ROBERT E. SHOPE
Yale Arbovirus Research Unit
New Haven, CT 06510
It has long been known that infectious diseases are indigenous to one or another part of the globe and can be spread. The historic spread of human infectious diseases includes syphilis to Europe in 1494, possibly from the Americas and resulting in rapid venereal spread through Europe; smallpox from Europe in 1518 to the New World where it virtually annihilated the Aztec empire; cholera from Asia to Europe, Africa, and sometimes the Americas in seven pandemics since 1800 , and most recently AIDS, probably from Africa to N. America and then throughout the world in the last two decades.
As far as we know, global climate change was not responsible for spread of these diseases in the past. More likely they spread as a result of human social and behavioral change. Nevertheless, spread of a very special set of diseases is apt to occur with climate change. These are diseases transmitted by arthropods---mosquitoes, sand flies, midges, and ticks---and other diseases transmitted from animals to people, which we call zoonoses. Climate change may also affect diseases spread by snails or by water, such as schistosomiasis and cholera, because changes in rainfall will have an impact on flow of rivers and levels of lakes; melting of polar ice may raise the sea level and inundate coastal and delta regions.
The infections that will spread with climate change have some commonalities.  They are focal, and their distribution is limited by the ecology of their reservoir, be it arthropod, snail, or water. They usually have a two- or three-host life cycle, meaning that in addition to infecting people, they infect a vector and frequently also a wild vertebrate animal host. Either the vector or the host, or both, are the reservoir. The range of the reservoir is delineated by temperature and sometimes water. In order to survive global climate change (and some of these infectious agents will not survive) the agents will need to have reservoirs that will survive; they will probably survive by moving in a polar direction, north in the Northern Hemisphere, in order to find a temperature range that is ecologically permissive. If the agent and reservoir are successful in the newly warmer climate, the agent can be expected to multiply more rapidly, and if the reservoir is an arthropod or snail, it too will develop more rapidly (it may also have a shorter life). It will be obvious to the reader, that the reservoir must survive the change, the agent must be able to move if the reservoir is translocated, and the reservoir must be able to adapt to conditions in the new ecologic zone.
Among the diseases that have been predicted to be more severe or move into more populated areas of North America are the mosquito-borne viral diseases dengue, St. Louis encephalitis, and yellow fever; the sand fly-borne protozoal disease leishmaniasis; the water-associated disease cholera; and the bat-borne vampire bat rabies. [2, 3] This chapter will illustrate how one of these, dengue, may spread, and it will suggest how some other diseases of Africa and Asia may extend their geographic range and cause more serious human illness than currently encountered.
Dengue is a human disease caused by any one of four serotypes of dengue virus. Dengue fever is a common affliction throughout the tropics, characterized by fever, rash, muscle and joint pains, and severe prostration especially in adults, but usually the disease is followed by complete recovery. Dengue hemorrhagic fever is a severe form found usually in children and most commonly in Asia. It is complicated by hemorrhage, shock and sometimes death. Dengue hemorrhagic fever cases in Thailand in 1990 numbered more than 300,000.(4) Dengue hemorrhagic fever usually occurs in children having a second infection with a serotype different from the first infecting virus. Small amounts of residual antibody after the first infection, enhance the infectivity of the second dengue virus and hence, for reasons that are not completely understood, enhance the severity of the second infection. Dengue virus is in the family Flaviviridae which in addition to dengue is comprised of yellow fever, Japanese encephalitis and viruses causing other serious arthropod-borne diseases of people and domestic animals.
Dengue viruses are transmitted by mosquitoes. The virus replicates in the mosquito, a process that takes one to two weeks from the time a mosquito imbibes infected human blood until the virus reaches the salivary gland of the mosquito and replicates to titer high enough to be transmitted. This incubation period in the mosquito is shorter if the ambient temperature is warmer. The most common vector is Ae. aegypti, a mosquito that is domesticated and breeds in and around human dwellings; in flower pots, water storage jars, cisterns, metal cans, discarded tires, and any other fresh water containers that people leave standing. The mosquito does not survive freezing weather and, thus, is primarily a tropical vector. Historically, Ae. aegypti was transported long distances in drinking water aboard sailing ships. One of the classic descriptions of a dengue epidemic is that of Benjamin Rush in Philadelphia in 1780. The mosquito and dengue virus were imported to Philadelphia during the summer, but the mosquito did not live over the winter and the disease disappeared. Sporadic cases of dengue continue to occur in the northern U.S. in travellers from the tropics, but the virus is not now transmitted outside of the tropics and subtropics because of the lack of the vector.
