Emerging Infections of International Public Health Importance

Objectives:

To know the definition of a trade-related infection
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 emergence of new infections

In looking at emerging infections, it is extremely thought-provoking to examine this nexus between the trade of commodities and transmission of infections. We hear a lot about trade in the news. There is discussion about the international trade regimes that are in place. Are they good for developing countries? Are they bad for developing countries? Whose interest is being served? It is a highly political process as are most international relations processes in the world today.

My own interest in trade goes back a long way. When I worked in Central Africa in the 80s, I went to the Central African Republic, a very poor country. At the time it was even poorer because the emperor of Bokassa had just recently vacated and the new republic was struggling. I went to a marketplace that was just outside Bangui, where a market was set up every Saturday morning. At this market there was nothing but manioch and beans, but there was a huge crowd of people. Wherever I go, I always go to the marketplace to watch how people engage in commerce. These local vignettes seem far removed from global trade but are probably part of the same drive.

We have a conceptual framework for studying trade-related infections. Four illustrative infections will be described to support this definition. We will then discuss surveillance, prevention and control options through WHO and WTO. These infections are HIV/AIDS, enteric infections from sprouts, cyclospora from raspberries and BSE from beef products.

Before we talk about specific trade related infections, I would like to talk briefly about globalization. Globalization is defined by Merriam-Webster’s Collegiate Dictionary (2000) as: to make global, especially to make worldwide in scope or application. The concept of globalization brings into the framework many things including: politics, culture, national security, finance, development, environment, and universal and country-specific values.

This slide shows a large gap in the availability of basic services such as sanitation and clean water around the world.

Globally, there are billions of people without these services, and this has a lot to do with the perpetuation of infection.

With the increasing number of “mega-cities”, this problem is expanding. This slide shows the ever increasing trend of urbanization.

Here is a picture of a shantytown in Bangladesh, developed due to the increased populations in urban areas.

We are also in a new era of financing. There is greater diversity and sources for financing for the public good in poor countries, but the funding is not stable or long term. This can affect economic stability in resource limited settings. When funding simply stops on a project, as can happen with long term plans, this compromises a government’s ability to perform sustained infrastructure development. Also, the global market is highly interdependent today. The collapse of the currency in Indonesia in 1996 is one example which had a ripple effect through the entire region.

Trade is intimately related to globalization. This slide looks back over 30 years of the trends in global trade through Comtrade, which is a data system that tracks every item of trade that crosses international boundaries.

You can see that there has been a huge increase in the past 10 years of global trade in food products. The value of food trade in 1994 in the United States alone is estimated at greater than $266 billion.

So what is a trade-related infection? Our working definition requires that a trade-related infection meet at least one of the following criteria.

Factor VIII concentrate was developed in the late 1970s, and has become the mainstay of treatment for hemophiliacs. Hemophilia is a blood clotting deficiency, and people who have this genetic disease have an absence of Factor VIII and are unable to clot normally. Hemophiliacs have bleeding crises and over time, if not treated, have joint obstruction and disability and early death. Factor VIII concentrate was thus of great importance. One unit was derived from 20,000 units of plasma, so it took 20,000 people to create one unit of this derived product.

We had an HIV epidemic in the U.S. between 1982 and 1985, and our blood supply was contaminated. Exclusion of blood from patients with HIV/AIDS was not systematic since a serologic test for HIV did not exist until 1985. So though we knew the disease existed and that there was a link to the blood supply, we did not have a tool to screen our blood supply. So despite our exclusionary criteria to try to keep our blood supply clean, there was no guarantee, and there continued to be transfusion-related HIV cases in the U.S.

It was known that Factor VIII could transmit hepatitis, because in 1982, there was a major hepatitis scare related to Factor VIII. At least one pharmaceutical firm had created a heat deactivation process for factor concentrate to maintain their product safety. The U.S. was the main exporter of factor VIII during this time.

The Japanese HIV epidemic was first noted in the early 1990s. HIV has a very long incubation period. So it took 7-10 years from the time of infection to the time of clinical illness. Japan has always maintained that their AIDS cases were related to the importation of foreign blood. Japan was accused of “denial” of its links to the Thai sex trade, but the timing suggests that importation of blood products was indeed the key route in Japan. The first cases in Japan were among the hemophiliac population. In 1993, 64% of HIV/AIDS cases were among that population.

