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Dengue and Dengue Hemorrhagic Fever

Dengue Branch and the Division of Vector Borne Infectious Diseases, Centers for Disease Control, CID, Fort Collins, CO. Duane J. Gubler, Sc.D and Edward B. Hayes, MD.

Publication date: 11/19/1992


Table of Contents

INTRODUCTION
History
Epidemiology

CLINICAL MANIFESTATION

DIAGNOSIS

TREATMENT

PATHOGENESIS

PREVENTION AND CONTROL

SUMMARY

ACKNOWLEDGEMENTS

REFERENCES

POINT OF CONTACT FOR THIS DOCUMENT:

Figures
World Distribution of Dengue
Aedes Aegypti Distribution in the Americas


INTRODUCTION

Dengue and dengue hemorrhagic fever (DHF) result from infection by any of four serotypes of dengue viruses. Transmission occurs through the bite of infected Aedes mosquitoes, principally Aedes aegypti, which is also the principal urban vector of yellow fever. Hundreds of thousands of cases of dengue and DHF are reported each year in tropical regions of the Americas, Africa, Asia and Oceania. From 1980 through 1987, 879 632 cases of dengue were reported to the Pan American Health Organization from countries in the American region.(1) Outbreaks of the more severe form of dengue, DHF, occurred in Cuba in 1981 (2) and in Venezuela in 1989.(3) The majority of DHF cases, however, occur in Southeast Asia. From 1981 through 1986, 796 386 cases of DHF and 9774 deaths caused by dengue were reported to the World Health Organization (WHO) from countries in Southeast Asia.(4)

Although dengue is primarily a health problem of tropical areas, it is of potential concern to health care providers in the continental United States for two reasons. Of primary concern is the risk of dengue transmission within the continental United States. One of the earliest, if not the first, dengue epidemics described in the medical literature occurred in Philadelphia in 1780.(5-7) Dengue epidemics were reported in various parts of the south- eastern United States through the 19th and 20th centuries, (6) most recently in Louisiana in 1945.(8) Massive regional efforts to control A. aegypti mosquitoes in the American region during the 1950s and 1960s resulted in the successful (although unfortunately impermanent) eradication of this species from many neighboring countries, but it was never eliminated from the southeastern United States, where it continues to thrive.(9) Outbreaks of indigenous dengue transmission occurred in Texas in 1980 and again in 1986.(10) Adding to the concern of indigenous dengue transmission is the recent establishment in the United States of another known dengue vector, Aedes albopictus, which was probably imported in shipments of tires from Asia.(11) This species was discovered in Texas in 1985, and focal infestations as far north as Illinois have subsequently been identified.(12)

The second reason dengue should concern health care providers in this country is the potential for encountering cases of dengue among travelers arriving from dengue-endemic areas.(13-15) From 1980 through 1989, 1457 suspected and 276 confirmed cases of dengue in the continental United States and Hawaii were reported to the Centers for Disease Control.(15) Nine of these were cases from the outbreak in Texas in 1986; all the rest were travelers arriving from dengue-endemic areas. Although the incidence of hemorrhagic dengue in United States travelers abroad is low,(13,15) clinicians in this country may encounter severe cases of dengue, particularly among immigrants from areas with a high incidence of DHF.(13-16)

History

The early history of dengue is clouded by the similarity of its clinical picture to that of other febrile illnesses. Dengue-like epidemics occurred in Egypt and on Java in 1779, but these may actually have been caused by chikungunya virus.(7) Dengue or dengue-like epidemics were reported through- out the 19th and early 20th centuries in the Americas, southern Europe, North Africa, the Middle East, Asia and Australia and on various islands in the Indian Ocean, South and Central Pacific and the Caribbean.(6,7) Generally these epidemics consisted of nonfatal febrile illnesses, often associated with rash and either muscle or joint pains.(7) Deaths occurred during dengue epidemics in Australia in 1897 and in Greece in 1928, when over 1000 deaths were reported.(17) Hemorrhagic manifestations, including gastrointestinal hemorrhage, were described during dengue epidemics in Texas and Louisiana in 1922.(14,18,19) Nevertheless through the first half of the 20th century, dengue was generally described as a self-limited, nonfatal febrile illness, with occasional hemorrhagic manifestations such as petechiae, epistaxis, gingival bleeding and menorrhagia, that only rarely resulted in more severe or fatal outcomes.