What is it about dengue that makes it so likely to spread with global climate change? The dengue viruses are distributed wherever Ae. aegypti mosquitoes occur. The mosquito lives in the tropics wherever people live. The mosquito thrives in areas of high rainfall, but it also paradoxically thrives in desert areas because people often provide water containers for breeding. Ae. aegypti does not stand freezing weather, thus, it is limited to tropical and subtropical regions. Two aspects of global warming are particularly worrisome. Firstly, the warming is expected to be greater in temperate zones than in the tropics, and secondly, the warming is expected to be more marked at night than during the day. Both conditions favor the spread of the mosquito into the temperate areas. The warming at night is especially favorable to Ae. aegypti because it is the extreme temperature, i.e. freezing which occurs at night, that is most deleterious to the mosquito.
Another vector of dengue virus, Ae. albopictus, is widely distributed in Asia. This species has evolved in its more northerly distribution in Asia in a manner that permits it to withstand freezing. The northern form of the mosquito is triggered by shortened periods of sunlight to enter diapause, a physiological state of the egg that makes the egg resist cold temperature and delays hatching until the spring. Thus, the mosquito is able to survive freezing. Ae. albopictus was introduced during the 1980's into the Americas and now represents a potential risk for transmission of dengue in the United States. The mosquito that established itself in the United States is the diapausing form, and it appears to have adapted well to the more northern states. Now in both Asia and North America, there is the potential with global climate change for the vectors of dengue to move further north, perhaps much further north than today.
The risk of explosive epidemics is enhanced because of two other properties of this vector-virus relationship. Firstly, within limits dengue viruses multiply more rapidly in mosquitoes at high temperatures than at low ones. Secondly, the mosquito also develops more rapidly at high temperatures than at low ones. This combination is conducive to a very short incubation period in the mosquito and rapid mosquito population increase. A short incubation period in the mosquito along with rapid population increase in turn can lead to more rapid, and sometimes explosive transmission in the human population. This prediction, however, should be accompanied by a caution. Warmer temperatures also lead to a shorter life span of the mosquito, and shorter life means less time to transmit the virus to another person. Some scientists hold that the short life span will favor less transmission even though the amplification of dengue virus will proceed faster at high temperatures. It remains to be seen which parameter will prevail.
A further concern is the rapid increase of the human population and the continued growth of cities in the twenty-first century. As the earth warms, and if conditions in the vast sparsely inhabited land masses in Canada, Alaska, and Siberia become more suitable for human dwelling, it is possible that new cities will spring up. The Aedes mosquitoes and dengue could follow if conditions are favorable.
Schistosomiasis is a parasitic disease caused by trematodes of three major species, Schistosoma mansoni, S. haematobium, and S. japonicum. The disease afflicts about 600,000,000 people in 79 countries of Africa, South America, and eastern Asia.  When first infected the patient may be acutely ill with skin rash or fever, abdominal pain, and malaise. Later the chronic phase manifests itself as urinary tract, liver, lung, or intestinal disease and varies according to the species of schistosome. Patients are chronically ill and after several years, the body's reaction to schistosomiasis may lead to death, usually by urinary tract obstruction, carcinoma of the bladder, portal or pulmonary hypertension, or some complication of these.
The life cycle of the parasite is complex involving snails, water, and human beings. The cycle is susceptible to environmental change, especially in water-associated stages. The cercariae (larvae) emerge from infected snails into water. These cercariae penetrate the intact human skin, and migrate through the tissues to find target sites in the human host. There they mature into adult worms, mate, and the female deposits eggs in the venous systems of the bladder or liver. The eggs migrate to the ureters or intestines, are excreted in urine or feces, and hatch in the water as miracidia that swim to find and enter a snail host. In the snail, the parasite undergoes two generations of sporocysts and emerges as the cercariae.
