Dengue Fever

Background
Dengue, the most common arboviral illness transmitted worldwide, is caused by infection with 1 of the 4 serotypes of dengue virus, family Flaviviridae, genus Flavivirus (single-stranded nonsegmented RNA viruses). Dengue is transmitted by mosquitoes of the genus Aedes, which are widely distributed in subtropical and tropical areas of the world, and is classified as a major global health threat by the World Health Organization (WHO).

Initial dengue infection may be asymptomatic (50%-90%), may result in a nonspecific febrile illness, or may produce the symptom complex of classic dengue fever (DF). A small percentage of persons who have previously been infected by one dengue serotype develop bleeding and endothelial leak upon infection with another dengue serotype. This syndrome is termed dengue hemorrhagic fever (DHF), although dengue vasculopathy has been proposed as a better term, as fluid loss into tissue spaces can lead to prolonged shock and complications, including gastrointestinal bleeding, a greater fatality risk than bleeding per se. Some patients with dengue hemorrhagic fever develop shock (dengue shock syndrome [DSS]), which may cause death.

Dengue virus transmission follows two general patterns—epidemic dengue and hyperendemic dengue. Epidemic dengue transmission occurs when dengue virus is introduced into a region as an isolated event that involves a single viral strain. If the number of vectors and susceptible pediatric and adult hosts is sufficient, explosive transmission can occur, with an infection incidence of 25%-50%. Mosquito-control efforts, changes in weather, and herd immunity contribute to the control of these epidemics. Transmission appears to begin in urban centers and then spreads to the rest of a country. This is the current pattern of transmission in parts of Africa and South America, areas of Asia where the virus has reemerged, and small island nations. Travelers to these areas are at increased risk of acquiring dengue during these periods of epidemic transmission.

Hyperendemic dengue transmission is characterized by the continuous circulation of multiple viral serotypes in an area where a large pool of susceptible hosts and a competent vector (with or without seasonal variation) are constantly present. This is the predominant pattern of global transmission. In these populations, antibody prevalence increases with age and most adults are immune. Hyperendemic transmission appears to be a major risk for dengue hemorrhagic fever. Travelers to these areas are more likely to be infected than are travelers to areas that experience only epidemic transmission.

Dengue fever–like illnesses were described in Chinese medical writings dating back to 265 AD. Outbreaks of febrile illnesses compatible with dengue fever have been recorded throughout history, with the first epidemic described in 1635 in the West Indies. In 1789, Benjamin Rush, MD, published an account of a probable dengue fever epidemic that had occurred in Philadelphia in 1780. Rush coined the term breakbone fever to describe the intense symptoms reported by one of his patients. Probable outbreaks of dengue fever occurred sporadically every 10-30 years until after World War II. The socioeconomic disruptions caused by World War II resulted in increased worldwide spread of dengue viruses.

The first epidemic of dengue hemorrhagic fever was described in Manila in 1953. After that, outbreaks of dengue fever became more common. A pattern developed in which dengue fever epidemics occurred with increasing frequency and were associated with occasional dengue hemorrhagic fever cases. Subsequently, dengue hemorrhagic fever epidemics occurred every few years. Eventually, dengue hemorrhagic fever epidemics occurred yearly, with major outbreaks occurring approximately every 3 years. This pattern has repeated itself as dengue fever has spread to new regions.

Although initial epidemics were located in urban areas, increased dengue spread has involved suburban and rural locales in Asia and Latin America. The only continents that do not experience dengue transmission include Europe and Antarctica. In the 1950s, 9 countries reported dengue outbreaks; today, the geographic distribution includes more than 100 countries worldwide. Several of these countries had not previously reported dengue, and many had not reported dengue in 20 years.

Dengue transmission spread from Southeast Asia into surrounding subtropical and tropical Asian countries, southern China and southern Taiwan, the Indian subcontinent and Sri Lanka, and down the island nations of Malaysia, the Philippines, New Guinea, northeastern Australia, and several Pacific islands, including Tahiti, Palau, Tonga, and the Cook Islands. Nepal has not reported dengue transmission. Hyperendemic transmission is reported in Vietnam, Thailand, Indonesia, Pakistan, India, Malaysia, and the Philippines. Dengue continues to extend its range.