In 1944 two immunologically distinct but related viruses, now referred to as dengue 1 (DEN-I) and DEN-2, were isolated by Sabin (21) from patients with clinically diagnosed dengue. In 1956 Hammon et al.(22,23) and coworkers isolated two new serotypes of dengue viruses, designated DEN-3 and DEN-4, as well as the previously recognized DEN-I and DEN-2, during epidemics of severe hemorrhagic illness among children in the Philippines.(22,23) Outbreaks of what came to be known as DHF24 occurred throughout Southeast Asia during succeeding years.(23,25) The term dengue shock syndrome was coined to describe the cases of DHF with shock, which clinical studies indicated was caused by increased vascular permeability and resultant intravascular hypovolemia.(26,27) Eventually the WHO case definition of DHF was modified to make increased vascular permeability the hallmark of the disease.(28) Cases of severe hemorrhage or even deaths caused by dengue infection that do not show evidence of increased capillary permeability are not currently classified as DHF according to WHO criteria.(28,29) The emergence of DHF in the Americas(1,15,30-32) is believed by some researchers to be following a similar pattern to that seen in Southeast Asia more than 30 years ago.(15,30) With the reinfestation of many countries in the American region by A. aegypti, dengue epidemics have recently struck cities and countries in the Americas that had been free of this disease for many years.(15,30,33) The worldwide distribution of endemic and epidemic dengue is shown in (Figure 1). The actual numbers of dengue and DHF cases reported are influenced by differences in surveillance and reporting systems as well as by varying and unclear applications of case definitions, making accurate assessments of global dengue incidence and trends difficult at present.

Epidemiology

Female A. aegypti mosquitoes acquire the dengue virus by biting an infected human during the viremic phase, which usually lasts for 4 to 5 days but may last up to 12 days.(34,35) An extrinsic incubation period in the mosquito of 8 to 10 days must pass before the virus can be transmitted.(5,20) The extrinsic incubation period is lengthened by cooler ambient temperatures. (36) After this extrinsic incubation period the mosquito may transmit the virus during every subsequent feeding of its life.

In most disease-endemic areas dengue transmission has a definite seasonality, but the reasons for the seasonal patterns are not fully understood. In some areas increases in dengue transmission coincide with periods of increased rainfall. (30,35) The interactions between temperature and rainfall or variations in daily microclimates may be important determinants of dengue transmission. (37) Cooler temperatures may affect adult mosquito survival, which may also influence transmission rates. Rainfall and temperature may affect patterns of mosquito feeding and reproduction. (35,37) Human behavior, such as the changes in patterns of water storage in containers, which serve as breeding sites for the mosquitoes, may also affect disease transmission patterns.(35)

The mechanism by which dengue virus circulation is maintained between epidemics is not fully understood. Forest cycles of dengue between monkeys and mosquitoes have been described, (35) but recent techniques of studying molecular evolution in dengue viruses indicate that viruses from forest cycles in Africa do not represent a natural maintenance reservoir for epidemic dengue in humans.(38)

Both dengue and DHF affect persons of all ages, but whereas dengue attack rates are either uniform across age groups (39,40) or in some studies increase with age, (41,42) most DHF cases occur among children younger than 15 years of age. (22,43-45) Some studies have found higher dengue attack rates among women than among men (39-41) and early work suggested that DHF was more common in girls than in boys, (43) but recent surveillance data from Thailand showed almost even proportions of boys and girls among the reported DHF cases.(46) Similar proportions have been found among DHF cases in Puerto Rico and Indonesia.(35,47)