The snail hosts of schistosomes differ for each of the major species of parasite. The host of S. hematobium is the genus Bulinus, that of S. mansoni is Biomphalaria, and that of S. japonicum is Oncomelania. The ecology of each genus of the parasite and snail differs, but some generalities hold. A major determinant of schistosome distribution is the distribution of the snail host. Snail populations are dependent on temperature, water, and water currents. The ecological conditions needed by snails for survival have been carefully studied. Snails of the species transmitting S. mansoni in Brazil had an optimum temperature of 25deg. to 28deg.C and lived at 7deg.C for several days; they died after 2 hours at 42deg.C. The shedding of cercariae stopped below 13deg.C and above 41deg.C. Most of these snails died when removed from water, although a few survived if humidity was high enough.  Snails of the species transmitting S. japonicum in contrast, survived dessication for several weeks, and died at temperatures above 30deg.C and below 0 to -5deg.C.  The optimum temperature of snail reproduction was 26deg.C. These studies established that ambient temperature is an important limiting factor of the survival of snails and of the shedding of cercariae.
Aquatic birds have been implicated in the distribution of Biomphalaria and Bulinus snails to new areas. This accidental airborne transport is very effective in seeding new sites.  In addition, these snails are hermaphroditic in nature and can self-fertilize and increase in numbers rapidly, once transported. Thus, the major question associated with global climate change is not how the snail will be transported and established, but rather, whether the temperature, water, and other conditions to support the snail and the schistosome parasite are adequate.
If the temperature in the tropics of Africa and South America rises sufficiently, it is likely that some of the present foci of schistosomiasis will be too hot to support the parasite. Areas of Africa on the east and west coasts already have high temperatures, and it has been suggested that this is the reason why Biomphalaria has not colonized these zones.  On the other hand, other areas in Europe, Asia, and the Americas, now too cold to support the host snails, can be expected in the future to be favorable ecologically for schistosomiasis.
Rift Valley fever is a disease with a track record of appearing in 1977 in epidemic form in Egypt where no trace of prior infection could be found, and again in 1987 in Mauritania of causing an epidemic where it had previously caused only inapparent infections. These two epidemics accompanied ecological change following the completion of dams; such ecological change may differ from that of global climate change, nevertheless I believe this dramatic disease is a prime candidate to be affected by global climate change.
The 1987 epidemic in southern Mauritania confirmed that Rift Valley fever had potential to cause serious human disease. [10-12] About 43% of cases presented with fever without life-threatening disease, but an additional 48% had jaundice and of these, 18% presented with hemorrhage. About half of these latter patients died. Another 5% had encephalitis and about 2% had retinitis that led to blindness. The disease also affects sheep, cattle, and other domestic animals causing abortion and fatal hepatitis. Mortality of nearly 100% is sometimes observed in newborn sheep.
Rift Valley fever is caused by a virus in the family Bunyaviridae, transmitted by mosquitoes and also through inhalation of aerosol from the infected blood and afterbirths of sick animals. The disease derives its name from the historic epizootics that occurred periodically after 1910 in sheep and cattle in Africa's Rift Valley that extends from South Africa through Tanzania, Kenya, Uganda, and Sudan. In East and South Africa, the disease appears in epizootics in the grasslands. These outbreaks follow heavy rains and the consequent emergence of large numbers of Aedes and Culex mosquitoes. Until 1977 it had never been reported north of the Sahara.
In 1977, there was an explosive outbreak in the Nile delta of Egypt. An estimated 200,000 human cases were observed with at least 598 deaths.  Studies of human sera collected prior to 1977 showed that this was a new disease to Egypt. Since the infection is ecologically restricted, its appearance in Egypt is believed to be a consequence of ecological change, perhaps linked to the building of the Aswan High Dam and inundation of 800,000 hectares for agricultural development between 1970 and 1977. There is no doubt that the virus was transported, probably from the Sudan where an epizootic was recorded in 1976. It could have been transported as a viremic animal or human, or an infected insect blown northward by the wind. 
