Dengue Virus Infection

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Dengue virus infection: Clinical manifestations and diagnosis

Authors: Stephen J Thomas, MD, Alan L Rothman, MD, Anon Srikiatkhachorn, MD, Siripen Kalayanarooj, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2020. | This topic last updated: Nov 25, 2019.
INTRODUCTION
Dengue is a febrile illness caused by infection with one of four dengue viruses (DENV) transmitted by Aedes aegypti or Aedes
albopictus mosquitoes during the taking of a blood meal [1-3]. Infection may be asymptomatic or present with a broad range of
clinical manifestations including a mild febrile illness to a life-threatening shock syndrome. Numerous viral, host, and vector
factors are thought to impact risk of infection, disease, and disease severity.
There are four closely related but serologically distinct DENV types of the genus Flavivirus, called DENV-1, DENV-2, DENV-3,
and DENV-4. There is transient cross-protection among the four types, which weakens and disappears over the months following
infection; therefore, individuals living in a dengue-endemic area with all types co-circulating are at risk for infection with any and
all DENV types.
Issues related to clinical manifestations and diagnosis of DENV infection will be reviewed here. Issues related to epidemiology,
pathogenesis, prevention, and treatment are discussed separately. (See "Dengue virus infection: Pathogenesis" and "Dengue
virus infection: Prevention and treatment" and "Dengue virus infection: Epidemiology".)
CLASSIFICATION SCHEMES
Overview — In 1997, the World Health Organization (WHO) published a classification scheme describing three categories of
symptomatic DENV infection: dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) [4]. (See
'WHO 1997 classification' below.)
The WHO 1997 classification scheme is data driven and evidence based but has been criticized [5]. The term DHF suggests that
hemorrhage is the cardinal manifestation of severe dengue; however, plasma leakage leading to intravascular volume depletion
and potentially shock is the most specific feature of severe dengue and the focus of clinical management guidelines and
algorithms [6,7]. In addition, some patients with severe illness requiring medical intervention do not meet all criteria for DHF. It is
generally believed that use of the 1997 WHO definition for DHF underestimates the clinical burden of DENV infection [8].
In response to a wide call to reevaluate dengue disease classification, in 2009 the WHO published a revised classification
scheme describing the following categories: dengue without warning signs, dengue with warning signs, and severe dengue [9]
(see 'WHO 2009 classification' below). This scheme was proposed to emphasize early recognition of warning signs and thus
optimize triage and management decisions. It has been adopted for case reporting and clinical management in many but not all
countries. The sensitivity and specificity of the categories in the 2009 scheme for guiding clinical management of patients are not
known. The 2009 classification has, in turn, been criticized for a lack of clarity in the criteria for severe dengue and for obscuring
distinct disease phenotypes within each category [10].
Dengue classification schemes support a range of activities from clinical triage and treatment to epidemiologic and vaccine and
drug studies. Each guideline has been evaluated by a number of groups, and the 2009 classification has not superseded the
1997 classification for all aspects of DENV infection [11-15]. The WHO issued additional documents on dengue management in
2011 and 2012 [16,17].
WHO 1997 classification — In 1997, the World Health Organization published a classification scheme describing three
categories of symptomatic DENV infection: DF, DHF, and DSS [4]. (See 'Classification schemes' above.)
https://nebulosa.icesi.edu.co:2104/contents/dengue-virus-infection-clinical-manifestations-and-diagnosis/print?search=dengue&source=search_r… 1/23
Dengue fever — DF (also known as "break-bone fever") is an acute febrile illness defined by the presence of fever and two or
more of the following but not meeting the case definition of dengue hemorrhagic fever [4] (see 'Dengue hemorrhagic fever'
below):
● Headache
● Retro-orbital or ocular pain
● Myalgia and/or bone pain
● Arthralgia
● Rash
● Hemorrhagic manifestations (eg, positive tourniquet test, petechiae, purpura/ecchymosis, epistaxis, gum bleeding, blood in
emesis, urine, or stool, or vaginal bleeding)
● Leukopenia
Dengue hemorrhagic fever — The cardinal feature of DHF is plasma leakage due to increased vascular permeability as
evidenced by hemoconcentration (≥20 percent rise in hematocrit above baseline), pleural effusion, or ascites [4]. DHF is also
characterized by fever, thrombocytopenia, and hemorrhagic manifestations (all of which may also occur in the setting of DF) [4].
