Emerging Infections of International Public Health Importance

Objectives:

To know the definition of an emerging infection
To be familiar with the paradigm of emergence and the factors of emergence as described in the 1992 IOM Report and modified in the 2003 Report
To gain a general insight into how the factors of emergence operate globally and in globalizing disease threats

The Institute of Medicine (IOM) report of 1992 brought forward a new focus on “factors of emergence”, but the actual process of how new infections emerged started much earlier. These are factors that are related to human activities that are changing the ecology of the microbiological world. These factors are affecting humans through emerging or re-emerging infectious diseases. Deforestation, change in air quality, climate, and other “macro” changes are of concern because they are a result of human activities. In 1992, a group of eminent scientists led by Joshua Lederberg got together and noted that the epidemiology of infectious disease is also changing at the “micro” level.

There has been an updated version of this report, the 2003 Microbial Threats to Health: Emergence, Detection, and Response.

On the left are factors of emergence that were highlighted in the 1992 report: microbial adaptation and change, human demographics and behavior (e.g. crowding and urbanization) the breakdown of public health (a general phenomenon throughout the late 1970s and early 1980s), technology and industry, international travel and commerce, and economic development and land use. When the IOM study group revisited these factors in 2003, they added new factors (listed on the right). These include: human susceptibility to infection (which has changed with the HIV pandemic and the aging of the human population), climate and weather, changing ecosystems, poverty and social inequality, war and famine (which is increasing), lack of political will (which ties in with the breakdown of public health), and the intent to harm (bioterrorism).

It shows that environmental factors interact with genetic and biological factors, ecological factors, and social, political, and economic factors. The interaction between microbes and humans, resulting in infection, is shown in the center.

Globalization is defined by Merriam-Webster’s Collegiate Dictionary (2000) as: to make global, especially to make worldwide in scope or application. Thus globalization, despite what we hear about it--either vilifying it or praising it--is just a general term. The globalization of an epidemic has recently been well demonstrated with the SARS epidemic.

The disease was globalized through travel and possibly through trade. As of June 2003, over 30 countries in the world had experienced SARS, a prime example of an emerging infection.

When globalization of factors occurs, it can create a change in the microbial ecosystem, which results in unexpected outbreaks or changes in the epidemiology of infectious diseases. This is a slide from WHO that shows the number of unexpected outbreaks.

On the left you see the various dimensions, and on the right I’ve listed the relevant questions. Globalization will be the context which we will all be working in; it is an inexorable future of the human community. Due to globalization, the milieu has already changed remarkably over the last two decades, influencing the pattern of infectious diseases.

In 1950, our population size was around 2.5 billion people, so we’ve more than doubled over these past few decades. In this global urban population graph, developing countries are shown in green and the developed countries in blue.

There is a rapid increase in population in developing countries, and we’re also seeing increasing urbanization in these poor countries. These situations create the mega-cities such as Sao Paolo, Brazil and Cairo, Egypt, where there are large urban populations with poor sanitary infrastructure.

where the population is about nine million. These are recent immigrants into Lima because of insecurity in the hinterlands. As you can see, they do have electricity, but the setting is very poor, without sanitation or access to clean water.

The bars show the access to water and sanitation and indicate the gap in access in developing countries. The gap continues to grow and the belief in public health establishments internationally has been that it is too expensive to provide clean water and sanitation to developing countries.

There is a profound difference in income between the U.S., with an average income of about $20,000, and the poorest countries of the world, which have an average income per capita in the hundreds of dollars.

The difference in quality and life expectancy is even greater than the actual monetary gap. In wealthy countries there are numerous “safety nets”, such as public insurance and housing programs, which act to cushion the blows of economic downturn and natural disasters. In poor countries these safety nets do not exist, because there is not the additional financing to invest in them and due to political and social factors. There is thus uneven global access to wealth, water/sanitation, public health services, and even to information and new technologies.

There has been a remarkable increase in international travel in the past thirty years.

If you look at the projections from the airline agencies, most of the increase from here on will be in the Asia-Pacific region. There was a slight dip with 9/11, but the overall trend continues to increase. International travel is really important in the global transmission of disease.

which puts together 30 years of FAO (Food and Agriculture Organization of the United Nations) data. In the last 30 years, there have been profound changes in the volumes of goods and services crossing borders. I like to think of emerging infectious diseases as travelers on the global express. Globalization has altered and enhanced certain transmission modes, and it has also led to the actual emergence of novel human diseases.

According to the IOM, an emerging infectious disease is a newly recognized, clinically distinct infectious disease or known infectious disease whose reported incidence is increasing in a given place or among a specific population.

