The current COVID-19 pandemic has exceeded any epidemiologic prevision, but increasing information suggests some analogies with the major viral outbreaks in the last century, and a general warning has been issued on the possibility that co-infections can make the differential diagnosis and treatment difficult, especially in tropical countries. Some reports have pointed out that presence of high Dengue antibodies can give a false negative testing for SARS-CoV-2. Muco-cutaneous manifestations are very frequent, with an apparent overlap among different pathogens. However, strong clinico-pathologic correlation might provide some clues to address differential. Waiting for laboratory and instrumental results, the timing and distribution of skin lesions is often pathognomonic. Histopathologic findings characterize certain reaction pattern, and provide insights on pathogenetic mechanisms. Unfortunately, skin assessment takes a back seat in severely ill patients, especially invasive exam such as biopsy. A literature retrieval was performed to collect from other epidemics as much information to counteract what has become the most frightening disease of our time.