DENGUE FEVER

An Environmental Plague for the New Millennium?

With 2.5 billion people at risk and estimated cases in the tens of millions, dengue is considered by many to be the second most important mosquito-borne disease in the world. Only malaria, with 600 million cases and 2 million deaths, has a greater impact on health in the developing world. From sporadic reports of cases among African villagers in the days of colonial expansion, classic dengue and its more lethal form, dengue hemorrhagic fever (DHF) now circle the globe and beset tropical cities with chronic illness and the continual threat of epidemic outbreaks.

Today, dengue is very much an environmental disease, affecting the urban and peri-urban settlements of more than 100 countries with seasonal outbreaks of illness carried by mosquitoes that thrive in the detritus of human consumption such as cast off bottles, tin cans and old tires. Children absorb the major impact of the infection and suffer the largest number of the estimated half million hospitalizations and 90% of the 25,000 deaths due to DIV.

With no specific treatment for dengue infection, prevention is the only effective alternative. Insecticides are a partial remedy but, resistance to affordable and environmentally safe chemicals and declining political will and infrastructure have all but eliminated this approach in most countries. Vaccines are in the pipeline but the system required to deliver them to half the world's population is problematic at best. Community action in removing the discarded containers in which the mosquitoes breed as well as personal protection with screens, repellents and residual insecticides may be the best hope for risk reduction. The development challenge is in building awareness and empowering people to take action against "yet another scourge" when their futures and those of their children seem so much in doubt.

This Capsule Report presents dengue and dengue hemorrhagic fever as diseases of development and urban sprawl and examines some of the alternatives that might reduce the risk as well as the impact of the world's most ubiquitous arbovirus.

The Worst Case Scenario - The Cuban Outbreaks

Before the 1970's, dengue experience in the Western Hemisphere was limited to the classical form of the disease. History records epidemics of classical dengue in Philadelphia in 1780 followed by at least four other major outbreaks that occurred in the southern U.S. and the Caribbean during the last half of the 19'h century. In the early 1940's a small epidemic occurred in the Gulf coast states with the epicenter being the port of New Orleans. Dengue all but disappeared from the New World during the urban yellow fever eradication campaigns of the 1940s and 50s. As part of those efforts, Aedes aegypti was declared eliminated from most areas in which dengue had previously been recorded. Discontinuation of the eradication programs in the 1970s was followed by a rapid repopulation of the region with the Ae. aegypti mosquito. This time it was not the vector of yellow fever but of dengue virus.

In 1977, Cuba was struck by an epidemic of classical dengue fever which began in the east and rapidly spread to the west. While there were no recorded deaths during the outbreak, more than 5 million people suffered the classical symptoms of the disease including fever, malaise, joint pains headaches, eye pain and sporadic rashes. The outbreak which largely affected Santiago, Cuba's second largest city, was determined to be caused by the dengue DEN I serotype. DEN I is one of four known serotypes of dengue virus. The epidemic burned itself out in a few months and for the next three years only scattered cases were observed by the local medical authorities.

In the summer of 198 1, Havana physicians started reporting outbreaks of a far more serious illness, with classic symptoms but with hemorrhages from the nose and mouth, bleeding under the skin and occasional occurrences of shock and death. With this major announcement, dengue hemorrhagic fever entered the new world. Before October 50' , 344 thousand such cases were reported and 116 thousand were admitted to hospitals. In the logistics nightmare which followed, thousands of people, ill from other causes were summarily discharged from the hospital to make way for the rapidly growing number of dengue cases.

Before the epidemic's completion, more than 9,000 people with life threatening illness had been treated and 158 deaths, 101 of whom were children, were reported. During the week of highest incidence ( June 30- July 6 ), hospital admissions for dengue averaged over 9,000 per day.

It was determined that the second major epidemic was caused by DEN 2 and it was suspected that the first epidemic had predisposed the Cuban population to DHF which made the second outbreak so severe. The Cuban epidemics were well studied and documented and are demonstrative of the public health and economic impact of a vector-borne disease on a population. All of Latin America would like to avoid the experience if possible.

Early scientists hypothesized that dengue originated in Africa and spread globally with the slave trade. Modern thinking favors the notion that dengue evolved from an infection of forest primates in the Malay Peninsula and spread along the early routes of commerce. In either case, there is general agreement that the virus began as an infection of mosquitoes that went on to invade both humans and primates.