(See 'Dengue fever' above.)
In the setting of DHF, the presence of intense abdominal pain, persistent vomiting, and marked restlessness or lethargy,
especially coinciding with defervescence, should alert the clinician to possible impending DSS [18]. (See 'Dengue shock
syndrome' below.)
The criteria for DHF comprise a narrow definition that does not encompass all patients with clinically severe or complicated
dengue infections [5,19]. (See 'Classification schemes' above.)
According to the guidelines, a DHF diagnosis requires all of the following be present:
● Fever or history of acute fever lasting 2 to 7 days, occasionally biphasic
● Hemorrhagic tendencies evidenced by at least one of the following:
• A positive tourniquet test – The tourniquet test is performed by inflating a blood pressure cuff on the upper arm to a point
midway between the systolic and diastolic pressures for 5 minutes. A test is considered positive when 10 or more
petechiae per 2.5 cm (1 inch) square are observed. The test may be negative or mildly positive during the phase of
profound shock. It usually becomes positive, sometimes strongly positive, if the test is conducted after recovery from
shock.
• Petechiae, ecchymoses, or purpura.
• Bleeding from the mucosa, gastrointestinal tract, injection sites, or other locations.
• Hematemesis or melena.
● Thrombocytopenia (100,000 cells per mm3 or less) – This number represents a direct count using a phase-contrast
microscope (normal is 200,000 to 500,000 per mm3). In practice, for outpatients, an approximate count from a peripheral
blood smear is acceptable. In healthy individuals, 4 to 10 platelets per oil-immersion field (100x; the average of the readings
from 10 oil-immersion fields is recommended) indicates an adequate platelet count. An average of 3 platelets per oil-
immersion field is considered low (ie, 100,000 per mm3).
● Evidence of plasma leakage due to increased vascular permeability manifested by at least one of the following:
• A rise in the hematocrit equal to or greater than 20 percent above average for age, sex, and population.
• A drop in the hematocrit following volume-replacement treatment equal to or greater than 20 percent of baseline.
• Signs of plasma leakage such as pleural effusion, ascites, and hypoproteinemia.
Dengue shock syndrome — DSS consists of DHF with marked plasma leakage that leads to circulatory collapse (shock) as
evidenced by narrowing pulse pressure or hypotension (table 1).
For a diagnosis of DSS, all of the above four criteria for DHF must be present plus evidence of circulatory failure manifested by:
● Rapid and weak pulse.
● Narrow pulse pressure (20 mmHg [2.7 kPa]) or manifested by:
• Hypotension for age – Hypotension is defined to be a systolic pressure 80 mmHg (10.7 kPa) for those less than 5 years
of age or 90 mmHg (12.0 kPa) for those greater than or equal to 5 years of age. Note that narrow pulse pressure is
observed early in the course of shock, whereas hypotension is observed later or in patients who experience severe
bleeding.
• Cold, clammy skin and restlessness.
WHO 2009 classification — In 2009, the World Health Organization introduced a revised classification scheme consisting of the
following categories: dengue without warning signs, dengue with warning signs, and severe dengue [9]. (See 'Classification
schemes' above.)
Dengue without warning signs — A presumptive diagnosis of dengue infection may be made in the setting of residence in
or travel to an endemic area plus fever and two of the following [9]:
● Nausea/vomiting
● Rash
● Headache, eye pain, muscle ache, or joint pain
● Leukopenia
● Positive tourniquet test
These clinical manifestations are described further above. (See 'Dengue fever' above.)
Dengue with warning signs — Dengue with warning signs of severe infection includes dengue infection as defined above in
addition to any of the following [9]:
● Abdominal pain or tenderness

● Persistent vomiting
● Clinical fluid accumulation (ascites, pleural effusion)
● Mucosal bleeding
● Lethargy or restlessness
● Hepatomegaly >2 cm
● Increase in hematocrit concurrent with rapid decrease in platelet count
Issues related to plasma leakage are described further above. (See 'Dengue hemorrhagic fever' above.)
