Emerging Infections of International Public Health Importance

Objectives:

To know the definition of a trade-related infection
Through the review of case studies to be able to characterize the
impact of global trade on the emergence and transmission of new
infections.
To learn the outlines of the World Trade regime, (in the SPS and TBT
agreements), as it relates to the emergence of new infections.

Global trade has reached a historically unprecedented volume: In 1999 a record $5.47 trillion worth of merchandise crossed international borders. Along with merchandise traveled infections introduced into products through cultivation, handling, processing, or packaging in unsafe settings. In particular, trade in biological products (blood derivatives, etc.,), and foodstuffs, (produce and meat, etc.), have been demonstrated to facilitate international transit of human infections. Unfortunately, patterns of trade-related infection can only be described for instances in which diagnostic, laboratory, and technological data are available along with epidemiological investigation. However, such well-documented instances are rare.

This lesson will describe a conceptual framework for understanding trade-related infection by using four illustrative global disease situations. These cases point to the increasing importance of cross-disciplinary studies encompass expertise in trade dynamics, epidemiological investigation, and molecular biology in describing and controlling global epidemics related to trade.

Trade is a major dynamic in globalization, a late 20th Century phenomena that has changed business paradigms and the way people and goods travel around the world. This discussion will not address the indirect affects of trade, ( i.e. is trade an effective driver of economic development for poor countries?, or, alternately, is the global market place trading safety and health for commercial gain?). We focus here on the direct impact trade has on infectious disease emergence and transmission and the impact the emergence of infection may have on trade. In addition, potential surveillance and monitoring information systems to assist in infection surveillance and control will be considered.

The explosion of global trade over the past three decades has occurred against the historical backdrop of inequity. The world’s population of more than six billion people has very uneven access to water and sanitation.

An estimated two billion people live without adequate sanitation, and over a billion people live without clean water. In addition, the world is becoming increasingly urbanized.

Many forces are driving migration to the cities: the search for economic opportunity, the decline in traditional rural economies, and the unstable political climate in rural areas are leading factors. Uncontrolled urbanization has stressed an already inadequate urban infrastructure, especially in poorer countries. In fact, most "mega-cities" will exist in poorer countries of the developing world by the end of the 21st century. Urbanization is the double-edged sword of globalization. While the concentration of populations may increase market access global trade, the ongoing lack of sanitary conditions has created serious obstacles for safe trade.

Growth of international trade has been phenomenal over the last 30 years. For example, agricultural trade, as represented by data from the United Nations Food and Agriculture Organization, is illustrated in the Figure below.

The top line indicates the increase in dollar value of fruits and vegetables in international agricultural trade, the value of meat and meat products are represented by the yellow line, and the value of dairy products and eggs are shown in green. Even though the trade of live animals has increased somewhat less rapidly than the other commodities, the amount of global trade has escalated consistently with slight exceptions in 1991 and toward the end of 2000. The World Trade Organization (WTO) describes an average 6% per annum increase per year over the past decade. All sources indicate that global trade will continue to increase.

Thus a trade related infection (TRI) is an infection which is related to trade either with trade as a amplifier of the infection, or trade disruption as an economic consequence of that infection. The first element of this definition, the relationship of the emergence of human pathogens to changes or stepped up production is an area of speculation. As the case studies below illustrate there is temporal and circumstantial evidence linking the emergence of new diseases to changes in production, but the mechanisms are not clear. For example, a recent review suggests that the processing of biological materials, (for example, for food production), can inadvertently result in the emergence of resistance in microorganisms. However the pathways through which such pathogens may emerge as trade related infections are in the early stage of definition.

The emergence of HIV/AIDS coincident with the growth in international trade in blood derivatives, salmonella with the growth of global seed and sprout trade, Cyclospora cayateniensis with fresh produce trade, and Bovine Spongiform Encephalopathy (BSE) and nvCJD with beef and beef product trade each illustrate an aspect of trade-related infection. Surveillance efforts can be improved from lessons gleaned from these experiences.

An estimated 40 million people are infected by HIV as of this writing. The majority are living in Sub-Saharan Africa, but the infection rate in South and Southeast Asia is growing rapidly. Although HIV is largely sexually transmitted, trade has certainly been a factor in its globalization. In 1982, when the first cluster of HIV disease was reported among gay men, a case coincidentally was described in a hemophiliac, which was linked with Factor VIII. The powdered derivative blood product (One unit is derived from up to 20,000 units of donor plasma.) supplanted cryoprecipitate as the preferred prophylactic for bleeding crises in hemophiliac patients. The United States had pioneered the production and lyophylization of Factor VIII in the late 1970’s and was the main exporter of Factor VIII in the 1980’s. Hepatitis transmission through pooled blood products was a known risk since studies in the 1970's and 1980's when 7-21% of recipients were shown to develop post transfusion hepatitis. Efforts by industry to perfect methods for the inactivation of viruses in plasma derived products were ongoing when HIV emerged.