Curiously, Rift Valley fever failed to establish itself in Egypt. The epidemic and epizootic swept through Egypt during 1977 and 1978, with sporadic infections detected until 1980, then there was no more evidence of the virus. The reservoir of the Rift Valley fever virus in sub-Saharan Africa has been a mystery. Recently, scientists believe they have discovered the secret through studies in Kenya. After heavy rains, epizootics start, involving sheep and cattle pastured in the grasslands. The rains flood large depressions, called "dambos" and from these depressions hatch massive number of Aedes mosquitoes. Larvae and pupae of Aedes lineatopennis collected in flooded dambos were raised to adults; both male and female adults were found infected with Rift Valley fever virus.  The most likely explanation for this finding is that the virus is in the mosquito egg and is passaged transovarially to the emerging mosquito. The mosquito itself appears to be the reservoir and, since rain is needed to hatch the eggs and heavy rain only occurs every few years, this phenomenon may explain the long periods between epizootics. It also offers an explanation why Rift Valley fever was not established permanently in Egypt. Possibly an appropriate mosquito capable of transovarial transmission is missing.
The 1987 epidemic in the Senegal River Valley of Mauritania illustrates a second principle of ecological change. Whereas in Egypt, the virus was transported to virgin territory, in Mauritania, Rift Valley fever virus was already there, although no human cases had been recognized in the sparse settlements. The Diama Dam was completed in 1986 near the mouth of the Senegal River. Ecological impact studies were commissioned both by the U.S. Government and by the French Government. Scientists at the Institut Pasteur warned "The existence of an important focus of Rift Valley fever virus in the south of Mauritania, and in proximity to the Senegal River and in particular to the Diama and Manantali Dams, constitutes a potentially important risk of amplification of the virus in relation to the migration of domestic animal herds and human populations which pass through this focus."  Shortly after the warning, the epidemic began near Rosso, a community that was a focus of herdsmen and their animals, some of them migrating into the area to seek the agricultural benefits of the Diama Dam. Over a thousand Rift Valley fever cases occurred in the town of Rosso alone with an estimated 47 deaths. 
Why is Rift Valley fever such a threat? Firstly, the virus is capable of infecting and being transmitted by a wide variety of mosquitoes and can maintain itself in non-immune populations of sheep and cattle, infecting people at the same time.(13) Secondly, it has demonstrated the ability to be transported. Thirdly, it can apparently adapt easily to ecological change. The two major epidemics in 1977 and 1987 were associated with localized ecological change. With global climate change we may well be embarking not on localized, but rather generalized change. For a disease that seems to have capitalized on two isolated opportunities, can one imagine the possible consequences when offered almost unlimited opportunities for spread to areas of ecological change?
Dengue, schistosomiasis, and Rift Valley fever are only three examples of major human diseases that can be expected to be influenced by global climate change. There are experimental vaccines for dengue and Rift Valley fever, and drugs for treatment of schistosomiasis. We can combat all three diseases with environmental sanitation and health education. In spite of these measures, we have not been successful in controlling them and we can expect local and world changes in temperature and rainfall to make their control more difficult.
Fortunately, the changes will happen gradually and if we act now, we have time to learn more about the epidemiology and ecology of the vector-borne and zoonotic diseases. We also have time to devise better control and prevention strategies. These studies will require interdisciplinary research. The trend today in graduate education and in university and government research is to specialization, and in infectious diseases the trend is to specialization at the molecular level. This trend is laudable to a point; many of our solutions will require understanding at the molecular level. However, this particular problem will also require training in more general and interdisciplinary fields including field ecology, general medicine, epidemiology, forestry and botany, entomology, climatology, and zoology to name a few.
We should aim to devise better direct intervention measures for these diseases. We also need more information about transport of agents, modes of transmission, their reservoirs, and the effect of temperature, rainfall, and other climate-related parameters on the vectors, vertebrate hosts, and the agents of disease themselves. Studies of ecology at the periphery of the ranges of the agents and their reservoirs would be especially valuable. Such information could be used to predict more accurately which of the diseases to target as threats, and which will be less likely to spread and/or become more severe.
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