Dengue in Travelers
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《新英格兰医药杂志》
Dengue virus infection is increasingly recognized as one of the world's major emerging infectious diseases.1,2,3 Dengue is endemic in most tropical and subtropical countries, many of which are popular tourist destinations.4 International travelers may both acquire and spread dengue virus infection. Health care providers need to understand the epidemiology, risk factors, clinical spectrum, diagnosis, management, and prevention of dengue in travelers.
The Virus, the Vector, and the Epidemiology of Dengue
Dengue virus belongs to the family Flaviviridae (single-stranded, nonsegmented RNA viruses) (Table 1) and has four serologically distinct serotypes (DEN-1, DEN-2, DEN-3, and DEN-4).1 Dengue virus serotypes are distinguishable by complement-fixation and neutralization tests.5 Infection with one serotype confers long-term immunity only to that serotype, and therefore persons may be infected up to four times.6 Humans are the main reservoir for the dengue virus, although nonhuman primates in Asia and Africa may also be infected.7
Table 1. Important Flavivirus Infections in Travelers.
Dengue virus is transmitted by mosquitoes of the genus aedes, such as Aedes aegypti and A. albopictus.1 A. aegypti, found worldwide in the tropics and subtropics, is the principal vector (Figure 1). It is an efficient vector because it is highly susceptible to dengue virus, feeds preferentially on human blood, is a daytime feeder, has an almost imperceptible bite, and is capable of biting several people in a short period for one blood meal.7 The mosquito is well adapted to life in urban settings and typically breeds in clean, stagnant water in containers that collect rainwater, such as tires, tin cans, pots, and buckets.1
Figure 1. World Distribution of Dengue, 2002.
Adapted from the Centers for Disease Control and Prevention.8
Dengue virus is now the most common cause of arboviral disease in the world, with an estimated annual occurrence of 100 million cases of dengue fever and 250,000 cases of dengue hemorrhagic fever and a mortality rate of 25,000 per year.7 Dengue virus infection has been reported in more than 100 countries, with 2.5 billion people living in areas where dengue is endemic6,8 (Figure 1). Most cases of dengue hemorrhagic fever are reported from Asia, where it is a leading cause of hospitalization and death among children.2 In Latin America, dengue hemorrhagic fever was a rare disease before 1981.2 The 1980s and 1990s saw a dramatic geographic expansion of epidemic dengue fever and dengue hemorrhagic fever from Southeast Asia to the South Pacific Islands, the Caribbean, and Latin America, with regions changing from nonendemic (no serotypes present) to hypoendemic (one serotype present) or hyperendemic (multiple serotypes present).9 The World Health Organization (WHO) classifies dengue as a major international public health concern because of the expanding geographic distribution of both the virus and the mosquito vector, the increased frequency of epidemics, the cocirculation of multiple virus serotypes, and the emergence of dengue hemorrhagic fever in new areas.1,7 The reasons for this resurgence are complex and include urbanization with substandard living conditions, lack of vector control, climatic change, virus evolution, and international travel.6
Risk among International Travelers
The marked increase in dengue during recent decades is in tandem with increasing reports of international travelers with dengue, including long-term expatriates, aid and development workers, and military troops stationed in and immigrants from countries where dengue is endemic.10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31 Dengue fever has been diagnosed in an increasing proportion of febrile travelers returning from the tropics, ranging from 2 percent in the early 1990s to 16 percent more recently.22,32,33,34 In some case series, dengue fever has been reported as the second most frequent cause of hospitalization (after malaria) among travelers returning from the tropics.13,22,34 The rate of self-reported dengue fever among Israeli travelers to Thailand in 1998 was 3.4 per 1000 travelers.35 Prospective studies of seroconversion rates in both asymptomatic and symptomatic travelers with a positive IgM antibody test for dengue revealed an incidence of dengue of 2.9 percent (after a mean of one month of travel)18 and 6.7 percent (after a mean of six months of travel)23; however, these data must be interpreted with caution since a positive test for IgM antibodies gives only a probable diagnosis, and prospective serologic studies are hampered by the cross-reactivity of enzyme-linked immunosorbent assays (ELISAs) with other flaviviruses.36
The true incidence of dengue in travelers is probably underestimated because in many countries it is not a disease that medical personnel are required to report and because it is often underreported in travelers who become ill during travel and is underdiagnosed because of the nonspecific nature of the infection.7 The rate of infection may be as high as that of malaria (without chemoprophylaxis) and higher than that of other travel-related diseases, such as hepatitis A or typhoid fever.4,37,38 Risk factors among travelers acquiring dengue relate to the duration, season, and destination of travel.18 Most dengue virus infections in travelers are acquired in Asia, followed by the Americas, with only a small proportion in Africa.11,12
In countries where dengue currently is not endemic but where a capable vector exists, new autochthonous cycles of infection may be established from infected travelers or immigrants who are coming from areas where the disease is endemic; this phenomenon has been reported in parts of the United States, southern Europe, and the Mediterranean.39,40 However, the risk of introduction of the disease to Western countries by travelers is difficult to assess.4 There have been isolated reports of returning travelers who have transmitted dengue virus infection to health care workers in countries where dengue is nonendemic by way of needle-stick injury41,42 or mucocutaneous exposure to blood43 — modes of nonvector transmission of dengue previously seen only rarely.