By the beginning of the 19thcentury, classic dengue was well known in the capital cities of Africa, Asia and Latin America. Even allowing for the lack of precision in diagnosis, several epidemics that were likely due to dengue virus had broken out in China, Indonesia, Egypt, Panama, Mexico, Burma, Zanzibar and Arabia. Even within the United States there were outbreaks in Philadelphia (1780) and in a broad band through the South from the Carolinas to Texas (1850).

Sporadic reports of a hemorrhagic form of dengue appear in official and personal communications during the Philadelphia epidemic of 1780. Prior to the Second World War, hemorrhagic dengue fever with shock and fatality were features of outbreaks in Australia, Beirut, Taiwan, and Greece. While the numbers of hemorrhagic cases were significant in these outbreaks, they were considered to be anomalous manifestations rather than a new public health threat.

The ecologic and demographic changes that followed World War 11 coupled with a new international mobility made possible by air travel, ushered in a global pandernic of dengue and DFIF that rapidly spread from Asia to the Indian subcontinent, to Australia and to Latin America. Evidence of the rapidity with which dengue establishes itself in a new geographic area is best illustrated by the case of Latin America. During the post-war years 1946 - 1963, there were no recorded dengue epidemics in the Americas. This fact was largely attributable to the highly effective campaigns of PAHO in the 1940s and 50s to eradicate the mosquito vector of urban yellow fever, Aedes aegypti. When the eradication program was discontinued in the 1970s, Ae. aegypti quickly re-infested the Americas and soon began to transmit dengue virus of all four serotypes.

There is little disagreement about the causes of the spread of dengue and DBT throughout the world. Gubler and Trent summarized the major factors in 1994.

• Aedes aegypti, the cosmopolitan vector of dengue virus, re invaded the Americas following a 10-year absence which resulted from a nearly successful eradication attempt. This exposed more than 300 million people with little or no immunity to dengue to vector mosquitoes capable of transmitting the virus.

• Most countries in which dengue is transmitted have no mosquito control. Partially a consequence of mosquito resistance to affordable insecticides and partially due to the loss of the infrastructure to sustain spray operations, few countries have effective programs to control mosquitoes of any species. In fact, the past two decades have seen a continuous deterioration of public health infrastructures of all types, including those that are responsible for surveillance and diagnosis of disease.

• Global trends in urbanization, substandard housing, and population growth have placed virus carriers in close proximity to susceptible people and the disposable containers accumulating around human habitations have provided ample breeding sites for the peri domestic mosquitoes that transmit the virus.

• In 1996, Gubler observed that there was a doubling of international airline passengers from 20 to 40 million during the decade between 1983 and 1994.

• Since half of those passengers are traveling in to or out of the tropics, the opportunities for international viral transmission are enormous.

The Current Situation

The global dengue pandemic which began in Southeast Asia in the wake of World War 11 has intensified during the past two decades until it affects virtually all continents with the possible exception of Antarctica. Epidemics are increasing in their frequency as well as the amount of illness they produce. The conditions responsible for dengue's spread ( urbanization, international travel, collapse of infrastructure ) continue to mount. It is not surprising that dengue is rapidly becoming a major global public health problem. There have been many attempts to summarize the regional situation. The following synopses have been borrowed from a variety of sources including CDC, PAHO, WHO and the writings of a number of individuals who have dedicated their lives to dengue control.

All four dengue serotypes have been reported from Africa each year since 1980. In 18 of Africa's 46 countries outbreaks of classic dengue are commonplace and hemorrhagic symptoms are seen on a regular basis. However, DHF in epidemic form is virtually unknown. The actual number of cases in African countries is unclear because diagnostic capabilities are extremely limited and reporting is sporadic.

Aedes aegypti is the principle vector in Africa's urban outbreaks but in some countries of East Africa, Ae. albopictus is an important agent of transmission. Both rural and urban cycles involving different serotypes have been found in adjacent areas of Senegal. However, there is little evidence that the two cycles interact.

