dengue diagnóstico y cuadro clinico

Official reprint from UpToDate

www.uptodate.com ©2015 UpToDate

AuthorsAlan L Rothman, MDAnon Srikiatkhachorn, MDSiripen Kalayanarooj, MD

Section EditorMartin S Hirsch, MD

Deputy EditorElinor L Baron, MD, DTMH

Clinical manifestations and diagnosis of dengue virus infection

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Dec 09, 2014.

INTRODUCTION — Dengue is the most prevalent mosquito-borne viral disease; it is estimated that over 390 million

dengue virus infections occur each year throughout the world, including 96 million that produce illness [1].

Symptomatic dengue virus infections can present with a wide range of clinical manifestations, from mild febrile

illness to a life-threatening shock syndrome or organ dysfunction [2,3]. Both viral and host factors are thought to

contribute to the manifestations of disease in each infected individual.

The various clinical features and the available methods for the diagnosis of dengue virus infections will be reviewed

here. The pathogenesis and measures to prevent and treat the disease are discussed separately. (See

"Pathogenesis of dengue virus infection" and "Prevention and treatment of dengue virus infection" and

"Epidemiology of dengue virus infections".)

VIROLOGY — There are four closely related but serologically distinct dengue viruses, called DENV-1, DENV-2,

DENV-3, and DENV-4, of the genus Flavivirus. There is only transient and weak cross-protection among the four

serotypes; therefore, individuals living in an area of endemic dengue can be infected with up to four dengue

serotypes in a lifetime. Multiple virus serotypes often co-circulate within the same region (hyperendemicity), causing

periodic epidemics.

CLINICAL MANIFESTATIONS — The typical clinical manifestations of dengue range from self-limited dengue fever

(DF) to dengue hemorrhagic fever with shock syndrome [4]. With wider availability of laboratory testing, there are

increasing reports of unusual clinical manifestations, as discussed below [3]. The risk of severe disease is much

higher in repeat infection than primary infection [5]. (See "Pathogenesis of dengue virus infection".)

Asymptomatic infection — Most dengue virus infections in adults are symptomatic [6]. For example, in a survey of

44 military personnel with serologic evidence of dengue virus, approximately 86 percent of infections were

symptomatic [7]. In contrast, most infections among children under age 15 years are asymptomatic or minimally

symptomatic. In one study of schoolchildren in rural Thailand, 53 percent of dengue virus infections were not

associated with a recognized febrile illness despite intense active surveillance [8].

Classic dengue fever — Classic dengue fever is an acute febrile illness accompanied by headache, retroorbital

pain, and marked muscle and joint pains, which evoked the term "break-bone fever" [9]. Symptoms typically develop

between 4 and 7 days after the bite of an infected mosquito; the incubation period may range from 3 to 14 days.

Dengue can essentially be excluded as the cause of symptoms in a traveler who develops illness more than 14 days

after returning from a dengue-endemic country [10].

Fever typically lasts for five to seven days [11]. Some patients have a biphasic ("saddleback") fever curve, with the

second febrile phase lasting one to two days; this has been described in approximately 5 percent of patients [7,11].

The febrile period may also be followed by a period of marked fatigue that can last for days to weeks, especially in

adults.

In a study including more than 3900 patients with dengue in Puerto Rico, the frequency of symptoms was influenced

by the patient's age and sex and differed in patients with primary versus secondary dengue virus infection [12]. All

symptoms were less frequent in patients ≤19 years of age. Joint pain, body aches, and rash were more common in

females. Constitutional symptoms and gastrointestinal symptoms were more common in patients experiencing a

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Clinical manifestations and diagnosis of dengue virus infection http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/clinical-mani...

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second infection, whereas rash was more commonly noted during primary infection.

High frequencies of myalgia, headache, and retroorbital pain among dengue cases in the studies listed above may

represent overestimates due to selection bias. Several studies of travelers or military personnel have reported these

"classic" symptoms of DF in 15 to 60 percent of patients [7,10,11,13]. Fever and extreme fatigue have been the

predominant symptoms of patients in these series. When a rash occurred, it appeared between two and five days

after the onset of fever.

Hemorrhagic manifestations — Hemorrhagic manifestations occur commonly in patients with DF and, in rare

cases, can be life threatening. In a large study in Thailand, spontaneous bleeding occurred in 68 percent of children

with DF [14]. The main bleeding sites were the skin (58 percent) and nose (19 percent); gastrointestinal bleeding

was less common (4 percent). In another series of 18 adults who acquired DF during travel, hemorrhagic

phenomena were noted in 22 percent; two patients had purpura and two had melena [11]. This clinical presentation

needs to be differentiated from dengue hemorrhagic fever, described below. (See 'Dengue hemorrhagic fever'

below.)

Other symptoms — Acute dengue virus infection often presents without the full picture of classical DF,

especially in children. Gastrointestinal or respiratory tract symptoms may dominate the clinical picture in some

patients. Among 3926 patients with laboratory-diagnosed dengue virus infections in Puerto Rico during 1990 and

1991 (one-third of whom were <15 years of age), the frequency of specific symptoms was as follows [12]:

Physical examination — The physical examination in patients with DF is generally nonspecific. Conjunctival

injection, pharyngeal erythema, lymphadenopathy, and hepatomegaly are observed in 20 to 50 percent of patients

[13]. The rash is typically macular or maculopapular and may be associated with pruritus (picture 1).