Clinical Aspects of Dengue Virus Infections
Pathogenesis
After an infected mosquito has bitten a person, the virus replicates in regional lymph nodes and is disseminated through the lymphatic system and blood to other tissues.44 Replication in the reticuloendothelial system and skin results in viremia.44 The incubation period ranges from 3 to 14 days, but it is usually 4 to 7 days. Infection with dengue virus of any of the four serotypes causes a spectrum of illness, ranging from no symptoms or mild fever to severe and fatal hemorrhage, depending largely on the patient's age and immunologic condition.7
Although the mechanisms for the development of severe hemorrhagic disease are not fully understood, the main risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome is thought to be secondary infection with another serotype.6,45 Cross-reactive but non-neutralizing anti-dengue antibodies from the previous infection bind to the new infecting serotype and enhance viral uptake of monocytes and macrophages. This antibody-dependent enhancement results in an amplified cascade of cytokines and complement activation, causing endothelial dysfunction, platelet destruction, and consumption of coagulation factors leading to plasma leakage and hemorrhagic manifestations.6,46,47,48 The severity of the disease also depends on the strain and serotype of the infecting virus, the age and genetic background of the patient,6,49,50 and the degree of viremia.51
Asymptomatic Infection and Acute Febrile Illness
Most persons, particularly young children, with dengue infections in areas where the disease is endemic are asymptomatic or they present with mild febrile illness.7 In adult travelers, the ratio of asymptomatic to symptomatic cases has been reported to be between 1:0.8 and 1:3.3,18,23 but these data were derived only from studies based on the diagnosis of dengue established by a positive test for IgM antibody.
Classic Dengue Fever
Classic dengue fever is characterized by the sudden onset of fever, accompanied by a severe headache, retro-orbital pain, and fatigue, and it is often associated with severe myalgia and arthralgia ("breakbone fever").44 The fever usually lasts five to seven days. A rash, typically macular or maculopapular and often confluent with the sparing of small islands of normal skin (Figure 2), has been reported in about half of infected persons. It usually appears near the time of defervescence, often lasts for two to four days, and may be accompanied by scaling and pruritus.11,13,52 Other signs and symptoms include flushed facies (usually during the first 24 to 48 hours), lymphadenopathy, injected conjunctivae, an inflamed pharynx, and mild respiratory and gastrointestinal symptoms. Patients with dengue fever may have hemorrhagic manifestations, such as petechiae, purpura, or evidence of a positive tourniquet test for capillary fragility; the test is positive if 20 or more petechiae appear in a 1-in.2 (6.25-cm2) patch on the forearm after deflation of the blood pressure cuff (Figure 3).44 Gum bleeding, epistaxis, menorrhagia, and gastrointestinal hemorrhage are only occasionally seen. Very rare complications of dengue fever include myocarditis, hepatitis,53 and neurologic abnormalities, such as encephalopathy and neuropathies.54 Laboratory findings commonly associated with dengue fever include thrombocytopenia, leukopenia with lymphopenia, mild-to-moderate elevations of hepatic aminotransferases and lactate dehydrogenase, and hyponatremia.7,13
Figure 2. Dengue Rash with Sparing of Islands of Skin.
Panels A and B show a maculopapular rash with island sparing. Courtesy of Eduardo Gotuzzo and David Freedman, Gorgas Tropical Medicine Course, Universidad Peruana Cayetano Heredia, Lima, Peru.
Figure 3. Positive Result on a Tourniquet Test.
The tourniquet test is performed by inflating a blood pressure cuff on the upper arm to a point midway between systolic and diastolic blood pressures for five minutes. A test is considered positive when there are 20 or more petechiae per square inch (6.25 cm2) on the forearm. Courtesy of Ann McCarthy, Tropical Medicine and International Health Clinic, Ottawa Hospital, Ottawa.