Dengue is given a low priority by most African countries because DHF is not present in epidemic form and competition for due in part to the lack of DFIF in epidemic form and part to a lack of resources to do much about it. For the moment, adding dengue to the list of maladies that are within current surveillance systems appears to be a primary thrust. Another priority is in building awareness of the infection on the part of health providers in order to facilitate diagnosis and treatment as well as to promote more accurate reporting.

Dengue virus of all 4 serotypes as well as DUF transmission is endemic in nearly every country of South East Asia and outbreaks of hemorrhagic disease have been recorded recently from Bangladesh, India, Sri Lanka and the Maldives. WHO reports indicate that the numbers of cases in the region have been increasing during the past 5 years as have the frequency of epidemics and cases of serious disease particularly in India, Sri Lanka and Myanmar.

DHF is now the leading cause of hospitalization and death of children in the 10 countries of the region and the numbers of cases in all age groups is more than 5 times that of 1980 or any of the preceding 30 years. Previously considered urban diseases, both dengue and DUT are now spreading to the rural areas.

South-East Asia's primary dengue vector is Ae. Aegipti. While Ae. albopictus is prevalent in the region, its role in dengue transmission remains uncertain.

Classic dengue fever was endemic throughout the Pacific during World War 11 and the decade thereafter with outbreaks occurring in 28 of the 36 countries of the region. The first cases of DBIF were observed in the Philippines in 1954 and their frequency has increased steadily to the point where DBY is among the top priority diseases in the region. Epidemics of DIV have occurred in China, Cambodia, Laos, Vietnam, Malaysia, Singapore and many of the islands of the South Pacific.

With all four serotypes present and an abundance of dengue vector mosquitoes, the Pacific Region is the highest risk region of the world with case fatality rates for DIIF climbing to more than 13% in some situations. Government supported prevention and control programs as well as emergency measures backed by WHO have been successful in reducing case rates in some of the most affected areas.

During the past decade, five Latin American countries have reported epidemics of dengue. This is significant in the light of the preceding 50 years of freedom from such episodes. Also important is the fact that in 1995, sixteen American countries reported confirmed cases of DI-W to the Pan American Health Organization. In 1996, a total of 276,758 cases of dengue, including 4,520 cases of DHF were reported from 41 countries of Latin America. While many countries reported only one serotype, Mexico, and Guatemala reported all four and Colombia, Ecuador, and Puerto Rico each reported three serotypes.

The alarming increases in dengue are attributed to the virtual explosion of Aedes aegypti populations that accompanied the abandonment of the mosquito control efforts that were so successful prior to 1970. Rapid urbanization and the proliferation of peri urban slums around most of Latin America's cities has presented an environment of trash and containers for mosquito breeding which are ideal for Aedes breeding. As if the Ae. aegypti populations were not enough, importation of a second vector, the Asian tiger mosquito, Aedes albopictus, has followed in the wake of brisk international trade in used automobile tires. Mosquito larvae suspended in water trapped in the tires have invaded habitats within the new world as far as Chicago.

A PAHO survey indicates that the annual cost of dengue control activities in the American region may exceed $200 million. This figure includes the costs incurred by 23 Latin American countries in 1995 but does not include expenditures by U.S. to keep dengue at bay.

In 1997, a PAHO led task force began work on a five stage regional strategy to control the vector which includes, chemical vector control, surveillance, public education and environmental management. The cost of the program will approximate $1.6 million per year, a modest investment if it achieves the objective of lowering the risk of epidemic dengue and DBF in the hemisphere.

As diseases, dengue and DIV begin in much the same way, with a fever of sudden onset, malaise, headache and pain in the muscles and joints. The severe joint pains associated with dengue led to the name "breakbone fever"which was common in the earlier part of the century. Rashes, nausea, vomiting and a very characteristic pain behind the eyes are also common dengue symptoms. A great mimic of other diseases, dengue is often mistaken for malaria, influenza, measles and typhoid. Specific immunological tests for ruling dengue in or out exist but are often unavailable within the 5 to 7 day course of the infection. In the majority of cases, the symptoms of classic dengue fever resolve and leave the patient somewhat weakened by the experience but with no permanent ill effects.

The appearance of petechial hemorrhages or small black and blue areas just under the skin may be the first sign of the more serious DUF manifestation of the disease. Occurring in 5 to 30% of cases the tiny hemorrhages may be accompanied by bleeding from the nose and gums with signs of blood in the urine and the stool. The bleeding is associated with a dimunition in circulating platelets that initiate blood clotting and with an increased fragility of the walls of the tiny capillaries that feed the tissues with nutrients and oxygen. Both of these phenomena are related to the presence of the virus.