It is difficult to get good data on trade in Factor VIII; the blood derivative data is not available through Comtrade. We recently did get some new figures, however, and we looked at the major providers. There was Alpha Therapeutic, which was owned at that time by Green Cross, Japan. Between 1981 and 1988, sales for plasma-derived blood products for Alpha Therapeutic went from $10 million to $38 million. U.S. Armour Pharmaceutical in 1982 sold $51 million for blood products and in 1988 $125 million. Hyland of Travenol Labs, which later became Baxter, had sales of $60 million in 1982 which increased to $98 million in 1988. Cutter division of Miles labs, which later became Bayer, had sales of $69 million in 1982 which increased to $123 million in 1988.

This graph shows the export of blood fractions and other immunological products from 1989-2000.

These are life saving technologies, so we have to figure out how to effectively screen these products to make and keep them safe.

Far more detail is provided in the Krever Commission Report published in 1997 by Canada. It is available on the Internet at Health Canada. It is a low-key report but is one of the most careful treatments of the HIV epidemics in hemophiliacs and the relationship to the export of blood products around the world. It actually tracks the fact that most governments, with the exception of the U.S., have compensated their hemophiliacs with public dollars for the damage of giving them contaminated medical products. It gives you the amounts compensated in France, Japan, and others, but for the U.S. it says ‘never.’

Global trade provides access to fresh produce year round. For years in northern markets, consumers could not buy certain kinds of fruits and vegetables in the winter months. We did not have the north-south trade we have now that brings you fresh tropical fruits.

Sprouts are important in many diets. They are particularly important in Japan and other countries with limited vegetable access domestically. And the problem with sprouts is that they do not have a cooking “kill” step in their preparation. Seeds are exported and hydroponically sprouted.

The problem here is that some bacteria that may contaminate your seeds can travel on the seed to the new destination. And seed trade is just an exploding part of global trade. It is very difficult to regulate it because you do not label each individual seed. It is a bulk product, and they mix seeds from different producing regions and countries.

CDC began a new salmonella surveillance system in 1995. There is an international network now called SALM-Net that the WHO runs, where they are trying to get all the countries to do standard serotyping for salmonella and shigella, which are the two major bacteria for enteric diarrheal infections in the developed world. When CDC established this new serotyping system, they found an unexpected bump in salmonella cases.

It was unexpected in the age group and also unexpected in the absolute number of cases that they picked up on their national surveillance. They traced it to two states, Michigan and Arizona. SALM-Net in Finland, which was just gearing up at the time, was reporting the same serotype of Salmonella stanley. You can see the epi curves peak during the same temporal period.

The surveillance system picked it up relatively late because it was still a relatively new system. When investigators did case control studies, alfalfa sprout exposure was found to have a significant increased risk for this variant of salmonella. For each of the three regions, you can see the high proportion of cases exposed to sprouts and the low exposure in controls, leading to high odds ratio estimates (the Finland OR is undefined because all cases were exposed).

PFGE, or Pulse Field Gel Electrophoresis, revealed exactly the same pattern of banding among the outbreaks.

There was a single type of Salmonella stanley globally that were affecting people. The investigators decided to trace these contaminated sprouts back to their source. They identified the retail outlets and the date of purchase of the sprouts or the seeds. Then they determined the shippers and growers who provided the sprouts to the distributors to these commercial outlets. They went through piles of invoices and delivery records to find the seeds suppliers, the lot numbers and the date they were sprouted through that distributorship. They did 50 successful trace backs and found that 9 growers used one single U.S. supplier. They found that the U.S. supplier obtained the seeds from a Netherlands distributor and the Netherlands distributor had a combination of seed lots from Hungary, Pakistan and Italy. So it was impossible to determine where the contaminated seeds ultimately came from-- Hungary, Pakistan or Italy.