Several authors have indicated that race may be a risk factor for DHF, but interpretation of the data presented thus far is confused by possible interaction of other risk factors and by the lack of clear selection criteria for the study groups used to compare rates between races. (45,48,49) A genetic risk for DHF was suggested by one study finding a possible relation- ship between histocompatibility antigens and DHF. (50)

The rate of DHF among dengue-infected individuals is difficult to determine but would be expected to vary with underlying risk factors and perhaps with the infecting virus strain.(35) Estimates of this rate have ranged from 1 to 7 DHF cases per 100 dengue infections.(1,51) Initially DHF case fatality rates, when the disease was not treated, were as high as 50%, (44) but with appropriate recognition and treatment the reported case fatality rate in Thailand has dropped to less than 1%. (46)

Infection with a particular dengue serotype is believed to provoke long lasting homotypic immunity.(17) In one study of experimental infection, heterotypic immunity lasted for 2 months, after which patients were susceptible to infection with another serotype.(20) Another study presented epidemiologic data that suggested that heterotypic immunity might last for up to 1 year.(52)


CLINICAL MANIFESTATION

Since the recognition of DHF in the 1950s investigators have sought to define the clinical differences between severe and mild forms of dengue. Mild hemorrhagic manifestations, such as epistaxis, petechiae, gingival bleeding and menorrhagia, are accepted as part of the clinical picture of classic dengue.(28) Manifestations of severe dengue include severe hemorrhage leading to shock through blood loss, (29) sudden increased vascular permeability leading to shock with or without hemorrhage (26,53) and severe encephalopathy with hepatitis.(54-56) The classification of severe dengue has been complicated by the variety of these clinical pictures, for which the underlying pathophysiology may be different. (29,35,57)

The following description of the clinical course of classic dengue infection is based on the work of Riley (5) and Sabin,(20) who observed and described adults with naturally acquired or experimentally induced infec- tions.

Two to 15 days after the bite of an infective mosquito, the patient typically suffers sudden onset of headache, fever, retroorbital pain, backache, bone and joint pain, weakness, depression and malaise. Some patients have an evanescent rash over the thorax and joint flexures. There may be flushing of the face and conjunctivitis as well as taste aberrations, anorexia, nausea, vomiting and abdominal pain. Lymphadenopathy and hepatomegaly may occur but splenomegaly is infrequent. Patients may complain of sore throat, cough, groin pain, hyperesthesia, dizziness, photophobia, eye pain and, rarely, a "yellow flamelike" color to objects.

Fever and associated symptoms may subside after 3 or 4 days and the patient may recover completely. Alternatively the decline in fever may be followed 1 to 3 days later by a resurgence of fever and symptoms, giving a "saddleback" appearance to the temperature curve. A second rash, varying in form from scarlatiniform and maculopapular to petechial and occasionally purpuric, may appear with the initial decline of the fever. Severe itching, especially of the hands and feet, may accompany this rash, which is sometimes followed by desquamation. The symptoms persist for 1 to 3 days more and then subside with the fever.

During the course of the illness there is often a relative or paradoxical bradycardia in the face of increased temperature. Patients may have hemor- rhagic manifestations such as epistaxis or menorrhagia. Jaundice is rare. Convulsions may occur with the onset of fever. The spinal fluid is almost always clear with no elevation of cell count but the pressure may be increased. Depression, weakness and blurred vision may resolve slowly during convalescence. Patients may take several weeks to recover completely.

Although these symptoms characterize "classical" dengue fever, dengue virus infection may also manifest as a nonspecific febrile illness which can be confused with influenza, measles or any nonspecific vital syndrome. The lack of a clear clinical pattern for dengue makes laboratory diagnosis a necessary part of any definitive evaluation of the disease.(58)

Patients who develop DHF or other severe manifestations of dengue generally have an onset of illness similar to that seen in "classical" or nonhemorrhagic dengue. (59) The course usually begins with the sudden onset of fever, headache, nausea, vomiting, abdominal pain, pharyngitis, lymphadenopathy and sometimes a rash, which may be petechial or even ecchymotic early in the course. (59,60)

