype A was associated with the highest risk of ICU mortality compared with the other phenotypes (B: odds ratio [OR], 0.303; 95% CI, 0.225-0.408; C: OR, 0.606; 95% CI, 0.458-0.801; D: OR, 0.547; 95% CI, 0.391-0.766). G-formula analyses suggested that albumin exposure-mortality associations varied across phenotypes. Higher simulated daily albumin exposure categories were associated with lower model-estimated ICU mortality risk in phenotypes B, C, and D, whereas no significant association was observed in phenotype A (risk ratio [95% CI]: 0.89 [0.72-1.07]). Directionally similar model-estimated association patterns were observed in the external validation cohort. IMPLICATIONS:This study identified four MAP/NEQ trajectory phenotypes in patients with septic shock that exhibited differential associations with ICU mortality and albumin exposure. Since this study adopts a retrospective observational design, findings regarding albumin are exploratory and hypothesis-generating rather than proof of treatment benefit. Prospective studies and randomized trials are needed to determine whether MAP/NEQ trajectories have clinical utility for risk stratification or treatment decision-making.
