First, dismiss any ideas about the effectiveness of old world treatments. Prior to the introduction of variolation Europe via the Ottomans in the early 1700s, smallpox was treated with the same humoral approach that dominated European medicine from Hippocrates onward. That is, the disease would be managed via bloodletting, purges, enemas, and the management of diet to avoid "hot" or "cold" foods depending on the effect the physician wanted to achieve. There was no prevention of smallpox before variolation (which had it's own problems) and it was not until vaccination was developed in the late 1700s that there was really effective prevention. No treatment for smallpox was ever developed and there remains to cure to this day. Instead, the vaccine is given early after exposure and then symptoms are managed.

High mortality rates in disease naive populations has its foundation in an epidemiological fact. For a disease such as smallpox, where exposure and recovery allows for lifelong immunity, there will always be a certain percentage of people who have been exposed and recovered. Perhaps they were exposed as infants while still protected by maternal antibodies, perhaps they were infected later and recovered, regardless of the details, they are immune. In a population that has never been exposed to a disease, there is not this pool of immune individuals; every person has the same susceptibility.

Compounding this epidemiological reality is the social logistics of organizing and providing care. In cases of widespread infection, there can be a lack of people well enough to provide adequate care to those who are unable to carry out activities of daily life. This can include such necessities as obtaining food and water, but also basic hygiene to avoid secondary infections which may complicate outcomes. If a group is small enough, then the mortality of a novel infection can lead to a fundamental fracturing of the social order. So it it not a surprise that we see the fusion of groups hit hard by disease into new confederations of people.

An interesting side note is the hypothesis put forward by Black (1994) where he suggests that the genetic bottleneck of the Bering crossing was a factor. Essentially, he proposed that the human leukocyte antigen (HLA) variability was lower in the Americas, which meant less variation in the immune response to infections, which meant everyone generally responded to disease in similar (immunological, molecular) ways. There was less chance of having a variant which conveyed a better response to infection, basically. This is not a universally accepted hypothesis though. For instance, Riley (2010) notes that while Black's proposal may have some merit, the epidemiological and social disruption factors are much more explanatory.

It was not that a higher rate died. The same percentage of infected Europeans and Native Americans died. However, there was a higher rate of infection in thie Native American population. This suggests that there was little immunity in the population, which would make sense because there seems to be no evidence of smallpox-like diseases in North America before the arrival of Europeans. Smallpox was just as deadly for the Europeans who caught it, and there were smallpox epidemics in colonial settlements too, they were just less frequent because a higher percentage of the population there had an inherited immunity to the disease.