The liver may become enlarged and pleural effusions may develop, usually beginning on the right side.(59,60) As the fever begins to drop around Day 3 to 5, circulatory instability may develop with signs of decreased peripheral perfusion. Profound shock may follow. (59,60) Disseminated intravascular coagulation and severe gastrointestinal hemorrhage have been described.(29)

The descriptions of such patients led to the following WHO case definitions for DHF: (1) fever; (2) hemorrhagic manifestations, including at least a positive tourniquet test (except in shock cases), and either major or minor bleeding phenomena; (3) thrombocytopenia (platelet count less than or equal to 100 000/ mm3); and (4) hemoconcentration (hematocrit increased by 20% or more relative to baseline values, or objective evidence of increased capillary permeability).(28)

In addition to this pattern of DHF, cases of severe dengue with massive gastrointestinal hemorrhage preceding the onset of shock, and without evidence of increased vascular permeability, have been described.(29) Many of these fatal hemorrhagic cases did not meet the WHO case definition for DHF. Severe encephalopathy with convulsions and/or coma has also been described with dengue infection.(29,54-56) Increased spinal fluid white blood cell counts (up to 27/ mm(3)) were found in one series(29) and normal spinal fluid was seen in another.(56)

Significant thrombocytopenia may occur in both DHF and "classical" dengue.(47,61,63) A fall in platelet count associated with a rising hematocrit may suggest the development of DHF.(59)

Results of coagulation tests may be abnormal; prolonged partial thromboplastin and thrombin times are noted more frequently than prolonged prothrombin times.(59) Elevated concentrations of serum aspartate amino- transferase have been noted in several studies.(56,59,62,64) Hyponatremia is commonly found in DHF patients with shock and may be a cause of convulsions.(56) Results of urinalysis are usually normal,(20) but hematuria, trace amounts of albumin and urinary casts have been reported. (47,60,65)


DIAGNOSIS

Classical dengue fever may be confused with a variety of febrile ill- nesses, including influenza, measles, typhoid fever and malaria. DHF may be confused with sepsis, toxic shock and any of the viral hemorrhagic fevers including yellow fever. Diseases with specific treatments, such as bacterial meningitis, sepsis, malaria and Lassa fever, should be ruled out.

Specific diagnosis of dengue infection is made by isolating the virus from the patient's blood. Acute serum samples are inoculated into tissue cultures of mosquito cells or directly into live Toxorhynchites or Aedes mosquitoes.(66,67) Isolates can be identified from 2 to 7 days after inoculation depending on the actual technique used.(35) Viruses are most likely to be isolated from acute serum samples obtained within 5 days after the onset of illness.(34,35) Specific dengue serotypes can be identified by the indirect fluorescent antibody test, with the use of type-specific monoclonal antibodies on the isolated virus.(67)

Immunodiagnostic methods for determining dengue infection include detection of anti-dengue IgM and IgG by enzyme-linked immunosorbent assay (ELISA) and detection of hemagglutination inhibition antibody. Dengue-induced hemagglutination inhibition antibody cross-reacts broadly with other flaviviruses such as yellow fever and St. Louis encephalitis viruses.(35) Complement fixation and neutralization antibody tests are more specific than hemagglutination inhibition.(35) Most serologic screening for dengue infection is now done with an IgM ELISA.(35,68) With appropriately timed samples, the sensitivity and specificity of this test in diagnosing dengue infection appear to be high. In a review of 131 patients from whom dengue virus was isolated at the Centers for Disease Control, Dengue Branch, 96% of the 76 samples drawn between 7 and 20 days after the onset of illness were positive by IgM capture ELISA (DJ Gubler, G Kuno, I Gomez, et al. unpublished data). A study of the performance of IgM ELISA in Thailand showed the sensitivity of this test in convalescent samples to be 97%, and none of the samples from the 2 groups of noninfected controls (98 soldiers and 39 schoolchildren) were positive.(69)