Japan traces its HIV/AIDS epidemic to importation of commercial product from the United States. In 1993, 64% of HIV/AIDS cases in Japan were among hemophiliacs. In the mid-1980’s the risk was defined, and heat treatment of the product was instituted. However, between the late 1970’s and the mid-1980’s, Factor VIII produced in the United States represented a risky product that introduced HIV into Japan and other economies.

The United States continues to be a major exporter of blood factions and modified immunological blood products, and innovative products are continuously under development.

With the value of this trade in 2000 reaching $1.4 billion dollars, according to the United States International Trade Commission, the potential for the introduction of other new agents, such as prions, remains a concern. A full case study of HIV/AIDS in Factor VIII traded internationally in the 1980’s would allow a more complete description of this potential risk and the transmission dynamics of infection. The People’s Republic of China is reportedly struggling with a potentially contaminated blood supply so further insight into how this risk has operated historically is topical.

Enteric disease risk in food is epitomized by two outbreaks that have been well described and studied: sprouts and salmonella (numerous serotypes), and raspberries and Cyclospora cayeteniensis. Sprouts are a hydroponically grown product in which the seeds are imported: alfalfa, radish, mung bean, and other seeds are traded around the world and then sprouted in the recipient country for marketing as sprouts. Sprouts have been linked with numerous epidemics internationally, and confirmed by molecular-level characterization of the pathogen. When the U.S. Center for Disease Control and Prevention (CDC) instituted a new algorithm for salmonella serotyping through its Public Health Laboratory Information System (PHLIS), outbreaks of Salmonella stanley in Arizona and Michigan were detected. Coincidentally, standardized serotyping within the Salmnet, a laboratory-based surveillance system of the European Union and the European Cooperation in Science and Technology, detected an outbreak of the same unusual serotype in Finland. A cooperative case control study was done within each of the affected areas. The results of these studies are summarized in Table 1. Thirty-nine percent of the cases consumed sprouts and only eight percent of controls reported consuming sprouts. In a similar study in Michigan that used neighborhood controls, 41 percent of the cases and 10 percent of the controls ate alfalfa sprouts. A case control study also was conducted in Finland, by the Finnish public health authorities and alfalfa sprouts were again identified through the case control methodology. In the Finnish experience, 100 percent of the cases reportedly ate sprouts compared to only 20 percent of the controls. Thus alfalfa sprouts were implicated as the source of these outbreaks. Restriction fragment length polymorphism (RFLP), pulsed-field electrophoresis (PFGE), and anti-microbial susceptibility assays were used to confirm the common source.

The PFGE pattern was identical across for isolates from cases in all of these geographically disperse areas. Culturing remaining seeds was unsuccessful and trace-back studies were undertaken to determine the source of contaminated product. Investigators were able to isolate retail outlets and dates of purchase through interviews of the cases. Suspect seed suppliers’ lot numbers and dates of sproutings were identified through delivery records and shipping invoices, resulting in 50 successful trace backs in the months following the outbreaks. A successful trace back is defined as when a case patient was able to identify which retail outlet they used during the five days prior to their illness. Nine growers were identified with a single large U.S. provider of seeds. This provider had a national market share of 60-70% and 96 % of the cases reported that they had eaten sprouts from this source. Records from the sprouters show that 46% of the seeds had been purchased from a distributor in the Netherlands. The distributor obtained seeds from Italy, Hungary and Pakistan, and it was unclear which source was implicated in these outbreaks.

In 1995 cylcospora cayateniensis was a newly identified enteric pathogen. Thus, when small clusters of human disease were detected in 1995 there was high scientific interest in defining the source. Inconclusive investigations carried out in New York and Florida suggested an association with raspberries and/or strawberries.

In 1996 multiple outbreaks occurred in the United States and Canada with a total of 1,465 cases reported. Due to the widespread nature of the problem, active investigation was undertaken. Based on food histories and trace-back studies multiple Guatemalan raspberries farms were implicated. There were varying points of entry of the product into the United States and many distribution patterns in North America.

This figure shows the epidemic curves of this outbreak; the top graph shows the disease clusters in the United States and Canada. Most clusters were in the United States; Canada had only eight events reported in that year.

