Experimental Models of Hospital-Acquired Infections After Traumatic Brain Injury: Challenges and Opportunities

Patients hospitalized after a moderate or severe traumatic brain injury (TBI) are at increased risk of nosocomial infections, including bacterial pneumonia and other upper respiratory tract infections. Infections represent a secondary immune challenge for vulnerable TBI patients that can lead to increased morbidity and poorer long-term prognosis. This review first describes the clinical significance of infections after TBI, delving into the known mechanisms by which a TBI can alter systemic immunological responses towards an immunosuppressive state, leading to promotion of increased vulnerability to infections. Pulmonary dysfunction resulting from respiratory tract infections is considered in the context of neurotrauma, including the bidirectional relationship between the brain and lungs. Turning to pre-clinical modeling, current laboratory approaches to study experimental TBI and lung infections are reviewed, to highlight findings from the limited key studies to date that have incorporated both insults. Then, practical decisions for the experimental design of animal studies of post-injury infections are discussed. Variables associated with the host animal, the infectious agent (e.g., species, strain, dose, and administration route), as well as the timing of the infection relative to the injury model are important considerations for model development. Together, the purpose of this review is to highlight the significant clinical need for increased pre-clinical research into the two-hit insult of a hospital-acquired infection after TBI to encourage further scientific enquiry in the field.