Loss of blood and serum leakage from the capillaries if sufficiently severe results in lowering of blood pressure and in a small but significant number of cases may lead to clinical shock. It is this dengue shock syndrome (DSS) which is responsible for the majority of DFIF deaths. Some 70% of these fatal reactions occur in young children who lack sufficient blood volume to be able to sustain blood pressure in the face of massive serum and blood leakage. For those fortunate enough to receive infusions of intravenous fluids during these crises, the outlook for survival and recovery is fairly promising. For a child in a village it may be a death sentence.

The following diagram, taken from WHO's publication "Dengue hemorrhagic fever: diagnosis, treatment and control" illustrates the various manifestations and clinical outcomes which may accompany a dengue infection.

The Biology of Dengue and DHF

Given the distribution of antibodies to the four serotypes among people who have had no history of infection, it may be concluded that the majority of cases may be sub clinical and unapparent. it is also suspected that dengue is often mistaken for other febrile maladies such as malaria, influenza, measles and typhoid fever.

Dengue pathology is largely due to the same cytotoxic effects that are seen in other flavaviruses such as Japanese encephalitis, West Nile fever and the tick-borne encephalitis viruses. Most organ systems can be affected but serious sequellae are most often associated with infection of the liver and the reticuloendothelial system.

Exactly what happens to convert classic dengue to DI-IF is not completely understood but appears to be related to sequential infection with two or more of the known dengue serotypes (DEN 1, DEN 2, DEN 3 and DEN 4 ). One theory advanced by Halstead is that an immune enhancement takes place in individuals who have been sensitized to one dengue virus serotype as a result of infection. The resulting non-neutralizing antibodies circulating in the victim after recovery may actually enhance the entry of a dengue virus of a different serotype into white blood cells which are usually the body's first line of defense. The blood cell's microchemical capabilities are subverted by the virus to produce biological substances that increase vascular permeability and result in leakage. While experimental evidence supports this explanation, the animal models available for experimental work are not ideal. The theory does not explain the small but persistent number of DBIF cases that have been observed in patients with no known history of previous dengue infection.

Other explanations for the occurrence of hemorrhagic dengue disease include; possible variation in the virulence of different strains of virus, independent of serotype, interactions of virus with other infectious or environmental agents, and genetic susceptibility of certain groups of individuals to the more lethal form of the disease.

The role of Aedes mosquitoes in the transmission of dengue fever was known in 1903, more than 35 years before the isolation of the virus. By 1926, investigations using human volunteers by the U.S. Army Medical Corps had incriminated both Ae. aegypti and Ae. albopictus as vectors of the disease. Since that time several more mosquitoes have been implicated or proven to be capable of carrying the virus but all are members of the subgenus Stegomyia which is composed of highly domestic species that prefer to feed on humans.

The success of dengue virus in infecting tens of millions people each year is largely attributable to the ability of Aedes aegypti to thrive in a variety of habitats in more than 100 countries. From its origins in Africa, Ae. aegypti spread to the western hemisphere in the 17' century, to the Mediterranean in the 18' , Asia in the I 91h and the western Pacific in the late 19 Ih and early 20 th century. The method of transport was probably in the water casks of sailing vessels. Regardless of its means of conveyance, this highly successful mosquito has populated the peri urban areas of nearly every country in the tropical and subtropical regions of the world.

Adult females lay their eggs singly on the damp walls of containers such as bottles, cans, water cisterns, and even natural containers such as the axils of plants. Ae. aegypti prefers clean water as opposed to that contaminated with organic debris and will hatch in hours after rain fills the container and submerges the eggs. This delayed hatching results in impressive blooms of larvae and adult mosquitoes about 10 days later.

The availability of natural and artificial containers to breed in and the climate are the major factors that control Ae. aegypti populations, so temperature and rainfall patterns can give a marked seasonality to them.