It was hypothesized that infected humans had contaminated the water sources that were used in crop treatments through insecticides and fertilizers. Based on the findings of the 1996 outbreaks in North America, the Guatemalan Raspberry Commission voluntarily implemented control measures that included hygiene and sanitation and a review of water sources used in cultivation. Unfortunately, despite these measures another large North American outbreak occurred in 1997 in multiple areas with multiple clusters of disease. Again, the Guatemalan raspberries were implicated. Given that voluntary controls had not been effective, the Guatemalan Raspberry Commission stopped exporting raspberries to the United States.

The end of raspberry importation from Guatemala to the United States was coincident to the end of clusters here. By 1998 the Food and Drug Administration formally prohibited the importation of Guatemalan raspberries based on the inability of the Guatemalan authorities to control contamination of the product. Canada did not restrict importation and had continued clusters of disease in 1998, while disease activity in the United States essentially stopped.

This outbreak underscores the same themes as the sprouts example: Laboratory capacity to diagnosis the agent coupled with careful epidemiological investigation was essential to define the problem, and the broad geographic distribution of the disease correlated with the wide geographic distribution of the product. In this fortunate case, the source was found and import restrictions imposed, bringing an end to the problem. But the incident raises a lingering question: Are trade restrictions the only workable remedy in this type of situation?

The final case of trade-related infection, nvCJD, is a continuing challenge. The first appearance of human cases of nvCJD in the United Kingdom was documented in the early 1990s.

Epidemiological studies suggested exposure to British beef was a risk factor. A large epidemic of Mad Cow Disease Bovine Spongiform Encephalopathy (BSE) had been diagnosed in British herds in the 1980s. It is hypothesized that changes in processing and rendering animal products in the 1980s may have allowed the introduction of a prion agent into cattle feed, and human consumption of the cattle instigated the human disease. (Prions are described as autocatalytic proteins that proliferate in the brain and cause spongiform encephalitis in humans.) Based on United Kingdom experiences, prion disease has a long incubation period of up to 10, 15, and almost 20 years, depending on the exposure history. The disease in humans is similar to classic Creutzfeldt-Jakob disease and causes an unremitting downhill course to eventual death. Currently, there is no definitive diagnostic test, no screening test for the presence of prions, and no clinical diagnosis other than that confirmed on brain biopsy, although are areas of active research. While it is possible that the changes in animal recycling and processing practices were somehow linked to a ramping up of the British beef industry for global markets, it is certain the detection and description of this infection has had major disruptive effects on global trade in beef.

The two key international organizations working in this arena-the World Trade Organization (WTO) and the World Health Organization (WHO)--have differing primary mandates, but some common policy concerns. Since 1995 global trade relations have been regulated and facilitated under the WTO and its agreements. While WTO provides a range of specific functions (see below), its "main function is to ensure that trade flows as smoothly, predictably and freely as possible."

Generally, WHO outbreak surveillance focuses on public health issues, such as outbreak alert and response, while specific trade statistics are not routinely examined. The two urgent-measures reporting requirements under the SPS and TBT agreements may offer some options for monitoring the interaction between infections and trade. These systems began in 1996 following the agreements of 1995. On initial analysis of the SPS agreement urgent-measures dataset, we found that reporting has markedly increased in frequency and diversity in 2000 and 2001. This suggests the system is still being operationalized in member economies. The major trade disrupters for the year 2000 were Bovine Spongiform Encephalopathy and Foot and Mouth disease. We are currently comparing the WHO and SPS urgent-measures datasets for similar time periods to ascertain the biases within the two systems and how they could complement one another to describe trade-related infections. The eventual goal of this work is to compile an evidence basis for understanding Trade related infections which can inform the work of WTO and WHO with their member states.

As globalization of trade and travel continues to impact the public health of the global village, coordination of international efforts across these arenas will become more frequent. The linkages between global traffic and infectious disease challenges are increasingly recognized by policy makers at the global level. This awareness can best become more generalized through systematic information sharing and consultation. At the national and local levels, the key operational levels for public health services delivery, increased insight into the importance of global trade and travel as a factor in disease occurrence is probably even more important. Such interchange between "sectors" of activity could facilitate outbreak prevention, detection and response related to global traffic. It is clear from the scale of global trade and the scale of unreported infectious disease that the case studies described likely represent a small fraction of incidents of trade related infections which occur. Active interchange between authorities in commerce and public health at the local and national level will be a key strategy in more completely describing this phenomenon. Such investigation will facilitate the timely prevention, detection and containment of trade-related infections in the future.

Study Questions:

What is a trade related infection? Give an example.
In internationally dispersed outbreaks, there are two "gold standards" by which the integrity of the epidemic is defined, i.e. common source. What kinds of evidence are these?
Which two international organizations are responsible for health and trade respectively? What are their mandates?