The pattern of HI response has been used to classify dengue infections as primary or secondary, based on the concept that initial, or primary dengue infections tend to elicit lower HI titers than do secondary infections (subsequent infections with a different dengue serotype or antigenically related flavivirus).(28) IgM:IgG ratios as determined by ELISA may be an alternative method of distinguishing primary from secondary infections. (69,70) The rise in neutralizing antibody in primary infection is believed to be relatively type-specific and can be used to determine the infecting serotype.(35) In secondary infections, because the immunologic cross- reactivity to different flaviviruses and anamnestic responses may result in heterologous titer elevations, the only reliable method for determining the infecting serotype is virus isolation.(35)

In summary diagnosis of dengue infection is best accomplished by obtaining an acute serum sample within 5 days after the onset of illness for virus isolation and antibody testing and a convalescent serum sample 14 to 21 days after illness onset for detecting IgG antibody titer rise and/or the presence of antidengue IgM.


TREATMENT

Treatment for classic dengue fever is supportive. Patients should be encouraged to drink plenty of fluids. Acetaminophen may be taken to control fever and aching if necessary. Aspirin is contraindicated both because of its anticoagulant effects and the increased risk of developing Reye syndrome. (56,71,72) Patients or parents should be carefully instructed of the need to seek medical attention immediately if major or ongoing hemorrhage, signs of impending shock or any change in mental status should occur. The onset of cardiovascular collapse in patients who develop DHF may be sudden.(28)

Patients with significant hemorrhage or signs of increased capillary permeability such as hemoconcentration, effusions, edema or low serum albumin, as well as patients with mental status changes or with abnormal fluid and electrolyte balance, should be hospitalized and may require admission to an intensive care unit. Isolation is not necessary in mosquito- free environments. Usual precautions handling blood specimens should be observed.

Intravenous fluid therapy is the mainstay of treatment for patients with DHF.(28,59) Patients with dehydration and hemoconcentration may require intravenous fluids similar in volume and composition to regimens used to treat dehydration due to diarrheal illness.(25) Patients in shock should be given fluids and other therapy according to accepted regimens for shock. (28,73) The administration of heparin may need to be considered in patients who develop DIC.(28,59)

There is some controversy over the role of steroids in treatment of severe dengue.(74) Studies by Sumarmo et al.(74,75) showed no benefit, over fluid therapy alone, of hydrocortisone injection given either 30 mg/kg/day or 50 mg/kg in a single dose. The potential effect of high dose methylprednisolone in certain severe cases may need further evaluation. (74,76)


PATHOGENESIS

The site of viral replication during dengue infection remains uncertain. Mononuclear phagocytes may be the most likely site,(57) but infection of megakaryocytes in the bone marrow has also been proposed.(61) Viral particles or antigen have been detected in monocytes in kidney, skin tissue, liver, spleen, thymus and lung.(57) Dengue virus has been isolated from peripheral blood leukocytes, as well as from autopsy tissue from liver, spleen, lymph node, bone marrow, thymus, heart, kidney, stomach and lung (DJ Gubler, unpublished).(57)

Several hypotheses have emerged to explain why DHF occurs in some individuals who are infected with dengue viruses. These include (1) changes or differences in viral virulence between serotypes and/or between strains within serotypes, (22,35,77-79) (2) interactions of dengue viruses with other environmental or infectious agents, (22) (3) differences in genetic susceptibility or other host factors, (35,50,56) and (4) the immunologic enhancement of dengue infection by antibody acquired from a previous infection with a different dengue serotype.(45)

