In the present study, we performed first a phylogenetic analysis to compare the relative distribution of HRV species or serotypes according to the respiratory site (URT versus LRT) and in protracted infection in hospital patients and lung transplant recipients. In the latter group, we evaluated the frequency of mutations and characterized mutation hot spot regions during the course of five natural human protracted infections, each caused by a different rhinovirus serotype. In one case, we followed intra-host rhinovirus genome variation at different time points in the URT and LRT over a period of 27 months using both classical and ultra-deep sequencing methods.