Classic dengue fever in travelers, although self-limiting and rarely fatal, can be incapacitating, may halt travel, and may require hospitalization and even evacuation and a return home.4,13 In one series from Israel, 30 percent of travelers who contracted dengue fever were evacuated, and 66 percent were hospitalized.13 Convalescence may be prolonged for weeks because of asthenia and depression.55
Dengue Hemorrhagic Fever and Dengue Shock Syndrome
The hallmark of dengue hemorrhagic fever is capillary leakage, accompanied by hemorrhagic manifestations. The presentation of patients in the first days of the illness is similar to that seen in dengue fever, but plasma leakage develops four to seven days after the onset of the disease, at approximately the time of defervescence. Abdominal pain and vomiting, restlessness, a change in the level of consciousness, and a sudden change from fever to hypothermia may be the first clinical warning signs and are often associated with a marked decrease in the platelet count.7
The diagnosis of dengue hemorrhagic fever is made on the basis of the following triad of symptoms and signs: hemorrhagic manifestations; a platelet count of less than 100,000 per cubic millimeter; and objective evidence of plasma leakage, shown either by fluctuation of packed-cell volume (greater than 20 percent during the course of the illness) or by clinical signs of plasma leakage, such as pleural effusion, ascites, or hypoproteinemia. Hemorrhagic manifestations without capillary leakage do not constitute dengue hemorrhagic fever. A positive tourniquet test is incorporated in the WHO clinical case definition of dengue hemorrhagic fever, but the definition differentiates poorly between dengue and dengue hemorrhagic fever and is not very specific.56 Mortality rates from dengue hemorrhagic fever can range as high as 10 to 20 percent, but they are as low as 0.2 percent in hospitals with staff experienced in the management of the disease.7,50,57
Dengue shock syndrome is characterized by a rapid, weak pulse with a narrowing pulse pressure of less than 20 mm Hg, or profound hypotension (systolic pressure of less than 90 mm Hg among those five years of age or older). The duration of shock is short. Typically, patients either recover rapidly after appropriate volume-replacement therapy is administered or die within 12 to 24 hours; the mortality rate is up to 40 percent.7
Within the European Network on Imported Infectious Disease Surveillance, dengue hemorrhagic fever was reported in 2.7 percent of 483 cases of dengue.12 The risk of dengue hemorrhagic fever was 4.3 times higher in immigrants and in persons visiting friends and relatives in areas where the disease is endemic than in general travelers.12 Dengue shock syndrome in travelers is uncommon, as is death from dengue,4 but two deaths were reported in a series of more than 200 cases of dengue imported to the United States between 1993 and 2000.27,28,29,30,31
Diagnosis and Differential Diagnosis
A confirmed diagnosis is established by culture of the virus, polymerase-chain-reaction (PCR) tests, or serologic assays (Table 2). All these tests have limitations. PCR testing is not available in many settings and is sensitive only in the very early stages of the disease.59 The test based on an increase in the IgG titer by a factor of four is difficult in routine clinical care because a second blood sample is required at the convalescent stage. Cross-reactions with other flaviviruses interfere with serologic testing, particularly the ELISA for IgG, and this affects the interpretation of test results in travelers exposed to other flavivirus infections, including those previously vaccinated against flavivirus infections, such as yellow fever and Japanese encephalitis.36 The most commonly used test for the diagnosis of dengue is the IgM capture ELISA, but this test is negative early in the course of the disease, should be performed only four to five days after the onset of symptoms, and gives only a probable diagnosis (Table 2).36 Rheumatoid factor may lead to an IgM capture assay that is false positive for dengue, and so may other flavivirus infections (albeit less so than with dengue IgG assays).36,59
Table 2. Laboratory Diagnosis of Dengue.
Primary infections are characterized by an increase in dengue-specific IgM antibodies 4 to 5 days after the onset of fever and by an increase in IgG antibodies only after 7 to 10 days.60 IgM antibodies are detectable for three to six months, whereas IgG antibodies remain detectable for life. In secondary infections, the level of IgM antibodies is lower than in primary infections and the antibodies are sometimes even absent, whereas levels of IgG antibodies rise rapidly in secondary infections, even during the acute phase.6 Thus, the presence of high titers of IgG early in the course of the disease is a criterion for secondary infection.
Therefore, since a laboratory-based diagnosis of dengue is often unavailable at the time of care, a clinical diagnosis is initially made on the basis of clinical manifestations and laboratory features developing over a period of time and as other potentially life-threatening diseases, such as malaria, are ruled out (Figure 4). A travel history is an important clue because the incubation period for dengue is less than two weeks; dengue can be ruled out if symptoms begin more than two weeks after the traveler or immigrant has left an area where the disease is endemic.58 Fever that persists more than 10 days usually rules out dengue.
Figure 4. Flow Diagram for the Clinical Diagnosis of Dengue in Returning Travelers.
Detailed outpatient and hospital flow diagrams are available from the World Health Organization (www.who.int/csr/resources/publications/dengue/en/074.pdf and www.who.int/csr/resources/publications/dengue/en/075.pdf).
The relation in time between the drop in the platelet count and the rapid increase in the hematocrit is unique to dengue hemorrhagic fever,61 and together with the clinical signs is sufficient to establish a clinical diagnosis of dengue hemorrhagic fever. However, the symptoms and signs of mild febrile illness or classic dengue fever are nonspecific and hard to distinguish from many other undifferentiated febrile syndromes. The differential diagnosis includes malaria, typhoid fever, leptospirosis, chikungunya, West Nile virus infection, measles, rubella, acute human immunodeficiency virus conversion disease, Epstein–Barr virus infection, viral hemorrhagic fevers, rickettsial diseases, early severe acute respiratory syndrome (SARS), and any other disease that can manifest in the acute phase as an undifferentiated febrile syndrome.44,62 A combination of laboratory variables (low platelet or leukocyte count and increased liver aminotransferase levels) is highly predictive of the diagnosis of dengue and may help to differentiate dengue from typhus52 and early SARS.62 A positive tourniquet test or leukopenia (5000 cells per cubic millimeter) are the two tests with the highest sensitivity (about 90 percent) for the diagnosis of early dengue, since the platelet count may initially be normal and drop only on subsequent days. If the two tests are combined, the sensitivity decreases, but the positive predictive value increases.63