Laboratory findings — Laboratory findings typical of DF include the following:

Dengue hemorrhagic fever — Dengue hemorrhagic fever (DHF) is the most serious manifestation of dengue virus

infection and can be associated with circulatory failure and shock. The four cardinal features of DHF, as defined by

the World Health Organization (WHO), include [3,5,18]:

Constitutional symptoms, including fever (90 percent)●

Headache, eye pain, body pain, and joint pain (63 to 78 percent)●

Rash (slightly more than 50 percent)●

Gastrointestinal symptoms including nausea or vomiting (more than 50 percent) and diarrhea (30 percent)●

Respiratory tract symptoms including cough, sore throat, and nasal congestion (each observed in

approximately one-third of patients)

●

Leukopenia is common in both adults and children with DF and is a useful diagnostic feature [13,15,16].●

Thrombocytopenia is noted in most patients with DF [17]. In several studies, platelet counts <100,000

cells/mm were observed in 16 to 55 percent of patients [11,15].

●3

Serum aspartate transaminase (AST) levels are frequently elevated in both adults and children with DF; the

elevations are usually modest (2 to 5 times the upper limit of normal values), but marked elevations (5 to 15

times the upper limit of normal) are occasionally noted [11,15].

●

Increased vascular permeability (plasma leakage syndrome) evidenced by hemoconcentration (20 percent or

greater rise in hematocrit above baseline value), pleural effusion, or ascites [15]

●

Marked thrombocytopenia (100,000 cells/mm or lower)● 3

Fever lasting two to seven days●

A hemorrhagic tendency (as demonstrated by a positive tourniquet test) or spontaneous bleeding (see

'Hemorrhagic manifestations' below)

●


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The term dengue shock syndrome (DSS) is used when shock is present along with these four criteria [18].

Although DF and DHF are frequently considered different diseases, physicians should recognize that the criteria

listed above define DHF narrowly. This definition highlights the importance of plasma leakage as a pathophysiologic

feature of severe dengue but does not encompass all patients with clinically severe or complicated dengue infections

[5,19]. Therefore, the case definition should not supplant good clinical judgment in the management of patients with

suspected dengue. (See 'Classification controversies' below.)

Plasma leakage — Plasma leakage is the most specific and life-threatening feature of DHF. The increase in

vascular permeability develops over a period of 24 to 48 hours. Shock may develop in patients with marked plasma

leakage, especially if supportive treatment is delayed. This clinical presentation is referred to as "dengue shock

syndrome" (DSS) and is associated with a case-fatality rate as high as 12 percent in some studies, even with

aggressive therapy [20].

Plasma leakage usually occurs between three and seven days after the onset of illness. This coincides with

defervescence, severe thrombocytopenia, and elevation of aminotransferases [15]. Abdominal pain is also reported

to precede the onset of plasma leakage in approximately 60 percent of patients with DHF [21-23]. The presence of

intense abdominal pain, persistent vomiting, and marked restlessness or lethargy, especially coinciding with

defervescence, should alert the clinician to possible impending dengue shock syndrome [24].

Chest radiography and chest/abdominal ultrasound are the imaging modalities useful for detection of plasma

leakage in DHF. In one study of 158 suspected cases in Thailand [25], right lateral decubitus chest radiograph was

sensitive for detection of pleural effusion, but ultrasound was useful for detecting larger effusions and also had the

advantages of evaluating for presence of peritoneal fluid. Plasma leakage was detected by ultrasound as early as

three days after the onset of fever; pleural effusions were more common than ascites or edema of the gallbladder

wall.

Hemorrhagic manifestations — The severity of hemorrhagic manifestations is quite variable among patients

with DHF. Spontaneous petechiae or ecchymoses were noted in approximately one-half of adults and children with

DHF in Cuba [21,22]. Other less-frequent hemorrhagic manifestations reported in these studies included:

hematemesis (15 to 30 percent of subjects), menorrhagia (40 percent of adult women), melena (5 to 10 percent),

and epistaxis (10 percent).

Microvascular fragility may be demonstrated by a positive "tourniquet test"; this test is performed by inflating a blood

pressure cuff on the arm to midway between systolic and diastolic blood pressures for five minutes [26]. The

pressure is released for at least one minute and the skin below the cuff is examined for petechiae. A finding of 10 or

more petechiae in a one square inch area is considered positive (picture 2).

Hemorrhagic manifestations are also common in dengue fever [14,27]; this can be severe, requiring hospitalization

and transfusion in rare cases [19]. (See 'Classic dengue fever' above.)

Other manifestations — In some cases, liver failure, central nervous system (CNS) dysfunction, and/or myocardial

dysfunction occur in the setting of acute dengue virus infection [28-31]. Liver failure has been documented

particularly after resuscitation from profound shock, and, in many cases, may be caused by prolonged hypoperfusion

or hypoxia rather than a direct viral effect.

Neurological manifestations that have been associated with dengue virus infection include encephalopathy and

seizures [29,30,32-34]. In case series, the frequency of such manifestations has been approximately 1 percent [35].

Symptoms include fever, headache, and lethargy; some patients may have no characteristic features of dengue

fever or dengue hemorrhagic fever on admission [30]. The diagnosis of dengue virus infection has been supported

by either serologic testing or viral isolation or detection by polymerase chain reaction in cerebrospinal fluid [30].

Permanent neurologic sequelae have been described [30,32].

Reye syndrome has been noted in children but may be associated with use of salicylate-containing medications

rather than dengue virus infection per se. Other neurologic syndromes that have been reported to be potentially


3 de 15 11/08/2015 10:07 p.m.

associated with dengue virus infection include acute pure motor weakness, mononeuropathies, polyneuropathies,

Guillain-Barré syndrome, and transverse myelitis [30,31].

Clinical and echocardiographic evidence of myocardial dysfunction has been described in hospitalized patients with

dengue [36]. Cardiac dysfunction does not appear to be the major cause of shock in most patients with DSS but may

reflect clinical response to intravenous fluid therapy. Histologic findings of myocarditis at autopsy have been

described in case reports; one noted positive staining for dengue viral antigens in cardiomyocytes [37]. A study of 81

hospitalized patients with dengue in Brazil described elevated levels of troponin-I or the N terminal fragment of

B-type natriuretic peptide in 15 percent of cases [38]. Two patients developed cardiogenic shock and died; dengue

viral antigen was detected in infiltrating inflammatory cells at autopsy. Echocardiography demonstrated abnormal

wall motion in three patients, one of whom had abnormal left ventricular ejection fraction.

