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

• Published in: American journal of respiratory and critical care medicine Vol. 196; no. 10; pp. 1325 - 1336
• Main Authors: Sapey, Elizabeth, Patel, Jaimin M, Greenwood, Hannah L, Walton, Georgia M, Hazeldine, Jon, Sadhra, Charendeep, Parekh, Dhruv, Dancer, Rachel C A, Nightingale, Peter, Lord, Janet M, Thickett, David R
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 15.11.2017
• Subjects: Accuracy; Adult; Age; Age Factors; Aged; Aged, 80 and over; Bacterial infections; Cell adhesion & migration; Clinical trials; Community-Acquired Infections - drug therapy; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Immune System Diseases - chemically induced; Immune System Diseases - drug therapy; Infections; Leukocyte Disorders - chemically induced; Leukocyte Disorders - drug therapy; Male; Middle Aged; Mortality; Neutrophils; Older people; Original; Pneumonia; Respiratory Tract Infections - drug therapy; Sepsis; Sepsis - drug therapy; Simvastatin - therapeutic use; Statins; immunosenescence; pneumonia; neutrophil; statins; sepsis
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201704-0814OC

Dysregulated neutrophil functions with age and sepsis are described. Statins are associated with improved infection survival in some observational studies, but trials in critically ill patients have not shown benefit. Statins also alter neutrophil responses in vitro. To assess neutrophil migratory accuracy with age during respiratory infections and determine if and how a statin intervention could alter these blunted responses. The migratory accuracy of blood neutrophils from young (aged <35 yr) and old (aged >60 yr) patients in health and during a lower respiratory tract infection, community-acquired pneumonia, and pneumonia associated with sepsis was assessed with and without simvastatin. In vitro results were confirmed in a double-blind randomized clinical trial in healthy elders. Cell adhesion markers were assessed. In vitro neutrophil migratory accuracy in the elderly deteriorated as the severity of the infectious pulmonary insult increased, without recovery at 6 weeks. Simvastatin rescued neutrophil migration with age and during mild to moderate infection, at high dose in older adults, but not during more severe sepsis. Confirming in vitro results, high-dose (80-mg) simvastatin improved neutrophil migratory accuracy without impeding other neutrophil functions in a double-blind randomized clinical trial in healthy elders. Simvastatin modified surface adhesion molecule expression and activity, facilitating accurate migration in the elderly. Infections in older adults are associated with prolonged, impaired neutrophil migration, potentially contributing to poor outcomes. Statins improve neutrophil migration in vivo in health and in vitro in milder infective events, but not in severe sepsis, supporting their potential utility as an early intervention during pulmonary infections. Clinical trial registered with www.clinicaltrialsregister.eu (2011-002082-38).