Severe dengue — Severe dengue infection includes dengue infection with at least one of the following [9]:
● Severe plasma leakage leading to:
• Shock
• Fluid accumulation with respiratory distress
● Severe bleeding (as evaluated by clinician)
● Severe organ involvement:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥1000 units/L
• Impaired consciousness
• Organ failure
CLINICAL MANIFESTATIONS
General principles — It is estimated that over 390 million DENV infections occur each year; approximately 96 million are
clinically apparent [20].
Clinically apparent dengue infections are more common among adults [21]; among children, most dengue infections are
asymptomatic or minimally symptomatic [22,23]. In one study including more than 3400 children in Southeast Asia and Latin
America with acute febrile illness, dengue accounted for approximately 10 percent of cases; the incidence of virologically
confirmed DENV infection was 4.6 and 2.9 episodes per 100 person-years, respectively, and the incidence of dengue
hemorrhagic fever (DHF) was <0.3 episodes per 100 person-years [24].
A primary DENV infection is the first wild-type infection an individual sustains; a secondary infection is the second wild-type
infection caused by a different DENV type. Secondary infections separated in time by more than 18 months represent the highest
risk for resulting in a severe clinical outcome [19,25,26]. (See 'Severe dengue' above.)
The incubation period of DENV infection ranges from 3 to 14 days; symptoms typically develop between 4 and 7 days after the
bite of an infected mosquito [27].
Patients with suspected dengue should be assessed carefully and directed to the appropriate care setting. Early recognition of
progression to severe disease and patients at increased risk for severe disease is essential, with prompt initiation of more
aggressive therapy when necessary. (See "Dengue virus infection: Prevention and treatment".)
Phases of infection — There are three phases that can be seen in the setting of DENV infection, a febrile phase, a critical
phase, and a recovery phase; however, the critical phase is not seen in all categories of infection [9]. The phases of infection are
described further in the sections below.
Within the WHO 1997 classification scheme, all three phases of infection occur in the setting of DHF and dengue shock
syndrome; dengue fever includes febrile and convalescent phases but no critical phase [9]. (See 'WHO 1997 classification'
above.)
Within the WHO 2009 classification scheme, all three phases of infection occur in the setting of severe dengue and dengue with
warning signs; dengue without warning signs includes febrile and convalescent phases but no critical phase. (See 'WHO 2009
classification' above.)
Issues related to the WHO classification schemes are discussed further above. (See 'Classification schemes' above.)
Febrile phase — The febrile phase of DENV infection is characterized by sudden high-grade fever (≥38.5°C) accompanied by
headache, vomiting, myalgia, arthralgia, and a transient macular rash in some cases [27-29]. Children have high fever but are
generally less symptomatic than adults during the febrile phase. The febrile phase lasts for three to seven days, after which most
patients recover without complications.
Headache, eye pain, and joint pain occur in 60 to 70 percent of cases [23]. Rash occurs in approximately half of cases; it is more
common during primary infection than secondary infection. When present, rash generally occurs two to five days after the onset
of fever [23]. It is typically macular or maculopapular and may occur over the face, thorax, abdomen, and extremities; it may be
associated with pruritus (picture 1 and picture 2). Additional manifestations may include gastrointestinal symptoms (including
anorexia, nausea, vomiting, abdominal pain, and diarrhea) and respiratory tract symptoms (cough, sore throat, and nasal
congestion).
Hemorrhagic manifestations may be observed in the febrile phase and/or critical phase (see 'Critical phase' below). The range
and severity of hemorrhagic manifestations are variable [5,7,30]. Major skin and/or mucosal bleeding (gastrointestinal or vaginal)
may occur in adults with no obvious precipitating factors and only minor plasma leakage. In children, clinically significant bleeding
occurs rarely, usually in association with profound and prolonged shock. Two Cuban studies noted spontaneous petechiae or
ecchymoses in approximately half of patients [31,32]. Other less frequent manifestations included hematemesis (15 to 30
percent), heavy menstrual bleeding (40 percent of women), melena (5 to 10 percent), and epistaxis (10 percent). Comorbid or
pre-existing medical conditions (such as peptic ulcer disease) may increase the risk for hemorrhage. Significant
thrombocytopenia is not always present when hemorrhagic manifestations occur; when present, it increases the risk of
hemorrhage.