I research trade-related infections, which captures the whole concept of emergence. We believe that emergence is hastened when you “scale up” agricultural production or the production of human biologicals to meet international trade market demands. As you look over case studies, you see that transmission is broadened through the transportation or trade in goods. Economic impact is large due to trade disruptions. As a public health worker, I believe that effective public health measures to improve safety measures and control outbreaks are the few strategies available to mitigate such infections. If decision makers are not going to invest in public health infrastructure, we will all pay a cost. Paying attention to public health is part of the cost of conducting trade business. This has a lot of ramifications, especially in poor countries, where it is very difficult to make public health a priority or where there is more focus on trade and technology and less for sanitation and clean water.

Examples of trade related infections include: new variant Creutzfeldt Jacob disease (bovine spongiform encephalopathy, or BSE), enteric bacteria (E. Coli O157:H7, salmonella, etc), and HIV/AIDS. We recently had the mad cow disease case in Washington State. BSE is a novel infection caused by prions, and the transmission route, from food animal into human host, is also a new phenomenon. The neurologic disease has prompted trade embargoes with significant economic implications. We found that the BSE impact in 2000 was well in the billions of U.S. dollars in global trade.

Food borne diseases are also trade related infections. When you scale up the slaughtering of beef, speed up the production line, or make the feedlots larger, you enable the transmission of food borne agents such as E. Coli O157:H7. This agent was not seen as an epidemic infection until large scale human infection occurred in a large, multi-state outbreak in 1997.

Perhaps even of greater risk is the burgeoning trade in innovative products for therapeutics derived from human material. An example is the role of factor VIII production and trade of blood products in broadening the transmission of HIV/AIDS. There appears to be a risk in scaling up of production and the pooling of biological products. Scaling up may be more efficient economically but biologically it has some unknown risks, which are not factored into that decision making process.

HIV/AIDS is an instructive example in the concept of emergence. The disease was officially documented in the early 1980’s, when they had a cluster of infections that was reported in the US. But it actually started quite earlier. People working in central Africa at the time started to see changes in the pattern of infection, where people were dying of tuberculosis at a much younger age than usual. In Uganda, people were coming up with yeast pharyngitis and strange infections that had not been seen before. So actually the overall landscape of infectious diseases was changing in central Africa long before the CDC publication of AIDS in the US in the early 1980’s.

HIV/AIDS has affected every continent in the world, in a short span of about 20 years. This is really impressive because it is not a very infectious disease. You have to have sexual contact with someone or share his or her blood to get the infection. There are about 15,000 new infections a day, 95% of the cases in developing countries. 1,700 are in children under age 15 years, and about 13,000 are in persons aged 15 and 49 years of age (among this age group, about 50% are women, and 50% are 15-24 years of age), people in their most productive years of life.

It is interesting to think about the factors of HIV emergence because it tells you how these factors interplay with each other. First of all, there was an increase in urbanization in central Africa, because there was ongoing warfare and displacement of populations and troops in the area around Lake Victoria. With the movement of the troops, people fled the countryside and entered urbanized settings. In that process, people changed their lifestyle, and lost some of their traditional cultural mores, which are actually very conservative. People started having more sexual partners due to the commercial sex trade, because women and girls tried to support themselves. There was also rape, which often accompanies armed conflict. Thus, the increase in the sex trade in urban areas (in addition to the increase in drug trade) facilitated the direct transmission of HIV/AIDS.

Global travel was also a route of transmission for the HIV epidemic. If you have read And the Band Played On, by Randy Shilts, you know about the flight attendant who infected people all over the Caribbean and Latin America in the early 1980’s. The sex trade in Thailand has also been important and when Japan claimed in 1990 that the majority of the HIV infection in that country was due to the importation of infected blood products from the US, this claim was greeted by some in the international community with skepticism. Tourists or business travelers who became infected while traveling may have infected their partners in their own countries.

In addition, the technology of clotting factor concentrate production and trade is really interesting. The U.S. blood supply was infected with HIV between 1980 at least up to about 1985 (when we could test for HIV and systematically exclude those with HIV infection from our blood supply). The US was also the major producers of factor VIII concentrate, where we fractionated the blood to create a clotting factor from tens of thousands of units pooled from donors. This was a great innovation for medicine, where we could lyophilize or freeze-dry the product so we could trade internationally.

All of this technological innovation occurred concurrently with the emergence of HIV. As a result, in Latin America (where I worked in the beginning of the HIV/AIDS epidemic), the major route of introduction was, in fact, through importation of infected blood products. In Costa Rica and some other middle income Latin American countries, hemophiliacs were some of the first to become infected. If you read Canada’s Kreever report, which was a comprehensive national commission report, they outline the HIV infection risks to hemophiliacs. They also report the compensation that governments have provided to their hemophiliac population because they became infected via a contaminated product. According to the report, the majority of Japanese hemophiliacs are also thought to have been infected during 1983-1985 by non-heat-treated factor concentrates imported from the US. It is only very recently that American hemophiliacs received any compensation in the United States.