Abdominal pain has been described as the predominant clinical feature in a small number of patients with dengue,

mimicking an acute abdomen. Acute kidney injury (AKI) has been reported in up to 3 percent of dengue cases in

several hospital-based case series [39-41]. Some cases may reflect complications of shock, but other mechanisms

include rhabdomyolysis, glomerulonephritis, and acute tubular necrosis. In a retrospective study of 1076 adult

dengue patients hospitalized at one center in Taiwan, rhabdomyolysis was noted in 9 cases (0.8 percent) [42]. Other

disease syndromes, including cholecystitis and retinal vasculitis [43], have been reported in patients in endemic

countries with serologic evidence of acute dengue; however, subclinical dengue infections are common in these

areas, and dengue virus infection has not been definitively established as the cause of these unusual

manifestations.

Hemophagocytic lymphohistiocytosis has been described in association with dengue fever [44,45]. (See "Clinical

features and diagnosis of hemophagocytic lymphohistiocytosis".)

CLASSIFICATION CONTROVERSIES — For several decades prior to 2009, the World Health Organization (WHO)

classified symptomatic dengue virus infections into three categories: undifferentiated fever, classic dengue fever

(DF), and dengue hemorrhagic fever (DHF). Subsequently, these categories have been criticized for several reasons

[46]:

These issues have been illustrated in studies among travelers and patients with documented dengue infection in

endemic areas [14,48]. In one study of travelers, two patients (0.9 percent) fulfilled the WHO case definition for DHF,

although 23 (11 percent) had what were considered severe clinical manifestations including internal hemorrhage,

plasma leakage, shock, or marked thrombocytopenia [48]. A secondary immune response was associated with both

spontaneous hemorrhage and other severe manifestations of disease.

As a result of these concerns, revised classification systems have been adopted [3,49], albeit with significant areas

of divergence:

Confusion arises because the term DHF suggests that hemorrhage is the cardinal manifestation, whereas

plasma leakage leading to shock is the most specific feature of severe dengue and is most important for clinical

management.

●

Some patients with severe clinical syndromes requiring medical intervention do not meet all the criteria for

DHF.

●

Classification is difficult when patients meet some but not all four diagnostic criteria, especially if pivotal clinical

laboratory data are unavailable.

●

The diagnostic criteria for DHF have been inconsistently applied in epidemiologic and scientific reports.●

Reporting that is limited to DHF according to the WHO classification scheme underestimates the disease

burden of dengue illness [47].

●

The WHO Special Program for Research and Training in Tropical Diseases and Pan-American Health

Organization have adopted a revised classification of "dengue" and "severe dengue"; "severe dengue" is

●


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DIFFERENTIAL DIAGNOSIS — Dengue virus infection should be considered in the differential diagnosis of a febrile

illness in any patient who has resided in or traveled to an appropriate region in the two weeks before the onset of

illness. Malaria, chikungunya, rickettsial infections, and leptospirosis are the travel-related illnesses that can be

mistaken for dengue fever.

Analysis of data from over 17,000 ill travelers in the GeoSentinel Surveillance Network found that dengue accounted

for 10 percent of post-travel systemic febrile illnesses, second only to malaria [50]. Mononucleosis related to

Epstein-Barr virus or cytomegalovirus, rickettsial infections, and typhoid or paratyphoid fever were the next most

common defined causes of systemic febrile illnesses in this study. Dengue was the most frequently identified cause

of systemic febrile illness among travelers returning from Southeast Asia (32 percent), the Caribbean (24 percent),

South Central Asia (14 percent), and South America (14 percent) and was only slightly less common than malaria

among travelers returning from Central America (12 percent of cases). (See "Evaluation of fever in the returning

traveler" and "Clinical manifestations of malaria" and "Epidemiology, microbiology, clinical manifestations, and

diagnosis of typhoid fever".)

Chikungunya virus, the causative agent of chikungunya fever, is an increasing problem in differential diagnosis of

travel-related febrile illness. Chikungunya is also transmitted by Aedes aegypti mosquitoes and has recently been

associated with widespread and often explosive outbreaks in areas infested by this mosquito [51]. Clinical features

of chikungunya fever overlap considerably with those of dengue fever. In several studies comparing the two

diseases, joint pain was reported somewhat more often by patients with chikungunya, whereas abdominal pain and

leukopenia were more common in those with dengue [52-54]. Joint swelling is highly specific for chikungunya,

having been reported by 85 (65 percent) of 131 patients with chikungunya versus 4 (4 percent) of 104 patients with

dengue in one study [52]. Conversely, bleeding manifestations and severe thrombocytopenia are relatively specific

for dengue.

In patients with fever and maculopapular rash, other viral exanthems should be considered, including measles and

rubella. Other RNA viruses associated with hemorrhagic fever syndrome include filoviruses (Ebola and Marburg),

arenaviruses (eg, Lassa fever, Junin), bunyaviruses (eg, hemorrhagic fever with renal syndrome, Rift Valley fever,

severe fever with thrombocytopenia syndrome), and flaviviruses (yellow fever, Kyasanur Forest disease); these are

mostly highly restricted in their geographic distribution. Severe illness with fluid accumulation or organ involvement

that is uncommon in dengue hemorrhagic fever (eg, peripheral or pulmonary edema, severe renal dysfunction)

should increase suspicion of these alternative diagnoses in the setting of a compatible exposure history.