Physical examination may demonstrate conjunctival injection, pharyngeal erythema, lymphadenopathy, and hepatomegaly [28].
Facial puffiness, petechiae (on the skin and/or palate), and bruising (particularly at venipuncture sites) may be observed [33]. A
tourniquet test should be performed by inflating a blood pressure cuff on the arm to midway between systolic and diastolic blood
pressures for five minutes [30,34]. The skin below the cuff is examined for petechiae one to two minutes after deflating the cuff;
presence of 10 or more new petechiae in one square inch area is considered a positive test (picture 3).
A biphasic ("saddleback") fever curve has been described in approximately 5 percent of cases; in such patients, acute febrile
illness remits and then recurs approximately one to two days later; the second febrile phase lasts one to two days [29].
Leukopenia and thrombocytopenia (≤100,000 cells/mm3) are common [28,29,35-38]. Serum aspartate transaminase (AST) levels
are frequently elevated; 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) occasionally occur [29,35]. Elevated liver enzymes are common in the febrile phase;
synthetic liver dysfunction (ie, elevated activated partial-thromboplastin time) and decreases in fibrinogen are not frequently
identified.
Between days 3 and 7 of the illness, the clinician must watch for signs of vascular leakage. Significant vascular leakage reduces
intravascular volume and decreases organ perfusion. Corresponding clinical manifestations may include persistent vomiting,
increasingly severe abdominal pain, tender hepatomegaly, development of pleural effusions and/or ascites, mucosal bleeding,
and lethargy or restlessness; laboratory findings may include a high or increasing hematocrit level (≥20 percent from baseline)
concurrent with a rapid decrease in the platelet count [31,32,39]. (See 'Dengue with warning signs' above and 'Critical phase'
below.)
Critical phase — The vast majority of DENV infections that progress to a critical phase result from secondary infections more
than 18 months from the first infection. However, a subset of critical infections occur in children less than one year of age, at the
time maternal antibody is below protective levels and the child experiences a primary wild type infection. In addition, severe
DENV infection may occur after primary infection in individuals with significant medical comorbidities.
Around the time of defervescence (typically days 3 to 7 of infection), a small proportion of patients (typically children and young
adults) develop a systemic vascular leak syndrome characterized by plasma leakage, bleeding, shock, and organ impairment
[35]. The critical phase lasts for 24 to 48 hours.
Initially, adequate circulation may be maintained by physiologic compensation, resulting in pulse pressure narrowing (systolic
pressure minus diastolic pressure ≤20 mmHg) (table 1); the patient may appear well, and the systolic pressure may be normal or
elevated. Nonetheless, urgent, careful resuscitation is needed; once hypotension develops, systolic pressure falls rapidly and
irreversible shock may follow despite aggressive attempts at resuscitation [4]. (See 'Dengue shock syndrome' above and 'Severe
dengue' above and "Dengue virus infection: Prevention and treatment", section on 'Treatment approach'.)
Hemorrhagic manifestations may be observed in the febrile phase and/or critical phase. (See 'Febrile phase' above.)
Imaging modalities for detection of plasma leakage include ultrasonography (of the chest and abdomen) and chest radiography.
In one study including 158 patients with suspected DHF in Thailand, ultrasonography around the time of defervescence was
helpful for detection of pleural effusion and peritoneal fluid; right lateral decubitus chest radiography was also useful for detection
of pleural effusion [40]. Plasma leakage was detected by ultrasound as early as three days after onset of fever; pleural effusions
were observed more commonly than ascites. Gallbladder wall thickening may also be evident [41].
Moderate-to-severe thrombocytopenia is common during the critical phase; nadir platelet counts ≤20,000 cells/mm3 may be
observed, followed by rapid improvement during the recovery phase [1]. A transient increase in the activated partial-
thromboplastin time and decrease in fibrinogen levels are also common.
Reversion of the critical phase of altered vascular permeability corresponds with rapid improvement in symptoms.