Another aspect of the HIV/AIDS epidemic is the greatly increased mortality from the disease in poor countries. Because the innovations in treatments are not shared equally globally, developing countries have a much greater rate of mortality from HIV. If you have HIV/AIDS in the U.S., you have access to anti-retroviral treatment, which generally allows you to extend your life. If you’re HIV-infected in sub-Saharan Africa, however, it’s very difficult to get access to anti-retroviral treatment because it is expensive and requires the curative services infrastructure. The overlay of the global epidemic on poor resource base countries enhanced the mortality in these developing regions. Once again, we hear the same thing we hear about improving sanitation in developing countries, that it just costs too much. When I was in the Central African Republic about five years ago, there was a funeral every day for someone with HIV/AIDS—this has enormous societal impacts.

Interesting questions to ask are: how did globalization of the market contribute to HIV transmission? Did “scaling up” of production have a role in enhancing transmission? This slide shows the U.S. export of blood fractions and modified immunological products between 1989 and 2000.

This is a continued area of research and export by pharmaceutical companies in the U.S. and other developed countries. Will there be another HIV? Will we find prions in the blood supply? In the UK, they do screen blood donations for prion disease by separating lymphocytes from the blood supply at great cost. In the US, living in the UK during years of BSE transmission is a factor for exclusion from blood donation.

What did we see with HIV/AIDS? Human demographics and behaviors were a part of emergence due to urbanization. There was breakdown of public health with war and destabilization, and it was difficult to get prevention in the form of information, condoms, and counseling and testing in poor economies. Technology and industry, along with international commerce, were central to the emergence as well.

Climate change is a new factor within the 2003 report. Its novelty is puzzling in that a number of climate research groups, including those at University of Washington, have been actively describing the phenomenon of global warming. But what this climate change might mean for infectious disease is a complex question, with different answers for different locations. Global warming and climate change are a real phenomenon. The discussion we currently get on a political level regarding this question depends on your perspective. You can go back thousands of years and say we have had ice ages and periods of global warming, but those changes were associated with massive extinctions. It depends on what you think is an acceptable future for human beings.

This slide by NOAA shows carbon dioxide concentrations from ice cores from 1734 to 1983.

Carbon dioxide is one of the green house gases as it traps the sun’s rays and hastens global warming through the green house effect. Since the Industrial Revolution, there has been a remarkable increase in greenhouse gases, correlated to an increase in the human population, and scientists have documented this back to 8,000 BC through “paleoclimate” studies. This slide shows human activities (note most are the same factors of infectious disease emergence), with the percent of contribution towards global warming.

This is the average temperature of the atmosphere in the last 130 years, up to 1990.

There is a general increase in the mean temperatures. This is the U.S. contribution of carbon dioxide.

Each year, 20 tons of carbon in the form of carbon dioxide, the mass of four adult elephants, are added to the atmosphere for each person in the U.S. We are the major consumers of energy and the major producers of carbon dioxide in the world. On this slide you see the major sources of carbon dioxide: power plants, factories, homes, vehicles, and forest fires.

This slide shows the concentrations of atmospheric carbon dioxide in Hawaii, 1958 to 1991.

The U.S. has the largest emission levels, with five metric tons of carbon per person, while India has the lowest, with less than 1 metric ton of carbon per person.

This is the argument for long-term variations in global temperatures and its relation to atmospheric carbon dioxide.

This goes back years before present, back to 160,000 years, and you can see that in the recent time period, we’ve had a major rise in both the temperature and carbon dioxide. The data comes from paleoclimate research, done with ice core measurement of carbon dioxide and also from some temperature records, which were fairly accurate in the 20th century. Even in the 19th century, people were measuring temperature pretty accurately in a number of observatories. Tree rings are also used; you can count tree ring growth and the distance between the rings and estimate what the ambient temperature must have been for that tree to grow that distance in its diameter.

Here is the Pacific Northwest, and I wanted to include this because we have pretty good measurements .

We have 76 precipitation stations in the state. Most stations have become wetter with an average increase of 2.9 inches over the last year. The positive trends are shown here as solid dots and negative trends as white dots, and we have mostly positive trends. We have been getting wetter for at least two decades in our state.

Similarly, temperature trends are shown as positive (solid) or negative (white).

We have 113 stations in the Pacific Northwest with very long records of temperature, with a general warming trend. We have regional average warming of 1.5 F per century in the last century.

