Influenza, evolution, and the next pandemic

Area of Science:

• Evolutionary biology
• Infectious disease epidemiology
• Pharmacology

Background:

• Influenza mortality rates show age-dependent variations, notably lower in children than adults during the 1918 pandemic.
• This age-related mortality pattern is observed across various infectious diseases and has been replicated in animal models.
• The difference may stem from enhanced infection tolerance in children, rather than superior resistance.

Purpose of the Study:

• To investigate the potential of combination generic drug therapies to modulate host responses in influenza.
• To explore whether these treatments can shift adult infection responses towards the more tolerant pediatric profile.
• To assess the feasibility of host response treatment for reducing mortality in influenza pandemics and other critical illnesses.

Main Methods:

• Review of epidemiological data on influenza mortality across different age groups.
• Analysis of preclinical models demonstrating age-related differences in infection response.
• Hypothesizing mechanisms of action for generic drugs (statins, angiotensin receptor blockers) on host response pathways.

Main Results:

• Age-dependent differences in mortality suggest a tolerance-based mechanism rather than resistance.
• Combination therapy with generic drugs may re-engineer damaging host responses to a tolerant phenotype.
• Potential mechanisms include modulation of endothelial dysfunction, mitochondrial biogenesis, and immunometabolism.

Conclusions:

• Treating the host response, rather than the pathogen, may be a key strategy for reducing global mortality during influenza pandemics.
• This approach could also mitigate mortality from seasonal influenza and other acute critical illnesses.
• Further laboratory and clinical studies are required to validate host response treatments across different age groups, particularly before and after puberty.