Convalescent phase — During the convalescent phase, plasma leakage and hemorrhage resolve, vital signs stabilize, and
accumulated fluids are resorbed. An additional rash (a confluent, erythematous eruption with small islands of unaffected skin that
is often pruritic) may appear during the convalescent phase (within one to two days of defervescence and lasting one to five
days) (picture 1).
The recovery phase typically lasts two to four days; adults may have profound fatigue for days to weeks after recovery.
Additional manifestations — Additional manifestations of DENV infection (typically occurring in the critical phase or later) may
include liver failure, central nervous system involvement, myocardial dysfunction, acute kidney injury, and others [42-46].
Liver failure has been described following resuscitation from profound shock; in many cases, it may be caused by prolonged
hypoperfusion or hypoxia rather than a direct viral effect [42,45]. In addition, abdominal pain (occasionally mimicking an acute
abdomen) has been described as a clinical manifestation in case series [47].
Neurologic manifestations associated with DENV infection include encephalopathy and seizures; permanent neurologic sequelae
have been described [42,43,48-50]. In case series, the frequency of these manifestations is approximately 1 percent [44]. Clinical
manifestations include fever, headache, and lethargy; some patients may have no characteristic features of DENV infection [43].
In such cases, the diagnosis has been supported by serologic testing, culture, or detection by polymerase chain reaction in
cerebrospinal fluid [43]. Other neurologic syndromes that have been reported to be potentially associated with DENV infection
include stroke, acute pure motor weakness, mononeuropathies, polyneuropathies, Guillain-Barré syndrome, and transverse
myelitis [43,44,46,51].
Cardiovascular manifestations (including myocardial impairment, arrhythmias, and, occasionally, fulminant myocarditis) have
been described in patients with DENV infection [52-54]. One study including 81 patients with DENV in Brazil noted elevated
levels of troponin or B-type natriuretic peptide in 15 percent of cases [53]. Another study including 181 children with DENV
infection noted transient left ventricular systolic and diastolic dysfunction was common and correlated with severity of plasma
leakage [55]. Reports of histologic findings of myocarditis at autopsy have been notable for detection of DENV antigens in
cardiomyocytes [53,56].
Acute kidney injury (AKI) has been reported in up to 3 percent of dengue cases [57-60]. Mechanisms of AKI may include shock,
rhabdomyolysis, glomerulonephritis, and acute tubular necrosis.
Retinal vasculitis and hemophagocytic lymphohistiocytosis have been described in association with DENV infection [61-63].
Bacterial coinfection with or following DENV infection occurs but is rare. Risk factors include pre-existing comorbidities and
severe illness at presentation. Persistent fever, rising white blood cell count, and signs and symptoms uncommon for dengue
should prompt evaluation for bacterial coinfection [64,65].
Immunized individuals — Dengue vaccines may not provide complete protection from dengue disease; immunized individuals
may present with attenuated disease. In addition, there is a theoretical possibility that immunization with a poorly immunogenic
dengue vaccine could increase the risk of severe dengue infection with subsequent exposure to wild-type virus. Issues related to
dengue vaccine are discussed separately. (See "Dengue virus infection: Prevention and treatment", section on 'Vaccination'.)
DIAGNOSIS
Clinical approach — The diagnosis of DENV infection should be suspected in febrile individuals with typical clinical
manifestations (fever, headache, nausea, vomiting, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations,
positive tourniquet test, leukopenia) and relevant epidemiologic exposure (residence in or travel within the past two weeks to an
area with mosquito-borne transmission of DENV infection). (See "Dengue virus infection: Epidemiology".)
A provisional diagnosis of DENV infection is usually established clinically. In regions and seasons with a high incidence of DENV
infection, the positive predictive value of clinical criteria is high, particularly for illnesses meeting all criteria for dengue
hemorrhagic fever (DHF) [66]. (See 'Dengue hemorrhagic fever' above.)
Early clinical presentations of dengue, chikungunya, and Zika virus infection may be indistinguishable. If feasible, laboratory
diagnostic confirmation is warranted, but often the results are not be available soon enough to guide initial clinical management.
Laboratory testing — Laboratory diagnosis of DENV infection is established directly by detection of viral components in serum
or indirectly by serology. The sensitivity of each approach depends on the duration of the patient's illness as well as when in the
course of illness the patient presents for evaluation (figure 1). Detection of viral nucleic acid or viral antigen has high specificity
but is more labor intensive and costly; serology has lower specificity but is more accessible and less costly.