Trade-related infections are not being picked up with their true frequency. We only find out about them when there is this unique connection between surveillance and importation of goods. I think the food supply is relatively safe considering the opportunity we have for really mucking it up, but I also do not think we have the full picture of how much we are moving infections around through this mechanism.

The next outbreak is somewhat similar in that it relates to the actual growing conditions of a food product. Cyclospora cayetanesis is an emerging infection that was first documented in 1977. It is a coccidian parasite that was first described in 1994, and outbreaks started in 1995. Its lifecycle is not completely understood. Humans are the only known host. Infectious spores that are ingested can cause a prolonged GI illness. The oocysts are excreted in the feces.

In 1995, we started seeing “sentinel” outbreaks of this agent, in New York and Florida, with three small clusters of disease. CDC responded rapidly but had an inconclusive case control investigation that suggested that either raspberries or strawberries might have been the source of these outbreaks.

Trace back and case control studies can be difficult detective work. There was a somewhat delayed GI illness, thus with delayed diagnosis, and it was difficult for people to recall what they ate. Additionally, the fresh fruit where they hoped to get the agent from was usually unavailable, and there was no brand name recognition.

In 1996, there were cyclospora outbreaks in the U.S. and Canada with a total of 1465 cases and 55 separate clusters. Rigorous case control and trace back studies were done and implicated Guatemalan raspberries--there appeared to be a widespread contamination in Guatemala prior to the export. There were multiple farms involved and various ports of entry into the North American markets and many different distribution patterns. The article by Herwaldt et al. in NEJM 1997 describes these outbreaks in detail. This slide shows you the number of outbreaks that occurred in the US and Canada.

The U.S. had 47 events and Canada had 8; the overall number of sporadic cases is shown below.

Investigators found that the water that was used in crop treatments for insecticide and fertilizer was contaminated with cyclospora. Infected humans probably contaminated the water sources. There were suboptimal conditions on these farms—ironically raspberries were the new cash crop for Guatemala that was started as a development strategy. They did not usually grow raspberries, but it was in response to the North American market opportunity as a means of bringing currency into the country. A single raspberry can cause this infection, and a simple water wash is not effective because it is sporulated. It is resistant to chlorine treatment of the water. The sporulated oocysts are good survivors, and you can get food and water-borne transmission.

We had another outbreak in 1997. The Guatemalan Berry Commission, which then was a new entity in Guatemala, implemented voluntary control measures for hygiene, water sources, and sanitation for the raspberry farms. The failure of this strategy resulted in another multistate, multi-cluster outbreak in the U.S. and Canada.

There was a suspension of exports from Guatemala to North American markets, and there was a drop in cyclospora outbreaks in 1997. Then in 1998, the FDA stepped in and prohibited the importation into the U.S. of any Guatemalan raspberries. There was thus this interesting “interventional” study where Canada was still importing Guatemalan raspberries while the U.S. was not. The U.S. had no outbreaks in 1998 while there were again multi-cluster outbreaks in Canada, related to raspberries. So the epidemiologic evidence is pretty strong for implicating Guatemalan raspberries. In the following years, tighter controls within Guatemala decreased the number of outbreaks.

This incident brings up several issues. Was this due to unsafe cultivation in resource limited setting of a newly introduced cash crop? What is the role of surveillance in being able to identify infection before illness? Is trade restriction the only effective control strategy?

Now we will review Mad Cow Disease, or Bovine Spongiform Encephalopathy (BSE). BSE is caused by a prion, which is an autocatalytic protein. This protein, because of its spatial configuration, causes a proliferation of similar proteins in affected neural tissue. However, it does not pass any genetic material, which makes it unique in the biological spectrum of infectious agents. The prion theory is still a hypothesis, and it is not fully proven by Koch’s postulates yet.

One of the books you can read is called Deadly Feasts, which is a dramatic account of how kuru, scrapie, and prions are related. Many now think scrapie may be caused by a prion. In the United Kingdom, there was a change in the way they handled the slaughter of cattle in the 1990’s. Rendering, husbandry practices were changed, bone meal from the rendered animals was incorporated into animal feed, and there was a silent global circulation of this product prior to the detection of the agents. So you had the same situation you had with HIV, where you had infection in a small number of cases, but with a silent, broad circulation in the world, prior to the end of the incubation period. The latency period is long--experts think it takes 10 years from the time of ingestion of the prion to the actual manifestation of neurologic disease in humans.