DIAGNOSIS — The diagnosis of acute dengue virus infection is mainly clinical. In developing countries, laboratory

confirmation is typically not available. In developed countries, laboratory confirmation is usually available only in

specialized reference laboratories and is often not sufficiently timely to assist in the management of the illness. (See

applied to patients who show severe plasma leakage (ie, leading to shock or fluid accumulation with respiratory

distress), severe hemorrhage (as defined by the treating physician), or severe organ impairment (defined as

aspartate transaminase [AST] or alanine transaminase [ALT] ≥1000, impaired consciousness, or severe

involvement of the heart or other organs) [49]. The revised classification further divides nonsevere dengue into

dengue with or without "warning signs" (abdominal pain or tenderness, persistent vomiting, clinical fluid

accumulation, mucosal bleeding, lethargy or restlessness, liver enlargement >2 cm, or increase in hematocrit

concurrent with rapid decrease in platelet count). Given the limited experience with this revised classification

scheme, its sensitivity and specificity for guiding management of patients in general practice are not known.

Therefore, these revised guidelines recommend laboratory confirmation of dengue virus infection when plasma

leakage is absent.

The WHO Regional Office for South-East Asia (SEARO) adopted a more modest revision of the older dengue

classification scheme [3]. The three categories of undifferentiated fever, DF, and DHF were retained, with the

addition of a fourth category of expanded dengue syndrome, encompassing those patients who present with

any of the unusual features described above in association with dengue virus infection, including those with

isolated severe organ dysfunction.

●


5 de 15 11/08/2015 10:07 p.m.

"Prevention and treatment of dengue virus infection".)

Clinical diagnosis — The clinical manifestations of dengue fever (DF) or dengue hemorrhagic fever (DHF) with or

without shock can be helpful in making a provisional diagnosis:

When dengue virus infection (DF or DHF) is suspected on clinical grounds, the patient should be treated empirically

as appropriate for the symptoms and signs present. (See "Prevention and treatment of dengue virus infection".)

Laboratory testing — Confirmation of acute dengue virus infection is most frequently accomplished using serology

[18,58]. Tests for detection of viral RNA or NS1 antigen are commercially available and more successful than

serology in detecting dengue virus infection in the early stages [59]. We favor the following diagnostic approach to

the patient with suspected dengue if laboratory support is available [18,58]:

A more detailed discussion of serologic testing and viral detection methods follows.

Serologic testing — The most frequently used serologic tests for the diagnosis of acute dengue virus infection

are the HI assay and IgG or IgM enzyme immunoassays. Complement fixation and neutralizing antibody assays are

One study of children with febrile illnesses in Thailand reported that some clinical features, such as a positive

tourniquet test, leukopenia, thrombocytopenia, and increased serum aspartate transaminase (AST) levels,

were more frequent in patients with dengue than in those with other febrile illnesses [15]. However, none of

these features of classic DF is sufficiently sensitive or specific to permit a reliable diagnosis.

●

A systematic review of the English language literature from 1990 to 2007 identified 15 studies that evaluated

the usefulness of clinical criteria to distinguish dengue from other febrile illnesses among populations living in

dengue-endemic areas [16]. Low platelets, white blood cell and neutrophil counts, elevated hepatic

transaminases, and the presence of petechiae were associated with a confirmed diagnosis of dengue across

multiple studies.

●

One study applied decision tree classification analysis to clinical, hematological, and virological data from 1200

patients presenting within the first 72 hours of an acute febrile illness [55]. Of these, 364 were dengue reverse

transcriptase-polymerase chain reaction (RT-PCR) positive; 173 had DF, 171 had dengue hemorrhagic fever,

and 20 had dengue shock syndrome. The diagnostic algorithm utilized platelet count, white blood cell,

neutrophil and lymphocyte counts, hematocrit, and body temperature and noted an accuracy of 85 percent for

classification of patients with dengue versus non-dengue illnesses.

●

In developing countries, dengue hemorrhagic fever is frequently diagnosed based upon the clinical case

definition established by the World Health Organization (WHO) [3,18]. In regions (and seasons) with a high

incidence of DHF, the positive predictive value of the case definition is high. Laboratory tests confirm dengue

virus infection in as many as 90 percent of such cases [56,57]. However, malaria, leptospirosis, or typhoid fever

must be considered in the differential diagnosis of DHF. (See 'Differential diagnosis' above.)

●

An acute phase serum or plasma sample should be obtained. If the acute phase sample is obtained ≥3 days

after the onset of illness, the IgM immunoassay (MAC-ELISA or equivalent) is the procedure of choice for rapid

confirmation of the diagnosis. The potential for a false-negative result remains elevated within the first six days

of illness. (See 'Serologic testing' below.)

●

If the acute phase sample is obtained within the first three days after the onset of illness or if the sample is

obtained within the first six days of illness and there is a negative IgM assay result, testing for the presence of

the dengue viral RNA or NS1 antigen has the highest diagnostic yield. (See 'Virus detection' below.)

●

To confirm a positive IgM result or if initial testing is negative in a patient with suspected dengue virus infection,

a convalescent phase serum sample should be obtained at least 10 to 14 days after the acute phase serum.

The acute and convalescent specimens should be analyzed together by a hemagglutination inhibition (HI) or

enzyme immunoassay to provide definitive serologic testing for acute dengue virus infection. These tests are

not licensed for use in the United States, however, and results do not affect clinical management.

●


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more technically demanding and are used in specialized laboratories only. Thus far, the US Food and Drug

Administration (FDA) has approved the IgM capture enzyme-linked immunosorbent assay (ELISA) for use in the

United States.

The HI assay remains the gold standard for serologic testing for dengue virus-specific antibodies [18]. Analysis of

paired acute and convalescent serum samples is essential; a fourfold or greater rise in HI antibody titer between

acute and convalescent samples defines acute infection.

The antibody response depends on whether the patient has primary or secondary dengue virus infection. In primary

infection, HI antibodies develop relatively late (after the fifth day of illness) and reach titers of less than 1:1250 in the

convalescent phase. In secondary infection, HI antibodies rise early and reach titers above 1:1250 (often 1:10,240 or

higher) in the convalescent phase.