Currently, dengue hemorrhagic fever is one of the leading causes of hospitalization and death in children in many Southeast Asian countries, with Indonesia reporting the majority of dengue hemorrhagic fever cases. Of interest and significance in prevention and control, 3 surveillance studies in Asia report an increasing age among infected patients and increasing mortality rate. Since 1982 in Singapore, more than 50% of deaths have occurred in individuals older than 15 years. In Indonesia, young adults in Jakarta and provincial areas make up a larger percentage of infected patients. During the 2000 epidemic in Bangladesh, up to 82% of hospitalized patients were adults, and all deaths occurred in patients older than 5 years.

The epidemiology of dengue fever in Africa is more poorly characterized. Aedes aegypti is present in a large portion of the Middle East and sub-Saharan Africa. Dengue fever is present in 19 countries on the African continent. In a 1993 epidemic in the Comoros, an estimated 60,000 persons were infected with dengue. Of note, no major dengue hemorrhagic fever epidemics have occurred in Africa, despite the fact that all 4 dengue serotypes circulate in the continent. This may be explained by a genetic factor in these populations.

In the Americas, dengue epidemics were rare postwar because Aedes mosquitoes had been eradicated from most of the region through coordinated vector-control efforts. Systematic spraying was halted in the early 1970s because of environmental concerns. By the 1990s, A aegypti mosquitoes repopulated most of the countries in which they had been eliminated.

Serotype 1 dengue (DENV-1) was introduced into a largely susceptible population in Cuba in 1977. Serosurveys indicated that more than 44% of the population was infected, with only mild disease reported. The first dengue hemorrhagic fever epidemic in the Americas occurred in Cuba in 1981 and involved serotype 2 dengue (DENV-2), with hundreds of thousands of cases of dengue in both children and adults, 24,000 cases of dengue hemorrhagic fever, 10,000 cases of dengue shock syndrome, and 158 reported deaths.

In 1997, Asian genotype DENV-2 was reintroduced, and dengue shock syndrome and dengue hemorrhagic fever were seen only in adults who had previously been infected with DENV-1 in 1977. Disease and case fatality rates were higher in those who had been infected with DENV-2 twenty years after their initial DENV-1 infection than those who were infected 4 years apart. Data from other countries supports the finding that the severity of secondary dengue infections appears to intensify with longer intervals between infections. Since then, dengue fever and dengue hemorrhagic fever cases have progressively increased.

A aegypti is abundant year-round in most countries in the Caribbean basin. Significant outbreaks of dengue have been reported in 2005 and 2006 in Puerto Rico, the US Virgin Islands, the Dominican Republic, Barbados, Curacao, Cuba, Guadeloupe, and Martinique.

Aedes albopictus, originally from Asia, is now found in limited areas of Brazil, Bolivia, Colombia, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Cuba, and the Cayman Islands. A aegypti is present in all countries in South America except Chile. Hyperendemic circulation of all 4 dengue serotypes is present in the northern countries of South America. Brazil (700,000 cases in 2002), Colombia, and Venezuela report the most cases of dengue and dengue hemorrhagic fever, with low-level transmission occurring year-round but with most occurring during periods of epidemic transmission.

In 1986, the first clearly identified local transmission of dengue in the United States occurred in Texas. Carriers of the virus were believed to have crossed the border from Mexico; the local vector population was then infected. Since then, seasonal autochthonous infection has been reported in both Texas and Hawaii. In 2001-2002, Hawaii experienced its first outbreak of dengue since World War II ended. The outbreak involved 2 variants of DENV-1 that were transmitted by A albopictus. Predominantly affecting young adults and adults, 122 cases of dengue fever spread slowly on Maui, Oahu, and Kauai. The epidemic was traced to viremic visitors from Tahiti, which was then experiencing a severe outbreak of the infection.

