Smallpox was once among the most feared infections in the world. It is most often characterized by deforming, rapidly spreading macules that cover the face, trunk, and extremities. In severe cases where petechiae develop in the conjunctiva, blindness can result. 

It is a disease that has existed for millennia, and was first identified in ancient Egyptian mummies. In the late 1700s, Edward Jenner introduced the first modern smallpox vaccine. Intense efforts by public health officials and healthcare workers led to the complete eradication of the disease by 1980. It remains the only human disease to hold this distinction. 

The successful eradication of smallpox is a shining example of how humanity can work together to drastically reduce or even completely eliminate a disease. Many individuals working in the rare disease space harbor hopes that nongenetic disorders will become rarer and rarer through a combination of early prophylaxis and timely treatment; we want the prevalence of rare diseases to go down, sooner rather than later. 

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However, the reality is that the prevalence of rare diseases, such as idiopathic pulmonary fibrosis (IPF), is rising and it is not an isolated example. Take, for example, cholangiocarcinoma (CCA): it was and still is considered an exceedingly rare disease, but its prevalence is rising at an alarming rate around the world. 

Read more about IPF etiology 

Why are diseases once considered rare becoming more common? Is there a threshold upon which rare diseases are no longer considered “rare”? What are some of the contributing factors that drive up disease prevalence in a given population? 

Factors Driving Increasing Prevalence 

In Advances in Therapy, Pergolizzi Jr. and colleagues conducted a narrative review to investigate the possible causes behind the rising global prevalence of IPF. 

An obvious factor driving up the prevalence of rare diseases is the “graying” population; a number of countries in Asia, such as Japan and South Korea, have sounded the alarm regarding the precipitous decline in birth rates, meaning that, for the first time in world history, there will soon be significantly more elderly people than the young. This also means that people are living to an age at which they become vulnerable to diseases such as CCA, which is insidious and tends to manifest only later in life. 

Another factor potentially fuelling the global prevalence of rare diseases is improved diagnostic tools and greater awareness of rare conditions. Having practiced in Malaysia, I have witnessed the increasing “westernization” of medicine; guidelines from the United States are given greater weight, and diagnostic tools and standards from the West are highly prized. This has the effect of making medicine more uniform, which is positive for cross-cultural communication; it also makes it easier for clinicians from various parts of the world to exchange views regarding rare diseases, raising their profile in the process.

The above are more optimistic proposals as to why the incidence of diseases such as IPF is increasing globally; an alternate explanation is that the air pollution index has worsened, a phenomenon seen in most major cities of the world. Scientists have long posited that environmental exposures, such as dust and particulate matter, can contribute to IPF pathogenesis. 

Reversing the Trend 

If the increasing occurrence of rare diseases is the result of comprehensive testing and diligent reporting, we may conclude that there is nothing to worry about, that we’ve made positive strides toward getting rare diseases recognized and treated accordingly. However, if the incidence of rare diseases is indeed rising even after possible confounding factors have been taken into account, then it is a trend that clinicians around the world should be worried about. 

Read more about IPF epidemiology

More patients ill with rare diseases mean more healthcare resource utilization, less productivity, greater drug interactions, and shortened survival. Major studies point to the fact that a rare disease diagnosis negatively impacts quality of life and imposes a significant disease and treatment burden on patients and their carergivers. 

With regard to the rising prevalence of IPF, some may point to the COVID-19 pandemic as a possible exacerbating factor. However, this increase in IPF cases predates the arrival of the pandemic. Nonetheless, it is scientifically plausible for COVID-19 to contribute to IPF etiology, given that viral infection is a risk factor for fibrogenesis. 

So how can we reverse the trend of rare diseases increasing in prevalence across the world? First, we need to ensure that the public is aware of possible lifestyle factors that can drive pathology, whether rare or not. Despite increasingly tight restrictions around recreational smoking, around one-tenth of individuals in the United States still smoke on a regular basis—we need to ensure that this figure goes down. We must also continue to create awareness about the links between excessive consumption of alcohol and liver cancer. 

Second, researchers should have the boldness to pursue curative therapeutic solutions where possible. At present, many rare diseases, including IPF and CCA, lack a definite, curative drug. As our knowledge of the mechanisms underpinning rare diseases matures, we should aim to eradicate them altogether, using the smallpox vaccine as both inspiration and template. 


Pergolizzi JV Jr, LeQuang JA, Varrassi M, Breve F, Magnusson P, Varrassi G. What do we need to know about rising rates of idiopathic pulmonary fibrosis? A narrative review and updateAdv Ther. 2023;40(4):1334-1346. doi:10.1007/s12325-022-02395-9

Meyer H, Ehmann R, Smith GL. Smallpox in the post-eradication eraViruses. 2020;12(2):138. doi:10.3390/v12020138

Brindley PJ, Bachini M, Ilyas SI, et al. CholangiocarcinomaNat Rev Dis Primers. 2021;7(1):65. doi:10.1038/s41572-021-00300-2