Immunoassays for the detection of dengue virus-specific IgG antibodies have demonstrated sensitivity and

specificity of approximately 99 percent and 96 percent, respectively, compared with the HI assay [60]. As with the HI

assay, diagnosis of acute dengue virus infection using the IgG ELISA requires testing of paired acute and

convalescent serum samples, showing a greater than fourfold rise in antibody titer.

One assay that can use a single blood specimen for diagnosis of dengue infection is the IgM antibody capture ELISA

or MAC-ELISA [58]. Dengue virus-specific IgM antibodies are typically detected by the MAC-ELISA by about the

sixth day of illness and persist for 30 to 90 days. If positive, this test can assist in rapid diagnosis of the patient with

dengue infection. However, the sensitivity and specificity of this assay is much lower than the HI assay. In one study

of Thai children with predominantly secondary dengue virus infections, only 29 percent of subjects had a positive

result in the MAC-ELISA by the time of defervescence [61]. Factors that reduce the sensitivity or specificity of the

MAC-ELISA include occasional blunting of the IgM antibody response in secondary dengue virus infections and the

potential for positive results to reflect recent rather than acute dengue virus infection.

The development of rapid diagnostic tests using immunochromatographic or immunoblot technologies has provided

a mechanism for bedside serological testing. However, in one report, diagnostic accuracy fell below the

manufacturer's claims; when eight of these available assays were tested in the field, only two had sensitivities of >50

percent and, of these, one assay also had low specificity [62].

A component of the antibody response is dengue virus serotype-specific; a substantial portion of the antibody

response has cross-reactivity with other dengue virus serotypes and even other flaviviruses. Cross-reactivity is more

problematic in secondary dengue virus infection and also in individuals who have been immunized with vaccines

against other flaviviruses such as Japanese encephalitis virus [63]. Although neutralizing antibody assays have

greater specificity than HI or ELISA assays, serologic assays cannot be relied on for identification of the infecting

dengue virus serotype [64]. (See "Pathogenesis of dengue virus infection" and "Yellow fever".)

Virus detection — Isolation of dengue virus or detection of dengue viral RNA or protein in an acute phase serum

or tissue specimen provides the most definitive confirmation of infection. However, the importance of specimen

timing and quality and the technical demands of these assays limits their clinical applications. As mentioned above,

when laboratory confirmation of illness is obtained, it is typically with serology.

In the United States, most diagnostic laboratory testing for dengue virus infection has been performed by the

Dengue Branch of the Centers for Disease Control and Prevention (CDC) [58]. Serum samples must be submitted

with appropriate clinical and epidemiologic information through state health department laboratories. A real-time

RT-PCR assay kit developed by the CDC was approved by the FDA in 2012 for diagnostic use in the United States

[65]. In both prospective and retrospective testing, the sensitivity and specificity of the test were ≥98 percent

compared with a reference method [66]. The CDC DENV-1-4 Real Time RT PCR Assay was designed to be

performed on equipment already in use in many clinical and public health laboratories in the United States, and it

should expand the availability of early diagnostic testing.

Virus isolation is generally performed only for epidemiologic or research purposes. Serum and plasma are the

preferred specimens for virus isolation, although virus can occasionally be isolated from liver tissues after clearance


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of virus from the serum [67]. Regardless of the specific method used, optimal detection is achieved when specimens

are obtained early after the onset of symptoms, during the febrile period. In one study of children in Thailand,

dengue viruses could be isolated from all plasma samples obtained at least two days before defervescence but from

no samples obtained two or more days after fevers resolved [61]. Virus isolation typically requires one to two weeks

[68].

RT-PCR has comparable sensitivity to viral isolation [69,70]. Although technically demanding and not widely

available, RT-PCR is the only method that can detect virus within a clinically meaningful time frame (one to two days

or less) [71-73].

Dengue viral proteins can be detected in tissue samples using immunohistochemical staining [74]. Liver tissues

appear to have the highest yield. However, since liver biopsy is rarely indicated in patients with suspected dengue

virus infection, this method is generally only used for postmortem diagnosis.

The dengue viral nonstructural protein 1 (NS1) can be detected in plasma, especially during the first five to six days

of illness. In one study, high levels early in infection were associated with DHF [75]. Two assays have become

commercially available outside the United States. The sensitivity of these assays for diagnosis of acute dengue

infection at the time of hospital admission is 50 to 70 percent, with specificity >95 percent [76,77]. However, neither

assay is formulated to provide either identification of the specific DENV serotype or quantitative measurement of

soluble NS1 protein levels.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and

“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with

some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

“patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

th th

th th

Basics topic (see "Patient information: Dengue fever (The Basics)")●

The clinical manifestations of dengue range from self-limited dengue fever to dengue hemorrhagic fever with

shock syndrome, which carries a significant mortality rate. The risk of severe disease is much higher in

secondary rather than primary dengue infection. There is also an increasing recognition of atypical syndromes

associated with acute dengue virus infection, some of which can be severe. (See 'Clinical manifestations'

above.)

●

Classic dengue fever is an acute febrile illness accompanied by headache, retroorbital pain, and marked

muscle and joint pains. Fever typically lasts for five to seven days. Hemorrhagic manifestations and

thrombocytopenia can also occur. Physical examination is nonspecific but may include a macular or

maculopapular rash in approximately half of cases. (See 'Classic dengue fever' above.)

●

Dengue hemorrhagic fever is the most serious manifestation of dengue virus infection and can be associated

with shock. The four cardinal features of dengue hemorrhagic fever include increased vascular permeability,

fever, hemorrhage, and marked thrombocytopenia (100,000 cells/mm or lower). (See 'Dengue hemorrhagic

fever' above.)

