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.7-9 Other analyses of these household transmission data did not find temporal associations between symptom severity and upper respiratory viral load.

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