Management
No specific therapeutic agents exist for dengue. Corticosteroids, carbazochrome (a drug that decreases capillary permeability), and antiviral agents have no proved role (although ribavirin, interferon alfa, and 6-azauridine have shown some antiviral activity in vitro).7,64,65 Prompt and correct institution of fluid replacement is thought to reduce mortality rates due to dengue hemorrhagic fever and dengue shock syndrome.66 Treatment is therefore based on symptoms and supportive, with the principal aim to prevent death. Mild or classic dengue is treated with antipyretic agents such as acetaminophen, bed rest, and fluid replacement (usually administered orally and only rarely parenterally); most cases can be managed on an outpatient basis. Aspirin and nonsteroidal antiinflammatory drugs are best avoided because they can increase bleeding. Intramuscular injections should not be given because they may cause large hematomas. Platelet counts and hematocrit determinations should be repeated at least every 24 hours to allow prompt recognition of the development of dengue hemorrhagic fever and institution of fluid replacement.66,67
Patients with a platelet count of less than 100,000 per cubic millimeter are usually admitted to a hospital since they have the highest risk of the development of dengue hemorrhagic fever (Figure 4). The critical period is often on the day of defervescence, typically four to seven days after onset of the illness. A decrease in the platelet count, which usually precedes the rise in hematocrit, is of diagnostic and prognostic value in cases of dengue hemorrhagic fever.67 A rise in the hematocrit of 20 percent indicates considerable plasma loss, and patients with this condition require intensive care with intravenous replacement of fluids such as normal saline and Ringer's lactate.66,68,69 In patients with worsening shock, colloid or crystalloid solutions should be added (10 to 20 ml per kilogram of body weight per hour), although some studies suggest that colloid solutions are superior to crystalloid solutions.44,66,69 If there is evidence of bleeding or disseminated intravascular coagulation, fresh blood or fresh-frozen plasma should be administered. Once the capillary leakage stops and resorption of extravasated fluid begins, care must be taken not to cause fluid overload and pulmonary edema.44 Therapy with parenterally administered fluids should be stopped or reduced when the hematocrit drops below 40 percent and is accompanied by improving clinical signs and urine output, which occur generally after 24 to 72 hours.44 Guidelines concerning the rate of intravenous infusion and specific time periods for infusion have been published by the WHO.70
Prevention of Dengue Infections in Travelers
Effective control of dengue remains elusive. Public health efforts have to focus on vector control and community-based programs to keep the environment free of potential breeding sources, but this is difficult because of the intimacy of aedes mosquitoes with humans. A vaccine that provides effective, long-term immunity against infection with all four serotypes of dengue is urgently needed. Poor financial support and the absence of an animal model are the main problems.6 In addition, a vaccine should provide protective immunity against the four serotypes of dengue virus to avoid the phenomenon of antibody-dependent enhancement.4 Live attenuated, tetravalent dengue vaccines have been shown to be immunogenic and safe and are undergoing further clinical trials.71 New approaches to the development of vaccines include the use of infectious clone DNA and naked DNA that may offer simpler and cheaper methods of manufacturing, as well as possible greater stability and safety.7
The single most effective preventive measure for travelers in areas where dengue is endemic is to avoid mosquito bites by using insect repellents containing N,N-diethyl-3-methylbenzamide (DEET),72 protective clothing (the most effective is permethrin-impregnated), and insecticides.4 Aedes mosquitoes bite during the day; hence, these measures must be taken during the day, particularly in the morning and late afternoon. The usefulness of insecticide-treated bed nets at night is therefore limited. Aedes mosquitoes are also indoor feeders and are often found in dark areas, such as in closets and bathrooms, behind curtains, and under beds. It is advisable to spray these areas with insecticides.4 Care should be taken not to leave trash, pots, or any other containers outdoors, since they can fill with rainwater and become breeding grounds.
Pretravel advice should include information about the risk of contracting dengue, destinations associated with high risk, and signs and symptoms of dengue infection. The Centers for Disease Control and Prevention (www.cdc.gov/ncidod/dvbid/dengue) and the WHO (www.who.int/topics/dengue/en/) provide information about countries where dengue is endemic and updates on new epidemic trends. There is no real "safe" season, although there seems to be a cyclical pattern and a rise in cases during the rainy season. Transmission is maintained even between epidemics.73 The main risk of exposure among travelers exists in urban and residential areas. It is also important to remind travelers that the symptoms of dengue may resemble those of malaria and that malaria should be ruled out first.
Reinfection with another serotype of dengue virus may predispose a person to the development of dengue hemorrhagic fever or dengue shock syndrome, which is associated with a high mortality rate.2 Therefore, repeated travel to countries where dengue is endemic may put those previously infected with dengue — travelers, immigrants, and persons visiting friends and relatives — at increased risk. No data on the extent of this risk are available, and therefore no evidence-based guidelines on pretravel screening for dengue are in place.
Until aedes mosquitoes can be effectively controlled or until a cost-effective vaccine is developed, cases of dengue infections will continue to escalate. Therefore, clinicians in areas where the infection is not endemic will see and have to treat dengue in increasing numbers of travelers returning from areas where the disease is endemic.
Source Information
From the Travellers' Health and Vaccination Centre, Tan Tock Seng Hospital, Singapore (A.W.-S.); and the Center for Geographic Medicine and Tropical Diseases, Chaim Sheba Medical Center, Tel Hashomer, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv — both in Israel (E.S.).
Address reprint requests to Dr. Wilder-Smith at the Travellers' Health and Vaccination Centre, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, or at epvws@pacific.net.sg.
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Wills BA, Dung NM, Loan HT, et al. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005;353:877-889.
Management of dengue fever: treatment. (Accessed August 8, 2005, at http://www.who.int/csr/resources/publications/dengue/en/024-33.pdf.)