●

3

Plasma leakage is the most specific and life-threatening feature of dengue hemorrhagic fever and usually

occurs over a period of 24 to 48 hours, typically coincident with defervescence. Severe plasma leakage can

occur in patients with minimal hemorrhagic manifestations. (See 'Dengue hemorrhagic fever' above.)

●


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REFERENCES

Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496:504.1.

Teixeira MG, Barreto ML. Diagnosis and management of dengue. BMJ 2009; 339:b4338.2.

WHO Regional Office for Southeast Asia. Comprehensive guidelines for prevention and control of dengue and

dengue haemorrhagic fever. Revised and expanded version. SEARO Technical Publication Series, New Delhi,India 2011.

3.

Simmons CP, Farrar JJ, Nguyen vV, Wills B. Dengue. N Engl J Med 2012; 366:1423.4.

Deen JL, Harris E, Wills B, et al. The WHO dengue classification and case definitions: time for areassessment. Lancet 2006; 368:170.

5.

SABIN AB. Research on dengue during World War II. Am J Trop Med Hyg 1952; 1:30.6.

Sharp TW, Wallace MR, Hayes CG, et al. Dengue fever in U.S. troops during Operation Restore Hope,Somalia, 1992-1993. Am J Trop Med Hyg 1995; 53:89.

7.

Endy TP, Chunsuttiwat S, Nisalak A, et al. Epidemiology of inapparent and symptomatic acute dengue virus

infection: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am J Epidemiol 2002;156:40.

8.

Rigau-Pérez JG. The early use of break-bone fever (Quebranta huesos, 1771) and dengue (1801) in Spanish.Am J Trop Med Hyg 1998; 59:272.

9.

Shirtcliffe P, Cameron E, Nicholson KG, Wiselka MJ. Don't forget dengue! Clinical features of dengue fever inreturning travellers. J R Coll Physicians Lond 1998; 32:235.

10.

Schwartz E, Mendelson E, Sidi Y. Dengue fever among travelers. Am J Med 1996; 101:516.11.

Cobra C, Rigau-Pérez JG, Kuno G, Vorndam V. Symptoms of dengue fever in relation to host immunologicresponse and virus serotype, Puerto Rico, 1990-1991. Am J Epidemiol 1995; 142:1204.

12.

Trofa AF, DeFraites RF, Smoak BL, et al. Dengue fever in US military personnel in Haiti. JAMA 1997;277:1546.

13.

Srikiatkhachorn A, Gibbons RV, Green S, et al. Dengue hemorrhagic fever: the sensitivity and specificity of theworld health organization definition for identification of severe cases of dengue in Thailand, 1994-2005. ClinInfect Dis 2010; 50:1135.

14.

Kalayanarooj S, Vaughn DW, Nimmannitya S, et al. Early clinical and laboratory indicators of acute dengue

illness. J Infect Dis 1997; 176:313.

15.

Potts JA, Rothman AL. Clinical and laboratory features that distinguish dengue from other febrile illnesses inendemic populations. Trop Med Int Health 2008; 13:1328.

16.

Hemorrhagic manifestations of dengue virus infection can range from spontaneous petechiae to profuse

bleeding. Severe bleeding sometimes occurs in the absence of plasma leakage. (See 'Classic dengue fever'

above and 'Dengue hemorrhagic fever' above.)

●

The diagnosis of acute dengue virus infection is based mainly on clinical signs and symptoms in endemic

countries. In settings where serologic assays are available, we favor use of an acute phase serum sample for

use in an IgM immunoassay (MAC-ELISA or equivalent) as the laboratory test of choice. If the IgM

immunoassay is negative and the serum was obtained within the first six days after onset of illness, we favor

testing the sample for dengue viral NS1 antigen by enzyme-linked immunosorbent assay (ELISA). (See

'Diagnosis' above.)

●

If the clinical suspicion of dengue virus infection is high and the assay results on the acute phase sample are

negative, we favor testing paired acute and convalescent sera for antibodies to dengue virus by

hemagglutination inhibition assay or IgG ELISA. (See 'Serologic testing' above.)

●


9 de 15 11/08/2015 10:07 p.m.

Halstead SB. Dengue. Lancet 2007; 370:1644.17.

WHO. Dengue hemorrhagic fever: diagnosis, treatment, prevention, and control. 2nd ed. Geneva: WorldHealth Organization, 1997.

18.

Phuong CX, Nhan NT, Kneen R, et al. Clinical diagnosis and assessment of severity of confirmed dengue

infections in Vietnamese children: is the world health organization classification system helpful? Am J TropMed Hyg 2004; 70:172.

19.

Tassniyom S, Vasanawathana S, Chirawatkul A, Rojanasuphot S. Failure of high-dose methylprednisolone in

established dengue shock syndrome: a placebo-controlled, double-blind study. Pediatrics 1993; 92:111.

20.

Díaz A, Kourí G, Guzmán MG, et al. Description of the clinical picture of dengue hemorrhagic fever/dengueshock syndrome (DHF/DSS) in adults. Bull Pan Am Health Organ 1988; 22:133.

21.

Guzmán MG, Kourí G, Martínez E, et al. Clinical and serologic study of Cuban children with denguehemorrhagic fever/dengue shock syndrome (DHF/DSS). Bull Pan Am Health Organ 1987; 21:270.

22.

Khor BS, Liu JW, Lee IK, Yang KD. Dengue hemorrhagic fever patients with acute abdomen: clinicalexperience of 14 cases. Am J Trop Med Hyg 2006; 74:901.

23.

Rigau-Pérez JG, Laufer MK. Dengue-related deaths in Puerto Rico, 1992-1996: diagnosis and clinical alarmsignals. Clin Infect Dis 2006; 42:1241.

24.

Srikiatkhachorn A, Krautrachue A, Ratanaprakarn W, et al. Natural history of plasma leakage in denguehemorrhagic fever: a serial ultrasonographic study. Pediatr Infect Dis J 2007; 26:283.

25.

Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005; 353:924.26.

