Health Status Progression Measured Using Weekly Telemonitoring of COPD Assessment Test Scores Over 1 Year and Its Association With COPD Exacerbations.

Background: A previous longitudinal study of chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) score changes suggested patients fall into 3 patterns: stable, improving, and worsening. This study assessed the evolution of CAT scores over time and its relationship to exacerbations. Methods: In total, 84 participants used a telemedicine platform to complete CAT weekly for 52 weeks. Completion rates, annualized change in CAT scores, and learning effects were measured, as well as CAT changes of >4 units during look-back periods of 4 and 8 weeks. In a subgroup of participants with at least a 25% completion rate (adherent group, n=68 [81%]), the relationship between change in CAT score and exacerbations at any time during the study was examined post hoc. Results: Linear regression showed that 50%, 22%, and 28% of the adherent subgroup had CAT scores indicating worsening, stable, and improving health status, respectively. In the adherent subgroup, 70% (n=7/10) of participants who had an exacerbation during the study had worsening CAT scores, versus 47% (n=27/58) without an exacerbation. The hazard ratio association between CAT score increase and moderate exacerbation was 1.13 (95% confidence interval: 1.03-1.24). Most participants experienced at least one CAT score change of >4 units, and 7% showed an initial learning effect with a median of 2 weeks. Conclusion: Measuring trends in CAT scores may allow future studies to group patients into 3 defined categories of change over time and quantify CAT change trajectories to assess treatment response and potentially predict medium-term outcomes within individual patients.

Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy.

PURPOSE: Pulmonary microvascular endothelial injury may be involved in the pathogenesis of pulmonary fibrosis (PF). The aim of this study was to evaluate the pulmonary vascular status in patients with PF by lung scintigraphic assessment of 123I-metaiodobenzylguanidine (123I-MIBG), which reflects latent endothelial cell lesions. METHODS: We assessed lung 123I-MIBG kinetics and clinical indices in 23 PF patients and 16 controls. Mean uptake ratios of lung to mediastinum (L/M) were calculated in anterior planar images at 30 (early image) and 270 (delayed image) min after intravenous injection of 123I-MIBG. The pulmonary mean washout rate (WR) of 123I-MIBG was also calculated. RESULTS: The L/M ratio in early images, but not in delayed images, was significantly lower in the PF patients than in the controls (L/M(early) 1.41+/-0.14 vs 1.53+/-0.10, p<0.01; L/M(delayed) 1.28+/-0.10 vs 1.33+/-0.07, p=NS). WR was significantly reduced in the PF patients compared with the controls (28.6%+/-3.1% vs 34.2%+/-5.1%, p<0.001). In the study subjects (PF patients plus controls) there were significant relationships between lung WR of (123)I-MIBG and other diagnostic parameters for the severity of PF, such as vital capacity (r=0.625, p<0.0001), total lung capacity (r=0.691, p<0.0001), carbon monoxide diffusing capacity (r=0.622, p<0.0001), serum angiotensin-converting enzyme activity (r=0.422, p<0.01), carbohydrate antigen KL-6 levels (r=-0.495, p<0.01) and surfactant protein-D levels (r=-0.461, p<0.01). When control subjects were excluded, similar significant correlations were observed between WR and %TLC (r=0.508, p<0.05), DL(CO) (r=0.593, p<0.01) and serum ACE activity (r=0.515, p<0.05) in the PF patients. CONCLUSION: These results suggest that endothelial cell injury plays a significant role in the pathogenesis of PF, and that lung WR of 123I-MIBG, which is a specific marker of endothelial damage, can serve as a novel diagnostic tool to evaluate the functional severity of PF.

In vivo evidence of endothelial injury in chronic obstructive pulmonary disease by lung scintigraphic assessment of (123)I-metaiodobenzylguanidine.

UNLABELLED: Scintigraphic evaluation of (123)I-metaiodobenzylguanidine ((123)I-MIBG) in the lungs is considered to recognize endothelial cell lesions. The aim of this study was to clarify the involvement of the pulmonary microvascular injury in the pathogenesis of chronic obstructive pulmonary disease (COPD). METHODS: We investigated lung (123)I-MIBG kinetics and clinical indices in 25 COPD patients and 12 control subjects. Mean uptake ratios of lung to mediastinum (L/M) were calculated in anterior planer images at 30 min (early image) and 270 min (delayed image) after intravenous injection of (123)I-MIBG. Pulmonary mean washout rate (WR) of the (123)I-MIBG was also calculated. RESULTS: The L/M ratios in both early and delayed images of COPD patients, as well as its WR, were significantly lower than those of the control subjects (L/M early: 1.26 +/- 0.18 vs. 1.54 +/- 0.11, P < 0.0001; L/M delayed: 1.20 +/- 0.12 vs. 1.33 +/- 0.09, P < 0.001; WR: 27.4% +/- 5.3% vs. 34.2% +/- 5.7%, P < 0.01). There were significant relationships between lung WR of the (123)I-MIBG and other diagnostic tests for the severity of COPD, such as forced expiratory volume in 1 s (% FEV(1.0): r = 0.386, P < 0.05), carbon monoxide diffusing capacity/alveolar volume (DL(CO)/V(A): r = 0.449, P < 0.01), arterial blood oxygen pressure (PaO(2): r = 0.474, P < 0.01), alveolar-arterial oxygen tension gradient [A-a]DO(2) (r = -0.446, P < 0.01), and percentage of low-attenuation area (r = -0.458, P < 0.01) in the study population. CONCLUSION: Because lung WR of the (123)I-MIBG is considered to be independent of an alteration of the pulmonary vascular surface area, these results suggest that the microvascular endothelial cell injury plays a significant role in the pathogenesis of COPD.

Endocytic internalization of adenovirus, nonspecific phagocytosis, and cytoskeletal organization are coordinately regulated in alveolar macrophages by GM-CSF and PU.1.

GM-CSF gene-targeted (GM(-/-)) mice have impaired pulmonary clearance of bacterial and fungal pathogens by alveolar macrophages (AMs). Because AMs also clear adenovirus from the lung, the role of GM-CSF in endocytic internalization of adenovirus by AMs was evaluated. Pulmonary clearance of adenovirus was severely impaired in GM(-/-) mice compared to wild-type (GM(+/+)) mice as determined by Southern analysis of viral DNA. Internalization of adenovirus by AMs was deficient in GM(-/-) mice in vivo and in vitro as determined by uptake of fluorescently labeled adenovirus or by PCR quantification of adenoviral DNA internalized within AMs. An AM cell line previously established from GM(-/-) mice (mAM) had impaired internalization of adenovirus and transferrin-coated 100-nm latex beads compared to MH-S, a GM(+/+) AM cell line. Phagocytosis of 4- micro m latex beads was also impaired in mAM cells as determined by confocal and fluorescence microscopy. Retroviral vector-mediated reconstitution of PU.1 expression in cultured GM(-/-) AMs restored phagocytosis of 4- micro m beads, endocytosis of adenovirus, and transferrin-coated 100-nm beads (independent of integrin alpha(V) and transferrin receptors, respectively), and restored normal cytoskeletal organization, filamentous actin distribution, and stimulated formation of filopodia. Interestingly, mRNA for the phosphoinositide 3 kinase p110gamma isoform, important in macrophage phagocytic function, was absent in GM(-/-) AMs and was restored by PU.1 expression. These data show that GM-CSF, via PU.1, regulates endocytosis of small ( approximately 100 nm) pathogens/inert particles and phagocytosis of very large inert particles and suggests regulation of cytoskeletal organization by GM-CSF/PU.1 as the molecular basis of this control.