These are the number of human cases of variant Creutzfeldt-Jakob disease as of the end of August in 2001.

Although the majority of cases have been in the United Kingdom, there have been cases in France and in Spain. We have one case in Atlanta, where a woman ingested beef while she was in the United Kingdom.

The diagnosis of variant versus normal Creutzfeldt-Jakob disease is based on qualitative laboratory immuno-fluorescent patterning that you see on the stained slides. In this WHO slide entitled “the great recycling”, it is apparent that many of the products find their way back into the food chain.

Cosmetics, medical products, and food products can all be affected. Looking at all these products, and where they went globally in the early 1990s, the range of impacted areas that became contaminated with prions is large.

VCJD was identified in humans in the mid-1990’s; beef exports from the UK dropped immediately, almost to zero.

An aside on prion disease: it does not solely travel in bovine products but also travels via human derived products. In fact, there was a product called lyodura, which was produced by a German pharmaceutical company. It was a surgical grafting product, a replacement for human material. There was a market for it in Germany, and it was also exported to and licensed in Thailand and Japan. Using human cadavers, the products were harvested from the dura matter, processed and exported for use in other humans. Those exports proved to be a source of Creutzfeldt-Jakob disease. There were clusters in Japan and Thailand in 1997. These cases are thought to have been classic sporadic Creutzfeldt-Jakob disease because there was no human-to-human transmission. But some Japanese pathologists believed very strongly that a number of those cases were actually new variant Jakob Creutzfeldt disease. The United States had its first case of BSE in a cow in December 2003; Japan had its first case also last year, as did Canada.

We recently got reports from WTO of the trade embargoes that took place for beef products last year, and it cost billions of US dollars. A prion is an agent that may be ingested via contaminated feed and it is also an agent that might be transmitted vertically from cow to calf. Control measures of slaughtering the affected animals may be reassuring for society but it is unclear if it is the most appropriate way to deal with this particular infectious agent.

There have been very stringent regulations put on the slaughter of beef since the UK experience in the mid-1990s. The regulations stipulate that you have to remove any neural tissue, which can be potentially infected, from the rest of the animal as you carry out slaughter. In addition, in the UK, they do not process downer animals, which are animals that cannot walk. In the U.S., we processed approximately 30,000 downer animals last year. Industry will continue to process downer cattle as long as they can get away with it, even though common sense tells us that it is not a very good idea. In fact, if an animal is exposed to contaminated feed, or there is a calf that gets it from maternal transmission, you may not see the clinical manifestations until they are six years old. We may be slaughtering animals before the disease has had an opportunity to manifest itself.

Another threat from beef through increased trade and the scaling up process is exemplified by the Jack-in-the-Box outbreak scenario of E. coli contaminated meat. Outbreaks of Salmonella, E. coli O157, and other enteric agents from contaminated meat coincide with this marked increase in meat trafficking worldwide.

The total amount is greater than $6 billion, and this is a major export item for the United States. Prior to the E. coli outbreak related to the Jack-in-the-Box hamburger restaurant occurred, there was consolidation of slaughterhouses in the U.S. There was also a shorter time of processing, increased burden on the animals, and “starving” of the animals which caused more shedding of bacteria into the stool. If you have one contaminated animal, the whole feedlot could get infected. Changes in production to dramatically increase yield and economize in expense predated outbreaks of emergent infections linked to meat products.

Primary prevention would be prevention of the emergence of new infections. If you look at the factors presented by the IOM, and you try to design scientific research agendas around those parameters, it is difficult. In this kind of research, you would involve agricultural scientists, microbiologist, veterinarians, business experts and economists, and legal professionals. It would be a very large project that looks at the megatrends, and how they impact at the microbiological level.

So you are back to common sense. And common sense will tell you if that if you bleed 20,000 people and put all their blood in a single unit and give it to somebody else, you have a risk of getting some infections from one of those 20,000 people. But is that enough common sense to stop doing it? Probably not. Certainly it is not going to stop the research and development of new immunologic products that can save lives.