Cao XT, Ngo TN, Wills B, et al. Evaluation of the World Health Organization standard tourniquet test and amodified tourniquet test in the diagnosis of dengue infection in Viet Nam. Trop Med Int Health 2002; 7:125.

27.

Nimmannitya S, Thisyakorn U, Hemsrichart V. Dengue haemorrhagic fever with unusual manifestations.Southeast Asian J Trop Med Public Health 1987; 18:398.

28.

Chhour YM, Ruble G, Hong R, et al. Hospital-based diagnosis of hemorrhagic fever, encephalitis, and hepatitisin Cambodian children. Emerg Infect Dis 2002; 8:485.

29.

Solomon T, Dung NM, Vaughn DW, et al. Neurological manifestations of dengue infection. Lancet 2000;355:1053.

30.

Patey O, Ollivaud L, Breuil J, Lafaix C. Unusual neurologic manifestations occurring during dengue fever

infection. Am J Trop Med Hyg 1993; 48:793.

31.

Misra UK, Kalita J, Syam UK, Dhole TN. Neurological manifestations of dengue virus infection. J Neurol Sci2006; 244:117.

32.

Araújo FM, Araújo MS, Nogueira RM, et al. Central nervous system involvement in dengue: a study in fatalcases from a dengue endemic area. Neurology 2012; 78:736.

33.

Sahu R, Verma R, Jain A, et al. Neurologic complications in dengue virus infection: a prospective cohort study.Neurology 2014; 83:1601.

34.

Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological complications of dengue virus infection. LancetNeurol 2013; 12:906.

35.

Yacoub S, Griffiths A, Chau TT, et al. Cardiac function in Vietnamese patients with different dengue severitygrades. Crit Care Med 2012; 40:477.

36.

Salgado DM, Eltit JM, Mansfield K, et al. Heart and skeletal muscle are targets of dengue virus infection.Pediatr Infect Dis J 2010; 29:238.

37.

Miranda CH, Borges Mde C, Matsuno AK, et al. Evaluation of cardiac involvement during dengue viralinfection. Clin Infect Dis 2013; 57:812.

38.

Lee IK, Liu JW, Yang KD. Clinical characteristics, risk factors, and outcomes in adults experiencing denguehemorrhagic fever complicated with acute renal failure. Am J Trop Med Hyg 2009; 80:651.

39.

Laoprasopwattana K, Pruekprasert P, Dissaneewate P, et al. Outcome of dengue hemorrhagic fever-causedacute kidney injury in Thai children. J Pediatr 2010; 157:303.

40.

Basu G, Chrispal A, Boorugu H, et al. Acute kidney injury in tropical acute febrile illness in a tertiary care41.


10 de 15 11/08/2015 10:07 p.m.

centre--RIFLE criteria validation. Nephrol Dial Transplant 2011; 26:524.

Huang SY, Lee IK, Liu JW, et al. Clinical features of and risk factors for rhabdomyolysis among adult patientswith dengue virus infection. Am J Trop Med Hyg 2015; 92:75.

42.

Chan DP, Teoh SC, Tan CS, et al. Ophthalmic complications of dengue. Emerg Infect Dis 2006; 12:285.43.

Tan LH, Lum LC, Omar SF, Kan FK. Hemophagocytosis in dengue: comprehensive report of six cases. J ClinVirol 2012; 55:79.

44.

Sharp TM, Gaul L, Muehlenbachs A, et al. Fatal hemophagocytic lymphohistiocytosis associated with locallyacquired dengue virus infection - New Mexico and Texas, 2012. MMWR Morb Mortal Wkly Rep 2014; 63:49.

45.

Wilder-Smith A, Tambyah PA. Severe dengue virus infection in travelers. J Infect Dis 2007; 195:1081.46.

Anderson KB, Chunsuttiwat S, Nisalak A, et al. Burden of symptomatic dengue infection in children at primaryschool in Thailand: a prospective study. Lancet 2007; 369:1452.

47.

Wichmann O, Gascon J, Schunk M, et al. Severe dengue virus infection in travelers: risk factors and laboratoryindicators. J Infect Dis 2007; 195:1089.

48.

Dengue: guidelines for diagnosis, treatment, prevention and control - new edition. World Health Organization,Geneva 2009, p. 1.

49.

Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among illreturned travelers. N Engl J Med 2006; 354:119.

50.

Burt FJ, Rolph MS, Rulli NE, et al. Chikungunya: a re-emerging virus. Lancet 2012; 379:662.51.

Taraphdar D, Sarkar A, Mukhopadhyay BB, Chatterjee S. A comparative study of clinical features betweenmonotypic and dual infection cases with Chikungunya virus and dengue virus in West Bengal, India. Am J TropMed Hyg 2012; 86:720.

52.

Lee VJ, Chow A, Zheng X, et al. Simple clinical and laboratory predictors of Chikungunya versus dengueinfections in adults. PLoS Negl Trop Dis 2012; 6:e1786.

53.

Mohd Zim MA, Sam IC, Omar SF, et al. Chikungunya infection in Malaysia: comparison with dengue infectionin adults and predictors of persistent arthralgia. J Clin Virol 2013; 56:141.

54.

Tanner L, Schreiber M, Low JG, et al. Decision tree algorithms predict the diagnosis and outcome of denguefever in the early phase of illness. PLoS Negl Trop Dis 2008; 2:e196.

55.

Guzman MG, Kouri GP, Bravo J, et al. Dengue haemorrhagic fever in Cuba. II. Clinical investigations. Trans RSoc Trop Med Hyg 1984; 78:239.

56.

Kalayanarooj S, Chansiriwongs V, Nimmannitya S. Dengue patients at the Children’s Hospital, Bangkok:1995-1999 review. Dengue Bulletin 2002; 26:33.

57.

