Longer Duration of Palliative Care in Patients With COPD Is Associated With Death Outside the Hospital.

Background: Patients with advanced chronic obstructive pulmonary disease (COPD) have a significant symptom burden despite maximal medical therapy, yet few are referred for concomitant palliative care. Objective: To evaluate the utilization and impact of palliative care on the location of death and to identify clinical variables associated with palliative care contact. Design: Retrospective chart review from 2010 to 2016 at the VA Western New York Healthcare System using ICD-9/10 diagnosis of COPD. Palliative care contact was identified by Z51.5 or stop code 353. Results: Only 0.5% to 2% of living patients received palliative care, increasing abruptly at death (6%). Lower diffusion capacity for carbon monoxide (DLCO) (greater emphysema) was associated with palliative care contact, independent of comorbid disease burden or age. Initial outpatient contact was associated with a longer duration of palliative care (P = .003) and death in a home-like setting. Outpatient palliative care was associated with more severe airflow obstruction (forced expiratory volume in 1 second, percent predicted [FEV1%]), whereas greater disease exacerbation frequency was associated with inpatient contact. COPD patients not referred to palliative care had a greater comorbid disease burden, similar FEV1%, fewer disease exacerbations, and a greater DLCO. Conclusion: Few patients with COPD received palliative care, similar to national trends. Initial outpatient palliative contact had the longest duration of care and death in the preferred home environment. The extent of emphysema (DLCO reduction) and more frequent disease exacerbations identified in patients were more likely to receive palliative care. Our study begins to define the benefits of palliative care in advanced COPD and confirms underutilization in the years before death, where a prolonged impact on the quality of life may be realized.

Bacterial regulation of macrophage bacterial recognition receptors in COPD are differentially modified by budesonide and fluticasone propionate.

RATIONALE: Patients with COPD have an increased risk for community-acquired pneumonia, which is further increased by inhaled corticosteroids. OBJECTIVE: To assess effects of the corticosteroids, budesonide and fluticasone propionate, on macrophage bacterial responses in COPD. METHODS: Monocyte-derived macrophages (MDMs) generated from blood monocytes from 10 non-smoker controls (NoS), 20 smokers without COPD (Sm), and 40 subjects with moderate to severe COPD (21 ex-smokers (COPD-ES) and 19 current smokers (COPD-S)) were pre-treated with budesonide or fluticasone (10 nM-1 µM) and challenged with live non-typeable Haemophilus influenzae (NTHI) or Streptococcus pneumoniae (SP). Cell surface bacterial recognition receptor expression (flow cytometry) and cytokine release (bead array) were analyzed. RESULTS: NTHI and SP reduced bacterial recognition receptor expression on MDMs from COPD and Sm, but not NoS (except TLR4). SR-AI and MARCO were reduced by both NTHI and SP, whereas other receptors by either NTHI or SP. Among COPD subjects, COPD-ES demonstrated a greater number of reductions as compared to COPD-S. NTHI reduced SR-AI, MARCO, CD11b, CD35 and CD206 in COPD-ES while only SR-AI and CD11b in COPD-S. SP reduced SRA-1, CD1d, TLR2 and TLR4 in both COPD-ES and COPD-S, and reduced MARCO and CD93 only in COPD-ES. All receptors reduced in COPD by NTHI and most by SP, were also reduced in Sm. Budesonide counteracted the receptor reductions induced by both NTHI (CD206 p = 0.03, MARCO p = 0.08) and SP (SR-AI p = 0.02) in COPD-ES. Fluticasone counteracted only SP-induced reductions in TLR2 (p = 0.008 COPD-ES and p = 0.04 COPD-S) and TLR4 (p = 0.02 COPD-ES). Cytokine release was equivalently reduced by both corticosteroids. CONCLUSIONS: Reduction in macrophage bacterial recognition receptors during bacterial exposure could provide a mechanism for the increased pneumonia risk in COPD. Differential effects of budesonide and fluticasone propionate on macrophage bacterial recognition receptor expression may contribute to the higher pneumonia incidence reported with fluticasone propionate.

Calcium restores the macrophage response to nontypeable haemophilus influenzae in chronic obstructive pulmonary disease.

Alveolar macrophages in chronic obstructive pulmonary disease (COPD) have demonstrated impaired bacterial phagocytosis and disordered cytokine secretion, which are calcium-dependent processes. We determined how calcium moderates the macrophage response to nontypeable Haemophilus influenzae (NTHI). We hypothesized that augmenting extracellular calcium during bacterial challenge would restore bacterial phagocytosis and cytokine secretion in monocyte-derived macrophages (MDMs) from subjects with COPD. We further determined whether restoration of pattern recognition and scavenger receptors correlated with the calcium-induced improvements in macrophage function. Monocytes were purified from whole blood from healthy control subjects (n = 20) and patients with moderate to severe COPD (n = 35), and cultured in suspension with granulocyte macrophage colony-stimulating factor to generate MDMs. The MDMs were incubated with fluorescently labeled NTHI with and without calcium lactate and calcium channel inhibitors. Phagocytosis efficiency was evaluated by flow cytometry. Supernatants were assayed for cytokines using bead array technology. Cell surface receptor expression was assayed by multicolor flow cytometry. Extracellular calcium significantly improved phagocytosis and cytokine secretion (IL-8, TNF-α, and macrophage inflammatory protein [MIP]-1α, and -1ß) in COPD MDMs. NTHI challenge led to statistically significant reductions in CD16 (FcγRIII), and extracellular calcium up-regulated both CD16 and macrophage receptor with collagenous structure (MARCO). Specific calcium channel inhibitors abrogated calcium-mediated MARCO up-regulation and cytokine secretion. Extracellular calcium improved phagocytosis, restored innate cytokine secretion, and increased cell surface expression of bacterial recognition receptors, CD16 and MARCO. These observations support the therapeutic use of calcium to improve macrophage function in COPD to decrease exacerbations and chronic bacterial infection.

IFN-γ acts on the airway epithelium to inhibit local and systemic pathology in allergic airway disease.

Inhibiting allergic airway inflammation is the goal of therapy in persistent asthma. Administration of medication via the airways delivers drug directly to the site of inflammation and avoids systemic side effects but often fails to modulate systemic features of asthma. We have shown that Th1 cells, through production of IFN-γ, inhibit many Th2-induced effector functions that promote disease. Using a newly generated mouse that expresses IFN-γR only on airway epithelial cells, we show that the airway epithelium controls a range of pathological responses in asthma. IFN-γ acting only through the airway epithelium inhibits mucus, chitinases, and eosinophilia, independent of Th2 cell activation. IFN-γ signaling through the airway epithelium inhibits eosinophil generation in the bone marrow, indicating that signals on the airway mucosal surface can regulate distant functions to inhibit disease. IFN-γ actions through the airway epithelium will limit airway obstruction and inflammation and may be therapeutic in refractory asthma.