Two competent vectors, A aegypti and A albopictus, are currently seasonally abundant in some areas of the southwestern and southeastern United States, including Texas, Arizona, New Mexico, Louisiana, Mississippi, Alabama, Georgia, and mid to south Florida. A aegypti has also been reported sporadically in portions of North Carolina, South Carolina, Tennessee, Arkansas, Maryland, and New Jersey. The range of A albopictus extends almost as far north as the Great Lakes. Since many cases of dengue in US citizens are due to endemic transmission in some US territories, the Centers for Disease Control and Prevention (CDC) currently conducts laboratory-based surveillance in Puerto Rico.

Dengue fever does not naturally occur in the European Union and in continental Europe because these areas do not have an appropriate vector population to allow further spread of dengue from viremic patients returning from other countries. As such, the disease is not statutorily notifiable in most member states. However, dengue does occur in several overseas territories of European Union members. In recent decades, reports of dengue infections in long-term expatriates, aid workers, military personnel, immigrants, and travelers returning from the tropics and subtropics have been increasing.

Since 2000, at least 8 areas previously without dengue have reported outbreaks, including Nepal, Bhutan, Macau, Hong Kong, Madagascar, the Galapagos, Easter Island, and Hawaii. The Pan American Health Organization (PAHO) reported that 2007 saw the highest number of dengue fever and dengue hemorrhagic fever cases (918,495) in the Americas since 1985.

Factors believed to be responsible for the spread of dengue include explosive population growth, unplanned urban overpopulation with inadequate public health systems, poor standing water and vector control, viral evolution, and increased international recreational, business, and military travel to endemic areas. All of these factors must be addressed to control the spread of dengue and other mosquito-borne infections. Unplanned urbanization is believed to have had the largest impact on disease amplification in individual countries, whereas travel is believed to have had the largest impact on global spread.

Over the past decade, the GeoSentinel Network of Travel Medicine providers has demonstrated that dengue has become more frequently diagnosed than malaria in travelers returning from tropical areas other than Africa. Such sentinel travel surveillance can augment global and national public health surveillance. More recent studies have not supported an earlier suggestion that climate change is also directly responsible for increased transmission.
Pathophysiology
Dengue infection is caused by 1 of 4 related, but antigenically distinct, viral serotypes: dengue virus 1 (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3), and dengue virus 4 (DENV-4). Genetic studies of sylvatic strains suggest that the 4 viruses evolved from a common ancestor in primate populations approximately 1000 years ago and that all 4 viruses separately emerged into a human urban transmission cycle 500 years ago in either Asia or Africa. Albert Sabin speciated these viruses in 1944. Each serotype is known to have several different genotypes.

Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity, but each individual can eventually be infected by all 4 serotypes. Several serotypes can be in circulation during an epidemic.

Dengue viruses are transmitted by the bite of an infected Aedes (subgenus Stegomyia) mosquito. Globally, A aegypti is the predominant highly efficient mosquito vector for dengue infection, but A albopictus and other Aedes species can also transmit dengue with varying degrees of efficiency.

Aedes mosquito species have adapted well to human habitation, often breeding around dwellings in small amounts of stagnant water found in old tires or other small containers discarded by humans. Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite and are easily disturbed during a blood meal, causing them to move on to finish a meal on another individual, making them efficient vectors. Entire families who develop infection within a 24- to 36-hour period, presumably from the bites of a single infected vector, are not unusual.

Humans serve as the primary reservoir for dengue; however, certain nonhuman primates in Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes acquire the virus when they feed on a carrier of the virus. The mosquito can transmit dengue if it immediately bites another host. In addition, transmission occurs after 8-12 days of viral replication in the mosquito’s salivary glands (extrinsic incubation period). The mosquito remains infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of dengue virus in mosquitoes has been documented. The eggs of Aedes mosquitoes withstand long periods of desiccation, reportedly as long as 1 year, but are killed by temperatures of less than 10°C.

Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 d) while viral replication takes place in target dendritic cells. Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, hepatocytes, and endothelial cells, result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections. Following incubation, a 5- to 7-day acute febrile illness ensues. Recovery is usually complete by 7-10 days.

Dengue hemorrhagic fever or dengue shock syndrome usually develops around the third to seventh day of illness, approximately at the time of defervescence. The major pathophysiological abnormalities caused by dengue hemorrhagic fever and dengue shock syndrome include the rapid onset of plasma leakage, altered hemostasis, and damage to the liver, resulting in severe fluid losses and bleeding. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding. Liver damage manifests as increases in levels of alanine aminotransferase and aspartate aminotransferase, low albumin levels, and deranged coagulationparameters(PT,PTT).

In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–alpha, interleukin [IL]–2). This is similar to that seen with fatal yellow fever and Ebola infections.

Most patients who develop dengue hemorrhagic fever or dengue shock syndrome have had prior infection with one or more dengue serotypes. In individuals with low levels of neutralizing antibodies, nonneutralizing antibodies to one dengue serotype, when bound by macrophage and monocyte Fc receptors, have been proposed to result in increased viral entry and replication and increased cytokine production and complement activation. This phenomenon is called antibody-dependent enhancement.

Some researchers suggest T-cell immunopathology may play a role, with increased T-cell activation and apoptosis. Increased concentrations of interferon have been recorded 1-2 days following fever onset during symptomatic secondary dengue infections. The activation of cytokines, including TNF-alpha, TNF receptors, soluble CD8, and soluble IL-2 receptors, has been correlated with disease severity. Cuban studies have shown that stored serum sample analysis demonstrated progressive loss of cross-reactive neutralizing antibodies to DENV-2 as the interval since DENV-1 infection increased. In addition, certain dengue strains, particularly those of DENV-2, have been proposed to be more virulent, in part because more epidemics of dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes.
Frequency
United States
In 1998, 90 confirmed or probable cases of dengue fever were imported into the United States, resulting in one fatality. The current estimate is 100 cases per year; however, the true number of dengue fever cases is believed to be higher because reporting is voluntary, many US physicians are not aware of dengue or its manifestations, and the manifestations are often nonspecific.

In 1999, more than 300 cases of dengue fever were reported from Nuevo Laredo, Tamaulipas, Mexico.Nuevo Laredo lies directly across the Rio Grande River from Laredo, Texas. At that time, no dengue cases had been reported in Laredo in more than 12 years. Aedes mosquitoes are present in both cities. The Texas Department of Health reviewed 494 patient records from 5 outpatient sites and was able to confirm 11 cases of dengue fever. Mosquito abatement measures were instituted in Laredo, and health care providers were notified of the dengue fever cases. In the latter half of 1999, Laredo-area health care providers identified 161 suspected dengue fever cases and serologically confirmed 18 cases. This report underscores the need for health care providers to be aware of dengue fever and its manifestations and to test for the infection in appropriate cases.
International
An estimated 2.5-3 billion people in approximately 110 tropical and subtropical countries worldwide are at risk for dengue infection. Yearly, approximately 50-100 million people are infected with dengue, and 250,000 individuals develop dengue hemorrhagic fever. Annually, approximately 500,000 individuals are hospitalized with the infection, and 24,000 deaths are attributed to dengue worldwide. The Pan American Health Organization (PAHO) member states reported twice as many cases of dengue fever and dengue hemorrhagic fever in 1998 as they did in 1997.