Rigau-Pérez JG, Gubler DJ, Vorndam AV, Clark GG. Dengue surveillance--United States, 1986-1992. MMWRCDC Surveill Summ 1994; 43:7.

58.

Blacksell SD, Mammen MP Jr, Thongpaseuth S, et al. Evaluation of the Panbio dengue virus nonstructural 1antigen detection and immunoglobulin M antibody enzyme-linked immunosorbent assays for the diagnosis ofacute dengue infections in Laos. Diagn Microbiol Infect Dis 2008; 60:43.

59.

McBride WJ, Mullner H, LaBrooy JT, Wronski I. The 1993 dengue 2 epidemic in North Queensland: aserosurvey and comparison of hemagglutination inhibition with an ELISA. Am J Trop Med Hyg 1998; 59:457.

60.

Vaughn DW, Green S, Kalayanarooj S, et al. Dengue in the early febrile phase: viremia and antibodyresponses. J Infect Dis 1997; 176:322.

61.

Blacksell SD, Newton PN, Bell D, et al. The comparative accuracy of 8 commercial rapidimmunochromatographic assays for the diagnosis of acute dengue virus infection. Clin Infect Dis 2006;42:1127.

62.

Yamada K, Takasaki T, Nawa M, et al. Antibody responses determined for Japanese dengue fever patients by

neutralization and hemagglutination inhibition assays demonstrate cross-reactivity between dengue andJapanese encephalitis viruses. Clin Diagn Lab Immunol 2003; 10:725.

63.

van Panhuis WG, Gibbons RV, Endy TP, et al. Inferring the serotype associated with dengue virus infections

on the basis of pre- and postinfection neutralizing antibody titers. J Infect Dis 2010; 202:1002.

64.


11 de 15 11/08/2015 10:07 p.m.

http://www.cdc.gov/media/releases/2012/p0620_dengue_test.html (Accessed on July 17, 2012).65.

Centers for Disease Control and Prevention. CDC DENV-1-4 Real-Time RT-PCR Assay. Package insert.http://www.cdc.gov/dengue/resources/rt_pcr/CDCPackageInsert.pdf (Accessed on November 15, 2012).

66.

Rosen L, Khin MM, U T. Recovery of virus from the liver of children with fatal dengue: reflections on the

pathogenesis of the disease and its possible analogy with that of yellow fever. Res Virol 1989; 140:351.

67.

Rosen L. The use of Toxorhynchites mosquitoes to detect and propagate dengue and other arboviruses. Am JTrop Med Hyg 1981; 30:177.

68.

Deubel V. The contribution of molecular techniques to the diagnosis of dengue infection. In: Dengue andDengue Hemorrhagic Fever, Gubler DJ, Kuno G (Eds), CAB International, CAB International 1997. p.335.

69.

Sudiro TM, Ishiko H, Green S, et al. Rapid diagnosis of dengue viremia by reverse transcriptase-polymerasechain reaction using 3'-noncoding region universal primers. Am J Trop Med Hyg 1997; 56:424.

70.

Chien LJ, Liao TL, Shu PY, et al. Development of real-time reverse transcriptase PCR assays to detect andserotype dengue viruses. J Clin Microbiol 2006; 44:1295.

71.

Johnson BW, Russell BJ, Lanciotti RS. Serotype-specific detection of dengue viruses in a fourplex real-timereverse transcriptase PCR assay. J Clin Microbiol 2005; 43:4977.

72.

de Oliveira Poersch C, Pavoni DP, Queiroz MH, et al. Dengue virus infections: comparison of methods for

diagnosing the acute disease. J Clin Virol 2005; 32:272.

73.

Hall WC, Crowell TP, Watts DM, et al. Demonstration of yellow fever and dengue antigens in formalin-fixedparaffin-embedded human liver by immunohistochemical analysis. Am J Trop Med Hyg 1991; 45:408.

74.

Libraty DH, Young PR, Pickering D, et al. High circulating levels of the dengue virus nonstructural protein NS1early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 2002;186:1165.

75.

Guzman MG, Jaenisch T, Gaczkowski R, et al. Multi-country evaluation of the sensitivity and specificity of twocommercially-available NS1 ELISA assays for dengue diagnosis. PLoS Negl Trop Dis 2010; 4.

76.

Blacksell SD, Jarman RG, Gibbons RV, et al. Comparison of seven commercial antigen and antibody enzyme-linked immunosorbent assays for detection of acute dengue infection. Clin Vaccine Immunol 2012; 19:804.

77.

Topic 3025 Version 23.0


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GRAPHICS

Rash in dengue fever

(A) Undifferentiated macular or maculopapular rash may occur over the face, thorax, abdomen, and extremities

during the acute phase of dengue. The rash is typically macular or maculopapular and may be associated with

pruritus.

(B) Convalescent rash is characterized by confluent erythematous eruption with sparing areas of normal skin. It is

often pruritic. The rash typically occurs within one to two days of defervescence and lasts one to five days.

Courtesy of Alan Rothman, MD.

Graphic 97534 Version 2.0


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Tourniquet test

Microvascular fragility may be demonstrated by a positive "tourniquet test"; this test is

performed by inflating a blood pressure cuff on the arm to midway between systolic and

diastolic blood pressures for five minutes. The pressure is released for at least one minute

and the skin below the cuff is examined for petechiae. A finding of 10 or more petechiae in a

one square inch area is considered positive.

Courtesy of Siripen Kalayanarooj, MD.

Graphic 97567 Version 2.0


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Disclosures: Alan L Rothman, MD Consultant/Advisory Boards: Sanofi Pasteur [Prevention and treatment of dengue virus infections(Tetravalent live-attenuated dengue vaccine Chimerivax-DEN)]. Anon Srikiatkhachorn, MD Nothing to disclose. Siripen Kalayanarooj, MDNothing to disclose. Martin S Hirsch, MD Nothing to disclose. Elinor L Baron, MD, DTMH Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures


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