Barrett AD. Current status of flavivirus vaccines. Ann N Y Acad Sci 2001;951:262-271.
Fradin MS, Day JF. Comparative efficacy of insect repellents against mosquito bites. N Engl J Med 2002;347:13-18.
Gubler DJ, Reiter P, Ebi KL, Yap W, Nasci R, Patz JA. Climate variability and change in the United States: potential impacts on vector- and rodent-borne diseases. Environ Health Perspect 2001;109:Suppl 2:223-233.(Annelies Wilder-Smith, M.)
The Virus, the Vector, and the Epidemiology of Dengue
Dengue virus belongs to the family Flaviviridae (single-stranded, nonsegmented RNA viruses) (Table 1) and has four serologically distinct serotypes (DEN-1, DEN-2, DEN-3, and DEN-4).1 Dengue virus serotypes are distinguishable by complement-fixation and neutralization tests.5 Infection with one serotype confers long-term immunity only to that serotype, and therefore persons may be infected up to four times.6 Humans are the main reservoir for the dengue virus, although nonhuman primates in Asia and Africa may also be infected.7
Table 1. Important Flavivirus Infections in Travelers.
Dengue virus is transmitted by mosquitoes of the genus aedes, such as Aedes aegypti and A. albopictus.1 A. aegypti, found worldwide in the tropics and subtropics, is the principal vector (Figure 1). It is an efficient vector because it is highly susceptible to dengue virus, feeds preferentially on human blood, is a daytime feeder, has an almost imperceptible bite, and is capable of biting several people in a short period for one blood meal.7 The mosquito is well adapted to life in urban settings and typically breeds in clean, stagnant water in containers that collect rainwater, such as tires, tin cans, pots, and buckets.1
Figure 1. World Distribution of Dengue, 2002.
Adapted from the Centers for Disease Control and Prevention.8
Dengue virus is now the most common cause of arboviral disease in the world, with an estimated annual occurrence of 100 million cases of dengue fever and 250,000 cases of dengue hemorrhagic fever and a mortality rate of 25,000 per year.7 Dengue virus infection has been reported in more than 100 countries, with 2.5 billion people living in areas where dengue is endemic6,8 (Figure 1). Most cases of dengue hemorrhagic fever are reported from Asia, where it is a leading cause of hospitalization and death among children.2 In Latin America, dengue hemorrhagic fever was a rare disease before 1981.2 The 1980s and 1990s saw a dramatic geographic expansion of epidemic dengue fever and dengue hemorrhagic fever from Southeast Asia to the South Pacific Islands, the Caribbean, and Latin America, with regions changing from nonendemic (no serotypes present) to hypoendemic (one serotype present) or hyperendemic (multiple serotypes present).9 The World Health Organization (WHO) classifies dengue as a major international public health concern because of the expanding geographic distribution of both the virus and the mosquito vector, the increased frequency of epidemics, the cocirculation of multiple virus serotypes, and the emergence of dengue hemorrhagic fever in new areas.1,7 The reasons for this resurgence are complex and include urbanization with substandard living conditions, lack of vector control, climatic change, virus evolution, and international travel.6
Risk among International Travelers
The marked increase in dengue during recent decades is in tandem with increasing reports of international travelers with dengue, including long-term expatriates, aid and development workers, and military troops stationed in and immigrants from countries where dengue is endemic.10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31 Dengue fever has been diagnosed in an increasing proportion of febrile travelers returning from the tropics, ranging from 2 percent in the early 1990s to 16 percent more recently.22,32,33,34 In some case series, dengue fever has been reported as the second most frequent cause of hospitalization (after malaria) among travelers returning from the tropics.13,22,34 The rate of self-reported dengue fever among Israeli travelers to Thailand in 1998 was 3.4 per 1000 travelers.35 Prospective studies of seroconversion rates in both asymptomatic and symptomatic travelers with a positive IgM antibody test for dengue revealed an incidence of dengue of 2.9 percent (after a mean of one month of travel)18 and 6.7 percent (after a mean of six months of travel)23; however, these data must be interpreted with caution since a positive test for IgM antibodies gives only a probable diagnosis, and prospective serologic studies are hampered by the cross-reactivity of enzyme-linked immunosorbent assays (ELISAs) with other flaviviruses.36
The true incidence of dengue in travelers is probably underestimated because in many countries it is not a disease that medical personnel are required to report and because it is often underreported in travelers who become ill during travel and is underdiagnosed because of the nonspecific nature of the infection.7 The rate of infection may be as high as that of malaria (without chemoprophylaxis) and higher than that of other travel-related diseases, such as hepatitis A or typhoid fever.4,37,38 Risk factors among travelers acquiring dengue relate to the duration, season, and destination of travel.18 Most dengue virus infections in travelers are acquired in Asia, followed by the Americas, with only a small proportion in Africa.11,12
In countries where dengue currently is not endemic but where a capable vector exists, new autochthonous cycles of infection may be established from infected travelers or immigrants who are coming from areas where the disease is endemic; this phenomenon has been reported in parts of the United States, southern Europe, and the Mediterranean.39,40 However, the risk of introduction of the disease to Western countries by travelers is difficult to assess.4 There have been isolated reports of returning travelers who have transmitted dengue virus infection to health care workers in countries where dengue is nonendemic by way of needle-stick injury41,42 or mucocutaneous exposure to blood43 — modes of nonvector transmission of dengue previously seen only rarely.