A 5-year prospective study in Thai children examined the relative economic burden of dengue infection in children on the local population. Most disability-adjusted life years (DALYs) lost to dengue resulted from long-duration illness in children who had not been hospitalized. The infecting serotype appeared to be a determining factor of DALYs lost, with DENV-2 and DENV-3 responsible for 30% and 29%, respectively. The mean cost of illness from dengue was significantly higher than that from other febrile illnesses.
Mortality/Morbidity

• Recovery from dengue infection is usually complete. Even patients who meet strict criteria for dengue hemorrhagic fever or dengue shock syndrome usually recover without sequelae.
• The fatality rate associated with dengue shock syndrome varies by country, from 12%-44%. In a 1997 Cuban epidemic, the fatality rate in patients who met criteria for dengue hemorrhagic fever or dengue shock syndrome was approximately 6%. The mortality rate associated with dengue fever is less than 1%.
• Data from the 1997 Cuban epidemic suggests that, for every clinically apparent case of dengue fever, 13.9 cases of dengue infection went unrecognized because of absent or minimal symptoms.
• Factors that affect disease severity include patient age, nutritional status, ethnicity, the sequence of infection with different dengue serotypes, virus genotype, and the quality and extent of available medical care.

Race

• Dengue affects all races. Some African and Haitian data demonstrate a relative dearth of dengue hemorrhagic fever and dengue shock syndrome during dengue fever epidemics, suggesting that these populations may share a genetic advantage to the virus. This merits further study.

Sex

• Dengue viruses affect both sexes.

Age

• Dengue affects people of all ages. In Southeast Asia, where dengue is hyperendemic, dengue hemorrhagic fever usually affects children younger than 15 years. However, in the Americas, where dengue is becoming progressively hyperendemic, dengue hemorrhagic fever shows no age predilection.

Clinical
History

• Fever in persons with symptomatic dengue fever may be as high as 41°C. The fever typically begins on the third day and lasts 5-7 days, abating with the cessation of viremia. Fever is often preceded by chills, erythematous mottling of the skin, and facial flushing (a sensitive and specific indicator of dengue fever). Occasionally, and more commonly in children, the fever abates for a day and then returns, a pattern that has been called saddleback fever. Patients are at risk for development of dengue hemorrhagic fever or dengue shock syndrome at approximately the time of defervescence. In travelers, symptoms that begin more than 2 weeks after they depart from an endemic area and fever that lasts longer than 10 days are probably not due to dengue.
• Headache is usually generalized. Retroorbital pain is common and is often described as severe.
• Patients may report nausea and vomiting.
• Patients typically describe a maculopapular or macular confluent rash over the face, thorax, and flexor surfaces, with islands of skin sparing. The rash typically begins on day 3 and persists 2-3 days.
• Patients may have severe myalgias, particularly of the lower back, arms, and legs, and arthralgias, especially of the knees and shoulders.
• Hemorrhagic manifestations may range from small amounts of bleeding from the nose or gums to melena, menorrhagia, or hematemesis.
• Abdominal pain is reported; often, abdominal pain in conjunction with restlessness, change in mental status, hypothermia, and a drop in the platelet count presages the development of dengue hemorrhagic fever.
• Patients report fatigue and malaise.
• Patients may report conjunctival injection, sore throat, and cough.
• Cardiomyopathy is reported, with tachycardia during the febrile period and bradycardia and conduction defect. Myocarditis and congestive heart failure are rare.

