Variability of sputum inflammatory mediators in COPD and α₁-antitrypsin deficiency

Abstract

There is inherent daily variability of sputum inflammatory mediators in stable-state patients with usual chronic obstructive pulmonary disease (COPD). The variability of pulmonary inflammation in patients with a 1 -antitrypsin deficiency (A1ATD) is unknown. Our study aimed to quantify this variability, in comparison to patients with usual COPD, in order to facilitate power calculations for proof of concept trials of putative specific anti-inflammatory agents in both groups.Sputum interleukin (IL)-8, myeloperoxidase (MPO), leukotriene B 4 (LTB 4 ) and differential cell counts were measured in 12 usual COPD patients and 12 A1ATD patients on nine occasions over a 1-month period. All samples were obtained in the stable clinical state.There was significant daily variability in all mediators in all patients. A1ATD patients had higher sputum concentrations of IL-8 and LTB 4 compared with usual COPD, but lower levels of MPO and absolute neutrophil counts. Patients with usual COPD had more intra-patient variability, A1ATD patients demonstrated greater inter-patient variability.There are increased concentrations of pulmonary inflammatory mediators but fewer sputum neutrophils in A1ATD compared with usual COPD. The daily variability of inflammatory mediators and cell counts was significantly reduced in both groups by averaging sequential samples. This can be utilised to perform power calculations for future proof of concept studies; averaging three sequential samples appears optimum.

Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin deficiency and COPD

“…However, the use of single spontaneously produced sputum samples also has limitations due to the daily variability of sample collection and dilution with nasopharyngeal secretions. This phenomenon has been described in subjects with A1AT deficiency and usual COPD, and could be minimised in future studies by averaging three sequential samples [41]. Nevertheless, despite this potential drawback, the differences and correlations described here remain robust.…”

Pulmonary Infections in the Elderly Lead to Impaired Neutrophil Targeting, Which Is Improved by Simvastatin

“…All subjects with capacity gave written informed consent, and those without such capacity were recruited using a personal consultee after approval from the South Central Oxford Research Ethics Committee (reference 11/SC/0356). A detailed description of the methods used is provided in the online supplement, including sputum sol, which was prepared as previously described (26).…”

The BLT1 Inhibitory Function of α-1 Antitrypsin Augmentation Therapy Disrupts Leukotriene B4 Neutrophil Signaling

“…Indeed, studies indicate that AAT can modulate activity of a number of cell types, including neutrophils (28,29), macrophages (30,31), pancreatic islet b cells (32), B cells (33) and mast cells (34). AAT deficiency (AATD) is a hereditary disorder characterized by low circulating levels of AAT and increased airway levels of LTB 4 (35). AATD is associated with the development of COPD often by the third or fourth decade, liver disease, and in rare cases skin panniculitis.…”