Emerging Infections of International Public Health Importance

Objectives:

Understand the importance of epidemic vector-borne diseases as emerging public health, social, and economic problems at the beginning of the 21st century
Understand why vector-borne diseases that were effectively controlled in by the 1970’s reemerged to become major epidemic diseases in the waning years of the 20th century
Know what will be required to reverse the trend of emergent/resurgent epidemic vector-borne infectious diseases

This lecture will give an overview of the problem with vector borne diseases. The discussion will focus on 4 case studies to illustrate what is occurring with vector-borne diseases worldwide.

Since man evolved vector borne diseases have been the scourge of mankind. Until the middle of the 20th century, vector borne diseases were probably the most important public health problems we faced in the world. In the 1960’s effective insecticides and improved treatment strategies improved the control of these diseases. Since the 1980’s we have seen a dramatic reemergence of vector-borne diseases along with other infectious agents. The case studies I will present for this topic will be plague, West Nile virus, Dengue virus and Yellow fever virus.

These 2 maps show the worldwide outbreaks of vector-borne parasitic and bacterial illnesses that occurred in the last decade of the 20th century.

This map lists the recent arboviral disease outbreaks in the past several years. These diseases are transmitted by predominately mosquitoes or ticks. There have been multiple outbreaks and epidemics of dengue which is not well illustrated on this slide.

Plague is the original emerging infectious disease that has caused several pandemic throughout history. Yersinia pestis, the bacteria that causes plague was responsible for killing approximately one quarter of the European population in the mid 1300’s thereby earning its name the Black Death. The last pandemic of plague began at the end of the 19th century and continued into the first part of the 20th century. It was this pandemic that established the current global distribution of enzootic plague. Plague was thought to be introduced into the United States at the turn of the 20th century by ships carrying infected fleas on rodents.

Plague exists naturally in a complex enzootic cycle. This cycle involves the fleas and small rodents such as squirrels, marmots, groundhogs, and urban rats. Humans tend to be come infected accidentally by being bitten by infected fleas from these affected animals. Cats can also get plague from these same rodent species and are a good sentinel system for surveillance. Plague is usually not spread from human to human unless it progresses to the pneumonic stage where the bacteria are transmitted by respiratory droplets. The pneumonic form of plague is the most dangerous and one of concern for bioterrorism.

In 1994, there were suspected cases of pneumonic plague in the Surat region of Gujarat state in Western India. My office received a call from an infectious disease specialist in the New Delhi regional office of the WHO requesting reagents for plague testing. He said they were urgently needed because of a suspected outbreak of pneumonic plague in Surat. When these samples were first tested at the local and national laboratories in India, the results were equivocal. No one could provide a definitive diagnosis on these patients but clinically the presentation was consistent with the pneumonic form of plague.

It is important to know the history of plague in India in order to understand why this recent outbreak was concerning. Plague was introduced in India before 1900, and between then and 1925, approximately 12 million deaths associated with plague occurred throughout India. The Indian health service implemented a very effective plague control program and by the 1950’s had effectively controlled plague on the Indian subcontinent. The last identified case of human plague was reported in 1966. A common perception was that plague had been eradicated, and the Indian government essentially disbanded the plague control program. There was very little research, no diagnostic capability and little epidemiologic capability for this disease. This was the current state of affairs when the suspected cases occurred in 1994 in Surat. In retrospect, plague eradication is near impossible due to the zoonotic reservoir of this disease. Retrospective review after the Surat incident did reveal small outbreaks of bubonic plague in India in the 1980’s and early 1990’s.

When word of a possible case of pneumonic plague in Surat hit the news, it created a panic. In the first 2 weeks of October approximately 500,000 people fled the city of Surat and went to other major cities in India as well as other countries.

This slide shows the potential spread of pneumonic plague within and outside of India.

The Division of Vector-Borne Diseases in Fort Collins, Colorado became involved in this potential outbreak because it was the only functional WHO Collaborating Center for Reference and Research on plague in the world at the time. In collaboration with WHO, the International Health Regulations were implemented for the first time in over 30 years. Plague reagents were sent to Indian laboratories and to 14 other countries to help in the diagnosis of plague. Educational materials for accurate diagnosis, treatment and testing were also provided. Surveillance was intensified in the United States and globally. We identified 13 persons with potential plague entering the United States; of these 13 none had plague, 2 had malaria, one had dengue and one had typhoid. In retrospect, there was evidence of a small, limited outbreak of pneumonic plague in Surat with less than 50 cases, but this posed little public health risk. There was no evidence of person to person transmission in any of the major Indian cities. There were no confirmed cases of plague in air travelers outside of India related to this event.

Lack of adequate diagnostics and epidemiologic capabilities led to over reporting of cases, lack of confidence in the government health agencies, and ultimately to public panic. This outbreak cost the Indian economy approximately 2-3 billion dollars. Other nations suffered economic loss as a result of reduced trade, travel and surveillance of disease costs. The total global estimated cost of these 50 cases was around 5-6 billion dollars. This event underscores the importance of international infectious disease surveillance.