Aedes albopictus also known as the Asian tiger mosquito was originally an Asian mosquito but during the past decade, has successfully populated countries of Latin America, Africa, the South Pacific and even the United States. The preferred habitat of Ae. albopictus is in the forest canopy and its food, wild animals. Extremely adaptable, Ae. albopictus has become urbanized, anthropophilic, and domesticated. Of equal concern, cold tolerant strains of the mosquito have been naturally selected and are able to survive the winters of northern China and Canada. The global exploitation of new habitats has been facilitated by the movement of eggs and larval mosquitoes in water trapped in used tires. Recent trends in recycling of tires has moved the mosquitoes throughout the world.

The mosquito becomes infected with virus as she takes a blood meal from and infected host. Since the value of the blood is in the biochemical components needed to mature eggs, only the female mosquito is involved in dengue transmission as is the case with other mosquito borne diseases such as malaria and encephalitis.

The measurement of non-health impacts of disease has not received as much attention in the past as it will in the future. Partly due to the lack of tools and partly because it has long been considered crass to try to put a price tag on the burden of loss and human suffering. Today, with more competition for resources, there is a need for disease control programs to justify their costs in light of the economic consequences of the "no control" option.

Estimates of the cost of disease are difficult to obtain because they may include the value of lost work, transportation for treatment, medicine and even the loss of income and productivity due to fatal illness in a wage earner. As a result there is only a hand full of such studies and even fewer examples in the area of communicable and vector borne diseases.

A 1995 study from Thailand by a group of scientists under the direction of Professor Santasiri Sornmani of Mahidol University attempted an analysis of social and economic factors surrounding 184 cases of DBIF in Thailand, in 1994. Their study considered the treatment seeking costs to the family, hospitalization and treatment expenses, lost work, the opportunity cost of lost work by caretakers and even the funeral and permanent economic loss of wage earners were calculated. Morbidity costs ranged between $157 and $198 depending on age. Mortality costs, including funeral expenses and 50 years of lost income were in excess of $ 120,000 per fatal case.

The investigators went on to estimate the costs incurred in 1994 for all expenditures to control and prevent dengue by the Ministry of Public Health, the City of Bangkok and the provincial governments came to $4.9 million. Using the total number of DFIF patients of 51,688 the total cost of prevention, treatment and control was about $13.4 million, half of which was paid by the families of the patients. Loss of potential income was not included in the calculation. By comparison, the morbidity and mortality statistics of DBY applied to the unit costs places the annual financial burden to the nation at $ 31.5 million even in a low prevalence year. In high years the figure would be closer to $51.5 million.

A very recent study by a group of CDC investigators summarizes more than a decade of experience with dengue in Puerto Rico from the perspective of economic impact. Their approach was to examine the disability- adjusted life years (DALY) lost as a result of illness or death from dengue and DHF. Their analyses show a steady increase in lost work and productivity due to the two diseases that has averaged 658 DALYs per one million people over the past I I years. Since the mean income of the most affected groups is difficult to determine, the present dollar value of those DALYs is not clear but the economic losses to drngue and DHF are believed to be greater than those from all childhood diseases (polio, measles, whooping cough, tetanus, or from meningitis, hepatitis or malaria.

• The search for an effective vaccine for dengue began in 1944, shortly after isolation of the virus. Although these early attempts involving development of attenuated virus in mouse brain conferred some protection to volunteers, the best results were only a reduction in severity of symptoms. Throughout the 1970s and 1980s, U.S. military organizations and WHO sponsored research laboratories conducted an intensive search for a tetravalent vaccine that could be used against all four strains with a single immunization. By simultaneous immunization to all four dengue serotypes it would be theoretically possible to eliminate the threat of DBY in the vaccinated person since sequential infection by more than one is believed to be necessary to initiate the hemorrhagic manifestations of dengue virus disease. Conversely, any attenuated virus vaccine that is not effective against all four serotypes might only intensify the likelihood of a DFIF epidemic.
  

• To date, several promising candidates are in development using attenuated, live vaccines as well as biologically engineered recombinant models. While they are in advanced stages of clinical testing, an approved and clinically useful vaccine that can confer immunity to infection is not a reality. WHO considers attainment of this goal to be a priority. In 1984 WHO established a Steering Committee on Dengue as a part of its Program for Vaccine Development but at present protective vaccines for dengue and DH F are still 5 to 10 years into the future.

What Can Be Done to Reduce the Dengue?