Secondary prevention can be done by prevention of dissemination through trade; this is trade embargo. Trade embargos should be based on scientific risk assessment accepted by the WTO in its dispute resolution process. Too often trade embargos are politically based and not based on science.

Surveillance and timely control, through enhanced surveillance systems is essential. The surveillance network is uneven around the world. SALM-Net, for example, is only available in a third of the countries around the world.

WHO has their global outbreak, alert and response network (GOARN). It is a network of networks that is about 5 years old.

They diversified their sources and reports through a resolution in the world health assembly that allows investigation of reports from the Peace Corps, airlines, a broad variety of industries, and other reporting systems.

WHO and WTO are two global agencies that do not necessarily have a joint working group for health related issues.

Each organization has its own set of regulations. The one joint commission is the Codex Alimantarius which was to set food standards worldwide for distribution. This is a 20th century policy tool, which needs a radical revision to meet the realities of the 21st century.

This slide shows the disparity among countries with regards to their adoption status of WHO policies.

Countries are not mandated nor punished for not adopting WHO recommended practices to improve health. It is complex and perhaps not well understood what the barriers are to adhering to the WHO recommendations.

The WTO establishes trade rules that basically solve trade problems. The WTO is actually a relatively small international organization with a budget of about $90 million. The evolution of the trade agreements is interesting. First there was GATT (General Agreement on Tariffs and Trade) 1947, which eliminated arbitrary trade and tariffs; Codex Alimentarius 1963 (FAO/WHO); Technical barriers to trade (TBT) 1979, which dealt with food additives and pharmaceuticals. WTO was created from GATT 1994, where SPS replaced the previous agreements of TBT.

As you can see from this slide Africa is poorly represented as part of WTO whereas more developed countries have greater representation and decision-making capability. All the OEOD nations send large numbers of representatives (average is 6.8 per country).

I have been working with APEC for a number of years, trying to get them to realize that trade is intimately linked to the health of people and you cannot have one without the other. The European Union, which is a treaty-based trading bloc, has sophisticated surveillance systems for legionnaire’s and enteric diseases among all its member countries, with very standardized laboratory protocols.

Then we have something called “urgent measures” at WTO, which allows a country to say, “I have to stop this trade today. I am not sure what the risk is, but I am stopping this trade because there is an issue with this country.” These urgent measures notifications are required of WTO member countries. They have to be filed with the reason for the embargo and a list of the countries that will be impacted.

GPHIN is a software tool that was designed by the Canadians about 5 years ago. It is a 24/7 web crawler that looks for key phrases on emerging infections. That process is now responsible for more than 60% of global outbreak alerts that WHO responds to. The reporting in WHO has greatly enhanced in diversity due to GPHIN. These are outbreak reports from GPHIN for 10-day periods in 2000 from the web.

These are processed in Canada and then sent to WHO in Geneva for rumor verification and outbreak response if needed. This slide shows where the majority of the reports to WHO are coming from.

In SPS (Sanitary and Phytosanitary Measures), the emergency notifications are not linked in any way with WHO or GPHIN. They were adopted in 1995, and have been revised every so often. We created a database for WTO to look at these.

This is the number of reports that were documented through 2001 using the new reporting system..

Urgent measures can only be used when a country does not have existing legislation to allow it to embargo trade. So it is really good for new infections, such as BSE or avian flu, because nobody has ever heard of it. But if you have something like cholera, you would not necessarily have to notify through here because you have existing legislation with regards to the disease, and most countries have the ability to embargo it.

Results from 2000 and 2001 showed that 28.6% of notifications were for animal products. The most reported objective or rational for notifying was animal health (42.2%) followed by food safety (37.8%). Over 50% of the notifications reported the existence of a recommendation, standard or guideline. Foot and mouth disease was most often the nature of urgency, followed by BSE. New Zealand (19%) and the United States (15.7%) reported most frequently.

But when you look at the countries who were notifying through the system, by GDP, agricultural imports and population size, you can see that the more affluent, actively importing, larger countries are using this notification system, as you would expect.