West Nile virus (WNV) was first introduced into the United States in the summer of 1999. West Nile virus is a member of the Japanese Encephalitis Serocomplex of flaviviruses. This complex of viruses has a worldwide distribution.

West Nile virus is an African virus that was isolated in Uganda in 1937 and had been limited to Africa, West Asia, Central Asia and some Mediterranean countries.

WNV exists naturally in a silent cycle involving the Culex mosquitoes and a variety of birds. It usually occurs in rural areas which are unknown to most people in that area. Normally in the bird-mosquito-bird cycle the birds do not die.

Through environmental changes and land use humans invade these areas and become infected. Horses and other domestic animals can also become incidentally infected.

The hallmark of the disease is a severe neurologic disease with encephalitis. It has a case fatality rate of 10-15 percent.

In 1999, the WNV was introduced into the United States. There were 62 cases of severe neurological disease with 7 fatalities.

There was also a significant die off of birds including crows, and blue jays. This differed from the previous known cycle of WNV in the African continent of rare bird deaths. We have isolated the virus from over 162 species of native North American birds.

In 1999, the geographic distribution of WNV cases in humans and birds was localized to 4 states: New York, New Jersey, Maryland, and Connecticut. In 2000, it began to spread into the northeastern states and into the south.

The virus has continued to spread from 2000-2002 to include most of the United States.
(Editors note: since this lecture and slide was made WNV has now been isolated either in humans or animals/birds in the entire lower 48 United States with the exception of Arizona, Nevada, Utah, Idaho and Oregon-see www.cdc.gov)

The number of mammals and other non-avian vertebrate species (total 19 species) affected, and the number of affected mosquito species (37 species), suggests that there may be separate mammal cycles. Depending on the mammal affected, this can put humans at more or less risk of infection. The expectation is that this will continue to spread westward and into Central and South America.

This schematic of the phylogenetic tree for WNV looks at the envelope gene. You can see that the virus currently circulating in the United States is similar to the virus that was present in the Middle East. How the virus entered the U.S. is not clear but there are several possibilities. An individual infected with the virus in the Middle East could have come to the United States where they were fed on by local mosquitoes. Other hypotheses of introduction include import of an infected bird or other animal, the incidental import of infected mosquitoes or even that it was introduced on purpose for bioterrorism. The current data however, do not support this latter hypothesis.

We have developed guidelines for surveillance, prevention and control of West Nile virus in the United States (this is available on line at the CDC website). Our surveillance focus is on dead birds. This is a very sensitive method for monitoring activity in an area. The second surveillance method is sentinel animals including chickens and equines. Chickens have been used for monitoring related flaviviruses, St. Louis encephalitis and western equine encephalitis. A third surveillance focus is on mosquitoes and the wild bird populations. The last surveillance tool is monitoring neurologic disease in the human population which is based on the classic passive case reporting.

This new disease has tremendous implications for public and animal health. Continued spread to new areas usually implies a new mosquito vector and a new set of reservoir hosts. Control of this disease will be difficult. Current evidence suggest this disease has been introduced into the Caribbean, and possibly into Central and South America, where there will be the additional challenge of distinguishing this virus from the existing flaviviruses dengue and yellow fever. We will need new diagnostic testing to help us in this area.

Dengue virus is caused by 4 viruses (DEN-1, DEN-2, DEN-3, DEN-4) which are closely related and have cross reactivity in serologic tests. There is no cross protective immunity among the different types. A person who lives in an endemic area can have up to 4 infections of dengue virus.

The transmission cycle of dengue is complex. The primitive cycle is an enzootic cycle where the virus cycles between non-human primates and canopy dwelling mosquitoes. Periodically it comes out into a rural epidemic cycle where it is transmitted by a different group of mosquitoes. The more important cycle is the urban endemic-epidemic cycle where this virus has adapted to humans. This is a unique feature among the arboviruses. This allows the virus to be maintained in an environment without needing an animal reservoir for its survival.

The primary vector for dengue virus in this urban cycle is the Aedes aegypti mosquito seen in this slide.

This mosquito is highly domesticated and prefers to feed on humans and live in the human environment. This allows for rapid dissemination of infection within a household and community.

This slide shows the WHO reported cases of dengue and dengue hemorrhagic fever from 1955 to 1999. There had been a resurgence of this disease in the 1970’s mostly as a result of discontinuing the mosquito control programs, and because of demographic and societal changes in the past 30 years.

If we look at this slide we can see even better the magnitude of the increase in cases. These are only cases of dengue hemorrhagic fever the more severe and fatal form of the disease. For every one case of dengue hemorrhagic fever there are usually 100-200 cases of dengue fever. This increase correlates with lack of effective vector control programs, increasing frequency of dengue virus introductions, and the huge increase in human populations susceptible to this disease.