With little to offer in the way of specific treatment or immunological protection, the key to dengue and DUF control is in reduction of man-vector contact and mosquito control. In those cases where infection becomes established and is recognized as such, medical science can offer good supportive care to prevent shock and the risk of secondary health problems such as dehydration and concomitant infections from claiming the victim. When the problems come to a prepared medical care delivery system one at a time, early diagnosis, good medical practice and supportive therapy usually results in a favorable outcome. When outbreaks are forced upon an unprepared and overburdened health care system, the results can be catastrophic.

In addition to improving reporting requirements for dengue and DHT, endemic countries should make modest investments in systems to monitor vector populations and assess the virus serotypes present in the human and mosquito populations. Other measures that worth investment include:

Improve dengue and DHF diagnosis and detection by physicians and other health careproviders. Quite surprisingly, dengue and DHF have a low index of suspicion in the minds of physicians, even in endemic areas. The ability of dengue to "mimic" other diseases like malaria, typhoid or even influenza makes differential diagnosis a challenge to all but the best prepared medical personnel. Investments in programs to improve provider awareness of dengue and DHF lead to earlier diagnosis and more favorable outcomes.

• Stockpile intravenous solutions and other critical care commodities. The survival of DUF cases often depends upon the availability of IV solutions and infusion kits. Measures to increase the on-hand stocks of these commodities and introduction of inventory control systems to ensure that expiry dates are not exceeded are good investments.
  

• Develop and circulate patient management protocols. Uniformity in case management results in better prognoses for DHF cases. Several excellent case management protocols for dengue and DDT have been developed. In service training of providers in the use of these protocols should be a priority for endemic countries.
  

• Devisefacility contingency plans tofree up hospital beds. The heat of an epidemic is not the best time to decide how to make room for massive increases in patient admissions. Multi institutional workshops to assist decision makers in preparing for emergencies will save confusion and save lives.
  

• Promote community participation in water systems development and management of containers in which mosquitoes breed Social action and awareness building about the role of containers in Aedes mosquito breeding combined with reasonable public policies concerning community cleanliness has had large effects on dengue rates in Latin America. Investments in improving water systems has residual benefit in dengue control in that it reduces reliance on water storage containers which are a favored breeding site for vector mosquitoes.
  

• Restrict imports of tires and promote vector control in international travel and commerce. The commercial value of recycling of tires and other potential breeding containers must be considered in light of increased risk. Appropriate policies concerning insecticide treatment of planes, ships and other long distance transport vehicles would have value in reducing the rate of spread of vector and virus populations.
  

• Develop regional laboratories to carry out surveillance activities. Effective dengue surveillance depends upon the continuous monitoring of three inter related parameters.

Epidemiologic tracking of dengue and DUT cases by location, age, season and geographic setting, Entomologic monitoring of vector mosquito populations according to density, season, infection status and breeding habitat, and Microbiological assessment of viruses in people and mosquitoes I I with respect to serotype, circulation in the environment and in relation to each other.

Appropriate surveillance is a technical undertaking which must be conducted with precision and requires considerable laboratory support. Few countries would be able to sustain an effective program without considerable outside support. The development of regional facilities which have linkages to international centers such as the CDC, NIH or WHO would be an appropriate investment that would have a high payoff in national contingency planning, disease containment and vector control.

Information Sources

The information used in preparation of this Capsule Report was adapted from a variety of sources including books, journal publications, WHO and CDC reports and materials from the internet. Without slighting any of the sources, the following references were especially comprehensive and the interested reader is advised to consult them for a more in-depth treatment.

"Dengue and Dengue Hemorrhagic Fever" 1997 Gubler, D.J. and G. Kuno Eds, CAB International

Meltzer, M. et al 1998. Using Disability-Adjusted Life Years to Assess the Economic Impact of Dengue in Puerto Rico: 1984-1994, Am J Trop MedHyg 59: 265-271

"Dengue Hemorrhagic Fever: Diagnosis, Treatment and Control" 1986, The World Health Organization, Geneva

"Technical Consultation on USAID's Infectious Disease Strategy" 1997, USAID Proceedings Report

Gubler D, Clark G, 1995. Dengue/Dengue Hemorrhagic Fever: The Emergence of a Global Health Problem. Emerg Infect Dis 15 5 -5 7