Clinical Aspects of Dengue Virus Infections
Pathogenesis
After an infected mosquito has bitten a person, the virus replicates in regional lymph nodes and is disseminated through the lymphatic system and blood to other tissues.44 Replication in the reticuloendothelial system and skin results in viremia.44 The incubation period ranges from 3 to 14 days, but it is usually 4 to 7 days. Infection with dengue virus of any of the four serotypes causes a spectrum of illness, ranging from no symptoms or mild fever to severe and fatal hemorrhage, depending largely on the patient's age and immunologic condition.7
Although the mechanisms for the development of severe hemorrhagic disease are not fully understood, the main risk factor for the development of dengue hemorrhagic fever and dengue shock syndrome is thought to be secondary infection with another serotype.6,45 Cross-reactive but non-neutralizing anti-dengue antibodies from the previous infection bind to the new infecting serotype and enhance viral uptake of monocytes and macrophages. This antibody-dependent enhancement results in an amplified cascade of cytokines and complement activation, causing endothelial dysfunction, platelet destruction, and consumption of coagulation factors leading to plasma leakage and hemorrhagic manifestations.6,46,47,48 The severity of the disease also depends on the strain and serotype of the infecting virus, the age and genetic background of the patient,6,49,50 and the degree of viremia.51
Asymptomatic Infection and Acute Febrile Illness
Most persons, particularly young children, with dengue infections in areas where the disease is endemic are asymptomatic or they present with mild febrile illness.7 In adult travelers, the ratio of asymptomatic to symptomatic cases has been reported to be between 1:0.8 and 1:3.3,18,23 but these data were derived only from studies based on the diagnosis of dengue established by a positive test for IgM antibody.
Classic Dengue Fever
Classic dengue fever is characterized by the sudden onset of fever, accompanied by a severe headache, retro-orbital pain, and fatigue, and it is often associated with severe myalgia and arthralgia ("breakbone fever").44 The fever usually lasts five to seven days. A rash, typically macular or maculopapular and often confluent with the sparing of small islands of normal skin (Figure 2), has been reported in about half of infected persons. It usually appears near the time of defervescence, often lasts for two to four days, and may be accompanied by scaling and pruritus.11,13,52 Other signs and symptoms include flushed facies (usually during the first 24 to 48 hours), lymphadenopathy, injected conjunctivae, an inflamed pharynx, and mild respiratory and gastrointestinal symptoms. Patients with dengue fever may have hemorrhagic manifestations, such as petechiae, purpura, or evidence of a positive tourniquet test for capillary fragility; the test is positive if 20 or more petechiae appear in a 1-in.2 (6.25-cm2) patch on the forearm after deflation of the blood pressure cuff (Figure 3).44 Gum bleeding, epistaxis, menorrhagia, and gastrointestinal hemorrhage are only occasionally seen. Very rare complications of dengue fever include myocarditis, hepatitis,53 and neurologic abnormalities, such as encephalopathy and neuropathies.54 Laboratory findings commonly associated with dengue fever include thrombocytopenia, leukopenia with lymphopenia, mild-to-moderate elevations of hepatic aminotransferases and lactate dehydrogenase, and hyponatremia.7,13
Figure 2. Dengue Rash with Sparing of Islands of Skin.
Panels A and B show a maculopapular rash with island sparing. Courtesy of Eduardo Gotuzzo and David Freedman, Gorgas Tropical Medicine Course, Universidad Peruana Cayetano Heredia, Lima, Peru.
Figure 3. Positive Result on a Tourniquet Test.
The tourniquet test is performed by inflating a blood pressure cuff on the upper arm to a point midway between systolic and diastolic blood pressures for five minutes. A test is considered positive when there are 20 or more petechiae per square inch (6.25 cm2) on the forearm. Courtesy of Ann McCarthy, Tropical Medicine and International Health Clinic, Ottawa Hospital, Ottawa.