Physical

• Fever is present.
• Rash is described as follows:
  • Up to half of patients with dengue fever develop a characteristic rash.
  • The rash is variable and may be maculopapular or macular.
  • Petechiae and purpura may develop as hemorrhagic manifestations.
• Conjunctival injection develops in approximately one third of patients with dengue hemorrhagic fever. Optic neuropathy has been reported and occasionally results in permanent and significant visual impairment.
• Pharyngeal injection develops in almost 97% of patients with dengue hemorrhagic fever.
• Generalized lymphadenopathy is observed.
• Hepatomegaly is present more often in dengue shock syndrome than in milder cases. Hepatic transaminase levels may be mildly elevated.
• Hemorrhagic manifestations include the following
  • Petechiae and bleeding at venipuncture sites are most common.
  • Results from a tourniquet test are often positive. This test is performed by inflating a blood pressure cuff on the upper arm to midway between diastolic and systolic blood pressures for 5 minutes. The results are considered positive if more than 20 petechiae per square inch are observed on the skin of the arm.
  • Other hemorrhagic manifestations include nasal or gingival bleeding, melena, hematemesis, and menorrhagia.
• Encephalopathy is a rare complication that may result from a combination of cerebral edema, intracranial hemorrhage, anoxia, hyponatremia, and hepatic injury.
• Dengue fever presents in a nonspecific manner and may not be distinguishable from other viral or bacterial illness. The PAHO has developed the following case definitions for the diagnosis of dengue fever and dengue hemorrhagic fever or dengue shock syndrome:
  • The clinical description of dengue fever is an acute febrile illness of 2-7 days duration associated with 2 or more of the following:
    • Severe headache
    • Retroorbital pain
    • Severe myalgias
    • Arthralgia
    • Characteristic rash
    • Hemorrhagic manifestations
    • Leukopenia
  • Laboratory criteria for diagnosis include one or more of the following:
    • Isolation of the dengue virus from serum, plasma, leukocytes, or autopsy samples
    • Demonstration of a 4-fold or greater change in reciprocal immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody titers to one or more dengue virus antigens in paired serum samples
    • Demonstration of dengue virus antigen in autopsy tissue via immunohistochemistry or immunofluorescence or in serum samples via enzyme immunoassay (EIA)
    • Detection of viral genomic sequences in autopsy tissue, serum, or cerebral spinal fluid (CSF) samples via polymerase chain reaction (PCR)
  • Cases are classified as suspected if they are compatible with the clinical description.
  • Cases are classified as probable if they are compatible with the clinical definition and satisfy one or more of the following criteria:
    • Supportive serology (reciprocal hemagglutination-inhibition antibody titer greater than 1280, comparable IgG EIA titers, or positive IgM antibody test in late acute or convalescent-phase serum specimen)
    • Occurrence at the same location and time as other confirmed cases of dengue fever
  • A confirmed case is one that is compatible with the clinical definition and is confirmed by the laboratory.
  • Criteria for the diagnosis of dengue hemorrhagic fever include a probable or confirmed case of dengue infection and hemorrhagic tendencies as evidenced by one or more of the following:
    • A positive result from the tourniquet test
    • Petechiae, ecchymoses, or purpura
    • Bleeding from the mucosa, gastrointestinal tract, injection sites, or other sites
    • Hematemesis or melena and thrombocytopenia (<100,000 cells/μL) and evidence of plasma leakage due to increased vascular permeability that manifests as one or more of the following: greater than 20% rise in average hematocrit level for age and sex, greater than 20% drop in hematocrit level following volume replacement compared to baseline, or signs of plasma leakage (eg, pleural effusion, ascites, hypoproteinemia)
  • Dengue shock syndrome is diagnosed in cases meeting all of the above criteria plus evidence of circulatory failure, such as the following:
    • Rapid, weak pulse
    • Narrow pulse pressure (<20 mm Hg), with increased peripheral vascular resistance (PVR) and elevated diastolic pressure
    • Hypotension
    • Cool, clammy skin
    • Altered mental status, although the patient may initially remain alert
  • The onset of shock may be subtle, indicated by raised diastolic pressure and increased PVR in an alert patient.
• The WHO classification system was recently studied in Indonesian children and was found to have a sensitivity of 86% (95% CI, 76-94) for the detection of dengue shock syndrome. The clinical reliability of the WHO criteria was compared with those of several modified systems, which added the above early predictors of compensated shock and considered models using varying combinations of evidence of hemorrhagic tendencies, thrombocytopenia, and hemoconcentration. These modified systems were found to yield higher sensitivities (88%-99%) for dengue diagnosis than the WHO classification system and were more in line with clinical determinations made by local expert physicians.
• A Belgian study examined predictors of diagnosis in 1962 febrile travelers and expatriates returning from the tropics. After malaria was ruled out, the main predictors of dengue infection included skin rash, thrombocytopenia, and leukopenia.

Causes
Dengue infection is caused by 1 of the 4 dengue viruses (ie, DENV-1, DENV-2, DENV-3, DENV-4) and is transmitted to humans by the bite of an infected mosquito.