The theory of immune enhancement, developed extensively by Halstead, (80) predicts that individuals who have been immunologically sensitized to one dengue virus serotype may develop nonneutralizing antibodies that actually enhance the entry of different serotype dengue viruses into mononuclear phagocytes, resulting in the increased activation of complement and kinins, and the release of mediators of vascular permeability. (57) This proposed mechanism has been supported by laboratory investigation, (57) and several studies have shown that during outbreaks a large majority of DHF patients show secondary immune response patterns.(17,81,82) However, cases of DHF have been described in patients with primary dengue infection, (34,35,78,79,83) and the denominators for estimating proportions of primary and secondary infections that result in DHF have been difficult to evaluate with certainty.(78) Carefully designed epidemiologic studies are needed to further evaluate this theory and to study the possible interaction of immune enhancement with other risk factors. The recognition of various forms of severe or fatal dengue that are different from DHF as defined by WHO may require revisions or additions to the case definitions required for such studies.(29)


PREVENTION AND CONTROL

A. aegypti is an anthropophilic, domestic mosquito which lives intimately with its human hosts.(35,51) These mosquitoes breed primarily in man-made containers such as water storage containers, old tires and flower vases in and around human dwellings. Elimination of these breeding sites is an effective and definitive method of controlling the vector and therefore of preventing transmission of dengue.(9,35,51) During the 1950s and 1960s widespread control campaigns directed by the Pan American Health Organization were successful in eradicating A. aegypti from many countries of Latin America, with the use of a combination of DDT, which has a long residual activity, and the systematic elimination of larval habitats. (9,51) Unfortunately vigilance and control lapsed during the 1970s, and most of the countries of tropical America have become widely reinrested with A. aegypti(9) (Figure 2). Nonresidual insecticides such as malathion, which kills mosquitoes on contact, have been used in attempts to control dengue epidemics. However, nonresidual insecticides applied from truck- mounted and aerial equipment were shown to be ineffective in studies conducted in Puerto Rico, where mosquitoes were found to hide within houses (IP Reiter, DJ Gubler and GC Clark, unpublished data). This approach will likely have similar limitations elsewhere. New efforts are focusing on community education and behavior modification in an attempt to encourage neighborhoods to control the vector through breeding site reduction. (9)

There is no dengue vaccine currently available for widespread public health use. Research continues on developing an effective and safe tetravalent vaccine that would circumvent the potential hazards predicted by the immune enhancement theory. Currently the only effective way to avoid dengue infection in areas where the disease is endemic or epidemic is to avoid being bitten by infected mosquitoes through the use of personal insect repellent and other insect barriers.


SUMMARY

Hundreds of thousands of dengue cases are reported worldwide each year. Given the difficulty in obtaining full reporting, the actual number of human infections is probably much higher than the number reported. Dengue is usually a nonspecific febrile illness that resolves with supportive therapy but the clinical spectrum ranges from asymptomatic infection through severe hemorrhage and sudden fatal shock. The pathophysiology of the severe forms of dengue may be related to sequential infection with different serotypes, variations in virus virulence, interaction of the virus with environmental and host factors or a combination of these factors. Control of dengue at the present time is dependent on control of the principal vector mosquito, A. aegypti. Efforts to achieve such control are now focusing on community education and action towards eliminating this mosquito's breeding sites near human dwellings. Vaccine development continues, but at present the only way to avoid dengue in an area where it is endemic or epidemic is to use repellents and mosquito barriers. The movement of people to and from tropical areas makes dengue an important differential diagnosis in any patient with an acute illness and history of recent travel to tropical areas. Because of continued infestation of the southeastern United States with A. aegypti, indigenous transmission in the continental United States remains a public health concern.


ACKNOWLEDGEMENTS

The authors thank Dr. Walter Orenstein for his thoughtful editorial assistance in preparing this paper and Ms. Katherine Bruce for her assistance in preparation of the manuscript.
Accepted for publication Nov. 19, 1992.

From the Dengue Branch (EBH) and the Division of VectorBorne Infectious

Diseases (DJG), Centers for Disease Control, CID, Fort Collins, CO. Key words: Dengue, hemorrhagic fever.

Address for reprints: Duane J. Gubler, Sc.D. Centers for Disease Control,

P.O. Box 2087 (Foothills Campus), Fort Collins, CO 80522.


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Figure 1

World Distribution of Dengue

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Figure 2

Aedes Aegypti Distribution in the Americas

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