Introduction
There is uncertainty about the extent to which the site of initial exposure within the pulmonary tree influences influenza virus infection risk and severity between humans. Experimental nasal instillation produces a range of illness from asymptomatic, symptomatic, to febrile. Studies that challenged humans by nasal instillation of virus, and others that challenged with aerosolized virus suggest that upper respiratory mucosal exposure, as opposed to airborne exposure may result in a higher proportion of milder, afebrile illnesses.1–3 Anisotropic infection is defined by Milton as infection whereby transmission mode influences illness presentation,4 and has been used to characterize human influenza.5 To minimize health risk associated with experimental human influenza infection, the majority of human challenge models have adopted viral inoculation by nasal instillation.6 Associations between symptomatology and nasal and throat mucosal viral load following symptom onset have been reported among volunteers receiving intranasal influenza virus challenge and among secondary household cases in Hong Kong.7–9Other analyses of these household transmission data did not find temporal associations between symptom severity and upper respiratory viral load;10 and observed upper respiratory mucosal viral loads11,12 or respiratory symptoms13 to be poorly predictive of transmission to household secondary cases, suggesting that other biomarkers of contagion such as exhaled breath aerosols should be explored. The current study compares fine aerosol shedding between influenza A/H3 nasally inoculated and naturally infected cases to test whether experimental, nasal induced infections have similar risk and rate of fine aerosol shedding compared with natural cases infected by any mode.