Over the last year, China has been working to contain a deadly outbreak of African swine fever (ASF) in pigs that is posing an unexpected threat to human health: shortages of the critical drug heparin. On August 3, 2018, China confirmed its first outbreak of ASF in Liaoning Province. Since then, China has reported 157 outbreaks across 32 provinces, resulting in the culling of more than 1 million pigs in an attempt to halt the spread of the disease. Other countries in the region have also reported cases of ASF, including Myanmar, Laos, Cambodia, and most recently, South Korea (reported its first case on Tuesday this week). We do not often discuss animal-specific diseases in Outbreak Thursday, but this week, we will look at the ASF outbreak and response as well as potential impacts on human health.
ASF is caused by the African swine fever virus, a DNA Asfivirus in the family Asfaviridae. ASF is a severe contagious hemorrhagic viral disease that exclusively affects pigs. In its acute form, it causes fever, vomiting, diarrhea, and death in wild and domestic pigs, with the mortality rate in domestic pigs approaching 100% in most outbreaks. Clinically, ASF closely resembles classical swine fever, or hog cholera, which is an economically devastating pandemic disease. ASF is primarily transmitted between pigs via direct contact between animals, contact with contaminated feed, or vectors such as Ornithodoros ticks. African swine fever virus is also highly persistent in the environment, remaining stable and infectious for 3-6 months in uncooked pork products. ASF is not known to infect humans or any other animals. Considering the devastating effects on pig populations and the associated significant economic ramifications, ASF has been identified as a potential agent of agroterrorism, reflected in its designation as a Select Agent by the US Department of Agriculture (USDA).
Prevention and Control
ASF is a serious threat to the pork industry, and outbreaks can result in significant economic losses. In countries with domestic transmission of ASF, culling affected or potentially affected animals is a principal intervention. Safe and sanitary disposal of carcasses also reduces the risk of spreading the disease to other pig populations. In addition, surveillance is key to detecting new cases and implementing effective interventions. There is currently no ASF vaccine available to prevent the disease in swine and no treatment for infected animals. Prevention and control of the disease are top priorities; many countries that have not yet detected ASF have implemented biosecurity policies and procedures to ensure that live pigs and pork products brought into the country are not infected/contaminated with ASF.
ASF and Heparin
The significance of global ASF outbreaks reach far beyond the economic losses and destabilization of the pork industry, including downstream effects on human health. One notable threat is a shortage of heparin in the US and elsewhere. Heparin is an anticoagulant drug used to prevent the formation of blood clots, which can be life-threatening. Heparin is the primary pharmaceutical intervention for preventing heart attacks during surgery and for use in dialysis patients. The active ingredient in commercially available heparin in the US is extracted from pig intestines. Bovine (cow)-based heparin was previously available in the US, but the use of these products was discontinued in the US in the 1990s due to the risk posed by prions. Heparin can also be produced from sheep or goats, but these products have never been tested in humans.
As the world’s largest producer of pork, China is a primary supplier (nearly 80% of the global supply) of the active pharmaceutical ingredients needed to manufacture heparin. The ASF outbreak has led to significant losses of pig populations in China. In fact, it is estimated that between 150 million and 200 million pigs have been lost to ASF in China since the beginning of the outbreaks. While culling is an important and effective intervention for containing the spread of ASF, the practice has potentially serious implications for heparin manufacturing, leading to preparations for a global heparin shortage. Fresenius Kabi (Germany), one of the world’s major heparin producers, has begun restricting allocation of the drugs due to raw ingredient shortages stemming from the ASF situation in China. While the US Food and Drug Administration (FDA) has not officially declared a product shortage, they are monitoring the situation closely, and the US House of Representatives Committee on Energy and Commerce has called for plans to address the threat of a potential shortage.
Vulnerability of the Healthcare Supply Chain
The global pharmaceutical supply chain requires a steady supply of raw ingredients from all over the world to be shipped to manufacturing and finishing facilities in numerous other countries. This complex and integrated system, which provides effective and safe medications worldwide, is heavily dependent on ingredients and products from far-off economies and highly vulnerable to disruptions in the supply of raw ingredients. We have seen acute supply interruptions for medical supplies in the past, such as the saline shortage following Hurricane Maria in Puerto Rico; however, the challenges posed by ASF may prove to be a much different issue. Supply disruptions due to a loss of production capacity (eg, damage from a hurricane) can potentially be mitigated by increasing production at other facilities or identifying new suppliers. For heparin, on the other hand, the issue is not production capacity but rather the supply of raw ingredients. There may simply be no alternative supply options, due to an inability to obtain sufficient access to the raw ingredients. Additionally, some experts believe that it could take years to bring the ASF outbreaks under control, which could mean a prolonged shortage of heparin that could drastically change how the drug is used in the US healthcare system and elsewhere and impact the use of a wide variety of procedures and treatments that require this drug.
At this point, there does not appear to be a viable replacement for the raw ingredients originating in China. There exist potential alternatives to pigs, but as noted above, the bovine-based products were discontinued in the US over concerns about prion disease, and sheep- and goat-based products have never been tested on humans. It would take considerable time and effort to conduct clinical trials for new heparin products and to develop and implement effective safety protocols that could alleviate safety concerns about bovine-based heparin products. Even if the ASF outbreaks were brought under control soon, it would take time for the pork industry in China to recover. Efforts are ongoing to develop methods for producing synthetic forms of the active ingredient in heparin, but additional work is needed in this area. While a number of alternative anticoagulant drugs do exist, they may not be suitable replacements for heparin in all situations or patients.
Hospitals and healthcare systems around the world may be faced with the need to change how they operate in order to mitigate these risks over a prolonged period of time. They must recognize the threat that the ASF outbreaks pose and proactively develop and implement protocols and policies to mitigate their impact on human health care. In the scenario of an extreme shortage, this could involve changing or developing new treatment protocols or making critical determinations regarding how to distribute limited available heparin supplies. These concepts are often addressed in the context of an acute emergency, but a prolonged ASF epidemic, and the associated impacts on heparin production, could necessitate their application in everyday healthcare operations. If the ASF outbreaks lead to a prolonged shortage of heparin, hospitals and healthcare systems may be forced to change their routine practices, which could potentially lead to the emergence of new routine standards of care.
The ongoing ASF outbreaks in China and other countries highlight the diverse and interconnected relationship between human and animal health, particularly the vulnerabilities that arise from disruptions to critical portions of these complex systems. The importance of One Health approaches to surveillance and outbreak response are often discussed in the context of trying to prevent animal diseases from spreading to humans, but the ASF outbreaks illustrate a larger One Health lesson. These outbreaks pose no direct threats to human health. Rather, the threat to humans stems from the downstream impacts of control measures implemented to protect agricultural and economic interests. As China continues to battle ASF, including the culling of millions of pigs, we can expect that production capacity for heparin will be limited to some extent. We must start planning now if we hope to mitigate the effects of these outbreaks on human health, potentially for years to come.
Photo courtesy of Pixabay.
Outbreak Observatory aims to collect information on challenges and solutions associated with outbreak response and share it broadly to allow others to learn from these experiences in order to improve global outbreak response capabilities.