This slides depicts the distribution of the vector for dengue, Aedes aegypti in the Americas. It is easy to see that with the expansion of the vector comes a return of the disease that had almost been eradicated in 1970.

There are approximately 2 1/2 to 3 billion people living in areas of risk for Dengue. Every year we estimate there are between 50 and 100 million cases of Dengue fever and several hundred thousand cases of Dengue Hemorrhagic fever depending on epidemic activity that year. Some years there will be more, some less. Even Hawaii, which hasn't had an epidemic in 56 years, has been affected.

This map of Maui and the Hawaiian islands that shows where cases of dengue have occurred in 2001. This is the first time in 56 years that Hawaii has had an epidemic and dengue. We think dengue was introduced into Maui, Hawaii by students who went to Tahiti on an exchange program in the spring of 2001. During that time there was a large dengue outbreak in Tahiti. Later in the summer of 2001, a musical group from Tahiti came to Hana, Maui for a series of concerts. We think these 2 events brought dengue to Hawaii. The area of Maui originally affected has a high population of Aedes albopictus mosquitos, one of the known common vectors for dengue. Aedes alpopictus however is not a very efficient vector which is why an explosive dengue epidemic was not seen in Hawaii.

The etiology of Dengue Hemorrhagic fever (DHF) relates to hyperendemicity. Hyperendemicity is the co-circulation of all 4 dengue viruses (DEN1-DEN4) in the same area. There are 2 theories for the pathogenesis, secondary infection or immune and virus or virulence. If you have multiple viruses circulating in a community, you have a greater probability of severe disease. I think both theories have validity and are not mutually exclusive.

These 2 slides show the change from 1970 to 2003 of the geographic distribution of the four serotypes of dengue virus. In 1970 most places had none or only one or in some cases 2 serotypes of dengue. Compared to 2003, the whole of the tropical world is hyperendemic.

This slide depicts the Iceberg concept of Dengue/DHF, where only the tip that projects out of the water represents DHF. In 1970 (iceberg on the left) the amount of dengue transmission was small compared to what we have in 2003 (iceberg on right). In order to control this disease we need to reduce the transmission back to what it was in the 1960’s.

Yellow fever is the last case study. Like dengue this is an old disease that was introduced into the American region in the 1600’s with the slave trade. The first human epidemic of yellow fever occurred in the 1640’s. Yellow fever is also primarily transmitted by Aedes aegypti mosquitoes in the urban environment. It caused devastating epidemics in the American region especially in urban areas.

This slide shows the world distribution of Yellow fever in 2002; it has a fairly limited global distribution, tropical South America and sub-Saharan Africa. In the Amazon basin of South America, yellow fever also exists in a primitive forest cycle. Our concern is that with the reinvasion of urban centers of Central and South America by Aedes aegypti, urban epidemics of yellow fever will again occur in the Americas..

This just shows the trends of Yellow fever reported by WHO for the past 50 years. The majority of the increase in cases is seen in Africa primarily because of the vector control programs in the Americas in the 1950s and 1960s. The concern is that now there are 150-300 million people that are susceptible to yellow fever who live in urban areas infested with Aedes aegypti in this region, and that urban epidemics may occur.

This slide highlights the area at high risk for yellow fever exposure, most of these urban cities have populations of more than 1 million, the potential for a large scale epidemic is great. Since dengue is more common an infection, the concern is that health care workers will misdiagnose yellow fever as dengue, leptospirosis, malaria, other hemorrhagic viruses and the transmission will continue.

This slide depicts the potential for the global spread of urban yellow fever. The largest area of concern is for Asia which has both a significant problem with dengue as well as the Aedes vectors for transmission of yellow fever. Asia also has the largest world population, over 2 billion people, who are at risk for this disease with no prior immunity.

The United States also has some risk and we have seen imported cases of Yellow fever, Dengue, malaria, as well as newer exotic mosquito vectors such as Aedes albopictus, Ochlerolatus bahamensis, Ochlerolatus togol, and Ochlerolatus japonicus. The exotic arboviral diseases that could pose a significant threat in the United States include Rift Valley fever, Japanese encephalitis, Venezuelan equine encephalitis, Dengue fever and Yellow fever.

Why have we seen such a dramatic resurgence of global vector borne diseases in the last 20-30 years.

To reverse the current trend in emergence and reemergence of the vector borne diseases we need to concentrate on the contributing factors we have just listed.

One current strategy that is being adopted is an integrative disease prevention program which includes active surveillance, strong emergency response component, a medical education program for physicians and nurses, and a community based integrated mosquito control program.

In summary, vector borne diseases have continued to emerge and reemerge in the past 20-30 years. Multiple factors have contributed to this increase. To control this rising problem we will need to reverse the current trends and use a more integrated prevention approach.

Study Questions:

Describe why vector-borne diseases resurged so dramatically in the last 20 years.
Describe what must be done to reverse the trend of emergence of epidemic vector-borne infectious diseases in the 21st century.
Name a vector-borne disease that has potential for causing a global public health emergency. Describe why.