Most of the climate work is done on a “macro” scale, as it’s very hard to make regional or local projections. The trend has been an increase over the last 100 years of 1.5 degrees and the projection is that we will see an increasing warmer trend with more wet weather. We are going to see a longer growing season, increased winter flooding and landslides, and reduced snow packs (good for transportation, bad for summer water supply). Higher in-stream and coastal ocean temperatures and reduced coastal upwelling will mean generally less favorable conditions for salmon and other cold-water species. We can expect increasing algal blooms that will lead to closing of shellfish beds because of domoic acid and other threats to human health.

What does it all mean for infectious diseases? First, warmer climates tend to be good for bacterial infections and those of you who have worked in the tropics are aware of how staph and strep thrive in those settings. Warmer weather will probably be better for vectors and the introduction of new illnesses as well. When you look at global climate change, the Northwest will only be moderately affected, but low-lying areas in South and Souteast Asia will be severely affected. There may come a point when places may become uninhabitable. The Pacific Northwest has had a lot of in-migration because of war and conflict elsewhere. We will continue to be a haven for people seeking quality of life and economic opportunity, and we may begin to see “climate refugees” from other areas in the country and from overseas. As we begin to accommodate those new citizens, they will introduce new infections and disease with them.

We have seen a comeback by vector-borne diseases internationally. Although not all mosquitoes are vectors of infectious agents, the range of mosquitoes has been increasing in the last decade. This is Aedes aegypti, the major vector for yellow fever and dengue.

This slide shows you the distribution of Aedes aegypti in the Americas and in the Carribbean, 1930s, 1970s, and 1990s.

In the 1970s, there was a mosquito eradication program, which was based largely on DDT. That eradication program was run by the Pan-American Health Organization (PAHO) as subscribed by all the countries except the U.S. in this hemisphere. It really had an impact between the 1930 and the 1970s, as you can see if you look at the distribution of this vector. The program was disbanded in the late 1970s; it didn’t take long for that vector to re-inhabit its entire previous zone.

One of the major risks we’re struggling with is urbanized yellow fever (e.g., in Lima, Peru), which is really a danger because the vaccine is not generalized. We have a generalization of the factors of emergence, the presence of risk and the absence of generalized prevention.

Dengue has emerged in all tropical and subtropical zones in the last 20 years, a remarkable growth.

This is the world distribution of dengue, with the areas infested with Aedes aegypti shown in yellow and Aedes aegypti and dengue activity shown in red. There are four serotypes of dengue virus and we used to see one serotype per tropical zone. If you went to the Caribbean 20 years ago, you would see only one type of dengue. But now you have all four serotypes circulating in all tropical zones. This has been primarily through human travel, where infected humans have been moving from zone to zone and those serotypes have become “hyper endemic” for dengue.

These are worldwide vector-borne parasitic diseases, vector-borne bacterial diseases and arboviral diseases.

The take home message from these three slides would be that there are many different types of pathogens which are transmitted through vectors. So as you get warmer, wetter weather, with the intrusion of new vectors, you will see a broad variety of disease, not simply a select few.

West Nile Virus is a novel infection in this hemisphere, but it is an old infection from the other hemisphere. It was always endemic in the Ukraine, Israel, and in the Black Sea region. West Nile Virus is believed to have arrived in this hemisphere when a bird was brought into NYC by an air traveler that caused the first NYC outbreak. When they first started counting West Nile Virus in NYC, they were afraid it was a bioterrorist event and they genotyped the sample and found that it was Israeli in origin. As in their endemic region, birds were dying and mosquitoes were transmitting the disease, but the host range for vertebrates in this hemisphere was unknown. Whenever an agent is introduced in a new environment, you do not know for sure what hosts will be affected, and this has strong implications for emerging, introduced infections. You know what it used to infect in the endemic region, but it is possible that it will infect a whole new range of hosts. In fact, we have seen the illness in humans, horses, cats, dogs, alligators, etc. It appears to have a broad range of vertebrate hosts here.

In summary, we have the factors of emergence being globalized, but the resource base remaining uneven, where access to housing, economic livelihood, clean water and sanitation has not changed much globally in the last decade. There is also no globalization of effective public health prevention or response to epidemics. But I think the ray of hope is that you do have increased global awareness of epidemics, because you have globalization of telecommunications and information. At the very least, we know what is occurring more accurately than we ever have before. You know, for example, that SARS emerged again in China, or that there was BSE in a cow in Washington. Such information reaches the rest of the world rapidly now. We know about these things in a timely way, even about Ebola outbreaks in remote parts of Africa, and so we have more time for public health preparedness and international response. The problem, however, is that it is really not possible to respond unless you have on-site response infrastructure and strategy. Unless you can investigate your outbreaks locally, you are not going to mitigate these problems.

So what are some of the priorities for the health in the new millennium? (These are just part of my own thinking).