Classic dengue fever in travelers, although self-limiting and rarely fatal, can be incapacitating, may halt travel, and may require hospitalization and even evacuation and a return home.4,13 In one series from Israel, 30 percent of travelers who contracted dengue fever were evacuated, and 66 percent were hospitalized.13 Convalescence may be prolonged for weeks because of asthenia and depression.55
Dengue Hemorrhagic Fever and Dengue Shock Syndrome
The hallmark of dengue hemorrhagic fever is capillary leakage, accompanied by hemorrhagic manifestations. The presentation of patients in the first days of the illness is similar to that seen in dengue fever, but plasma leakage develops four to seven days after the onset of the disease, at approximately the time of defervescence. Abdominal pain and vomiting, restlessness, a change in the level of consciousness, and a sudden change from fever to hypothermia may be the first clinical warning signs and are often associated with a marked decrease in the platelet count.7
The diagnosis of dengue hemorrhagic fever is made on the basis of the following triad of symptoms and signs: hemorrhagic manifestations; a platelet count of less than 100,000 per cubic millimeter; and objective evidence of plasma leakage, shown either by fluctuation of packed-cell volume (greater than 20 percent during the course of the illness) or by clinical signs of plasma leakage, such as pleural effusion, ascites, or hypoproteinemia. Hemorrhagic manifestations without capillary leakage do not constitute dengue hemorrhagic fever. A positive tourniquet test is incorporated in the WHO clinical case definition of dengue hemorrhagic fever, but the definition differentiates poorly between dengue and dengue hemorrhagic fever and is not very specific.56 Mortality rates from dengue hemorrhagic fever can range as high as 10 to 20 percent, but they are as low as 0.2 percent in hospitals with staff experienced in the management of the disease.7,50,57
Dengue shock syndrome is characterized by a rapid, weak pulse with a narrowing pulse pressure of less than 20 mm Hg, or profound hypotension (systolic pressure of less than 90 mm Hg among those five years of age or older). The duration of shock is short. Typically, patients either recover rapidly after appropriate volume-replacement therapy is administered or die within 12 to 24 hours; the mortality rate is up to 40 percent.7
Within the European Network on Imported Infectious Disease Surveillance, dengue hemorrhagic fever was reported in 2.7 percent of 483 cases of dengue.12 The risk of dengue hemorrhagic fever was 4.3 times higher in immigrants and in persons visiting friends and relatives in areas where the disease is endemic than in general travelers.12 Dengue shock syndrome in travelers is uncommon, as is death from dengue,4 but two deaths were reported in a series of more than 200 cases of dengue imported to the United States between 1993 and 2000.27,28,29,30,31
Diagnosis and Differential Diagnosis
A confirmed diagnosis is established by culture of the virus, polymerase-chain-reaction (PCR) tests, or serologic assays (Table 2). All these tests have limitations. PCR testing is not available in many settings and is sensitive only in the very early stages of the disease.59 The test based on an increase in the IgG titer by a factor of four is difficult in routine clinical care because a second blood sample is required at the convalescent stage. Cross-reactions with other flaviviruses interfere with serologic testing, particularly the ELISA for IgG, and this affects the interpretation of test results in travelers exposed to other flavivirus infections, including those previously vaccinated against flavivirus infections, such as yellow fever and Japanese encephalitis.36 The most commonly used test for the diagnosis of dengue is the IgM capture ELISA, but this test is negative early in the course of the disease, should be performed only four to five days after the onset of symptoms, and gives only a probable diagnosis (Table 2).36 Rheumatoid factor may lead to an IgM capture assay that is false positive for dengue, and so may other flavivirus infections (albeit less so than with dengue IgG assays).36,59
Table 2. Laboratory Diagnosis of Dengue.
Primary infections are characterized by an increase in dengue-specific IgM antibodies 4 to 5 days after the onset of fever and by an increase in IgG antibodies only after 7 to 10 days.60 IgM antibodies are detectable for three to six months, whereas IgG antibodies remain detectable for life. In secondary infections, the level of IgM antibodies is lower than in primary infections and the antibodies are sometimes even absent, whereas levels of IgG antibodies rise rapidly in secondary infections, even during the acute phase.6 Thus, the presence of high titers of IgG early in the course of the disease is a criterion for secondary infection.
Therefore, since a laboratory-based diagnosis of dengue is often unavailable at the time of care, a clinical diagnosis is initially made on the basis of clinical manifestations and laboratory features developing over a period of time and as other potentially life-threatening diseases, such as malaria, are ruled out (Figure 4). A travel history is an important clue because the incubation period for dengue is less than two weeks; dengue can be ruled out if symptoms begin more than two weeks after the traveler or immigrant has left an area where the disease is endemic.58 Fever that persists more than 10 days usually rules out dengue.
Figure 4. Flow Diagram for the Clinical Diagnosis of Dengue in Returning Travelers.
Detailed outpatient and hospital flow diagrams are available from the World Health Organization (www.who.int/csr/resources/publications/dengue/en/074.pdf and www.who.int/csr/resources/publications/dengue/en/075.pdf).
The relation in time between the drop in the platelet count and the rapid increase in the hematocrit is unique to dengue hemorrhagic fever,61 and together with the clinical signs is sufficient to establish a clinical diagnosis of dengue hemorrhagic fever. However, the symptoms and signs of mild febrile illness or classic dengue fever are nonspecific and hard to distinguish from many other undifferentiated febrile syndromes. The differential diagnosis includes malaria, typhoid fever, leptospirosis, chikungunya, West Nile virus infection, measles, rubella, acute human immunodeficiency virus conversion disease, Epstein–Barr virus infection, viral hemorrhagic fevers, rickettsial diseases, early severe acute respiratory syndrome (SARS), and any other disease that can manifest in the acute phase as an undifferentiated febrile syndrome.44,62 A combination of laboratory variables (low platelet or leukocyte count and increased liver aminotransferase levels) is highly predictive of the diagnosis of dengue and may help to differentiate dengue from typhus52 and early SARS.62 A positive tourniquet test or leukopenia (5000 cells per cubic millimeter) are the two tests with the highest sensitivity (about 90 percent) for the diagnosis of early dengue, since the platelet count may initially be normal and drop only on subsequent days. If the two tests are combined, the sensitivity decreases, but the positive predictive value increases.63
Management
No specific therapeutic agents exist for dengue. Corticosteroids, carbazochrome (a drug that decreases capillary permeability), and antiviral agents have no proved role (although ribavirin, interferon alfa, and 6-azauridine have shown some antiviral activity in vitro).7,64,65 Prompt and correct institution of fluid replacement is thought to reduce mortality rates due to dengue hemorrhagic fever and dengue shock syndrome.66 Treatment is therefore based on symptoms and supportive, with the principal aim to prevent death. Mild or classic dengue is treated with antipyretic agents such as acetaminophen, bed rest, and fluid replacement (usually administered orally and only rarely parenterally); most cases can be managed on an outpatient basis. Aspirin and nonsteroidal antiinflammatory drugs are best avoided because they can increase bleeding. Intramuscular injections should not be given because they may cause large hematomas. Platelet counts and hematocrit determinations should be repeated at least every 24 hours to allow prompt recognition of the development of dengue hemorrhagic fever and institution of fluid replacement.66,67
Patients with a platelet count of less than 100,000 per cubic millimeter are usually admitted to a hospital since they have the highest risk of the development of dengue hemorrhagic fever (Figure 4). The critical period is often on the day of defervescence, typically four to seven days after onset of the illness. A decrease in the platelet count, which usually precedes the rise in hematocrit, is of diagnostic and prognostic value in cases of dengue hemorrhagic fever.67 A rise in the hematocrit of 20 percent indicates considerable plasma loss, and patients with this condition require intensive care with intravenous replacement of fluids such as normal saline and Ringer's lactate.66,68,69 In patients with worsening shock, colloid or crystalloid solutions should be added (10 to 20 ml per kilogram of body weight per hour), although some studies suggest that colloid solutions are superior to crystalloid solutions.44,66,69 If there is evidence of bleeding or disseminated intravascular coagulation, fresh blood or fresh-frozen plasma should be administered. Once the capillary leakage stops and resorption of extravasated fluid begins, care must be taken not to cause fluid overload and pulmonary edema.44 Therapy with parenterally administered fluids should be stopped or reduced when the hematocrit drops below 40 percent and is accompanied by improving clinical signs and urine output, which occur generally after 24 to 72 hours.44 Guidelines concerning the rate of intravenous infusion and specific time periods for infusion have been published by the WHO.70
Prevention of Dengue Infections in Travelers
Effective control of dengue remains elusive. Public health efforts have to focus on vector control and community-based programs to keep the environment free of potential breeding sources, but this is difficult because of the intimacy of aedes mosquitoes with humans. A vaccine that provides effective, long-term immunity against infection with all four serotypes of dengue is urgently needed. Poor financial support and the absence of an animal model are the main problems.6 In addition, a vaccine should provide protective immunity against the four serotypes of dengue virus to avoid the phenomenon of antibody-dependent enhancement.4 Live attenuated, tetravalent dengue vaccines have been shown to be immunogenic and safe and are undergoing further clinical trials.71 New approaches to the development of vaccines include the use of infectious clone DNA and naked DNA that may offer simpler and cheaper methods of manufacturing, as well as possible greater stability and safety.7
The single most effective preventive measure for travelers in areas where dengue is endemic is to avoid mosquito bites by using insect repellents containing N,N-diethyl-3-methylbenzamide (DEET),72 protective clothing (the most effective is permethrin-impregnated), and insecticides.4 Aedes mosquitoes bite during the day; hence, these measures must be taken during the day, particularly in the morning and late afternoon. The usefulness of insecticide-treated bed nets at night is therefore limited. Aedes mosquitoes are also indoor feeders and are often found in dark areas, such as in closets and bathrooms, behind curtains, and under beds. It is advisable to spray these areas with insecticides.4 Care should be taken not to leave trash, pots, or any other containers outdoors, since they can fill with rainwater and become breeding grounds.
Pretravel advice should include information about the risk of contracting dengue, destinations associated with high risk, and signs and symptoms of dengue infection. The Centers for Disease Control and Prevention (www.cdc.gov/ncidod/dvbid/dengue) and the WHO (www.who.int/topics/dengue/en/) provide information about countries where dengue is endemic and updates on new epidemic trends. There is no real "safe" season, although there seems to be a cyclical pattern and a rise in cases during the rainy season. Transmission is maintained even between epidemics.73 The main risk of exposure among travelers exists in urban and residential areas. It is also important to remind travelers that the symptoms of dengue may resemble those of malaria and that malaria should be ruled out first.
Reinfection with another serotype of dengue virus may predispose a person to the development of dengue hemorrhagic fever or dengue shock syndrome, which is associated with a high mortality rate.2 Therefore, repeated travel to countries where dengue is endemic may put those previously infected with dengue — travelers, immigrants, and persons visiting friends and relatives — at increased risk. No data on the extent of this risk are available, and therefore no evidence-based guidelines on pretravel screening for dengue are in place.
Until aedes mosquitoes can be effectively controlled or until a cost-effective vaccine is developed, cases of dengue infections will continue to escalate. Therefore, clinicians in areas where the infection is not endemic will see and have to treat dengue in increasing numbers of travelers returning from areas where the disease is endemic.
Source Information
From the Travellers' Health and Vaccination Centre, Tan Tock Seng Hospital, Singapore (A.W.-S.); and the Center for Geographic Medicine and Tropical Diseases, Chaim Sheba Medical Center, Tel Hashomer, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv — both in Israel (E.S.).
Address reprint requests to Dr. Wilder-Smith at the Travellers' Health and Vaccination Centre, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, or at epvws@pacific.net.sg.
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