During the first week of illness, the diagnosis of DENV infection may be established via detection of viral nucleic acid in serum by
means of reverse-transcriptase polymerase chain reaction assay (typically positive during the first five days of illness) or via
detection of viral antigen nonstructural protein 1 (NS1; typically positive during the first seven days of illness). In primary infection,
the sensitivity of NS1 detection can exceed 90 percent, and antigenemia may persist for several days after resolution of fever; in
secondary infection, the sensitivity of NS1 detection is lower (60 to 80 percent) [67-69].
Immunoglobulin (Ig)M can be detected as early as four days after the onset of illness by lateral flow immunoassay or IgM
antibody capture enzyme-linked immunosorbent assay (figure 2) [1]. Detection of IgM in a single specimen obtained from a
patient with a clinical syndrome consistent with dengue is widely used to establish a presumptive diagnosis. The diagnosis may
be confirmed via IgM seroconversion between paired acute and convalescent phase (obtained 10 to 14 days after the acute
phase) specimens; a diagnosis of acute DENV infection may be established by a fourfold or greater rise in antibody titer.
For symptomatic patients with epidemiologic risk for infection with Zika virus as well as DENV, the diagnostic approach is
summarized in the figure (algorithm 1 and table 2) [70]. (See "Zika virus infection: An overview", section on 'Epidemiology'.)
The likelihood of IgG detection depends on whether the infection is primary or secondary (figure 2). Primary dengue infection is
characterized by a slow and low titer antibody response; IgG is detectable at low titer beginning seven days after onset of illness
and increases slowly. Secondary dengue infection is characterized by a rapid rise in antibody titer beginning four days after onset
of illness, with broad cross-reactivity.
Serologic tests are unreliable for diagnosis of acute DENV infection in individuals who have been vaccinated with a dengue
vaccine within the previous several months [71]. In addition, serologic diagnosis of dengue may be confounded in the setting of
recent infection or vaccination with an antigenically related flavivirus such as yellow fever virus, Japanese encephalitis virus, or
Zika virus. (See "Dengue virus infection: Prevention and treatment".)
DENV infection can be established by virus isolation (culture); in general, this is not warranted as a clinical diagnostic tool since
results are usually not available in a clinically meaningful time frame.
Dengue viral proteins can be detected in tissue samples using immunohistochemical staining [72]. Liver tissues appear to have
the high yield; biopsy is rarely indicated in patients with suspected DENV infection, so this method is generally used only for
postmortem diagnosis.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of DENV infection includes:
● Other viral hemorrhagic fevers – Other viruses capable of causing hemorrhagic fever include Ebola virus, Marburg virus,
Lassa virus, yellow fever virus, Crimean-Congo hemorrhagic fever, hantavirus (hemorrhagic fever with renal syndrome), and
severe fever with thrombocytopenia syndrome virus (SFTSV). These illnesses can all cause severe multiorgan system
illness accompanied by hemorrhage. The diseases may be distinguished based on relevant epidemiologic exposure and
polymerase chain reaction or serologic testing. (See "Clinical manifestations and diagnosis of Ebola virus disease" and
"Marburg virus" and "Yellow fever" and "Lassa fever" and "Crimean-Congo hemorrhagic fever" and "Renal involvement in
hantavirus infections" and "Severe fever with thrombocytopenia syndrome virus".)
● Chikungunya – Chikungunya virus and DENV cause similar symptoms and signs and are transmitted by the same mosquito
vector (table 3). In 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 [73-75]. Joint swelling is
highly specific for chikungunya; bleeding manifestations and thrombocytopenia are relatively specific for dengue. The
diagnosis of chikungunya virus infection is established via serology or reverse-transcriptase polymerase chain reaction (RT-
PCR). (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
● Zika virus infection – DENV and Zika virus infections have similar clinical manifestations and are transmitted by the same
mosquito vector. Unlike DENV infection, Zika is commonly associated with conjunctivitis (table 3). Coinfection with Zika,
chikungunya, and DENVs has been described [76-78]. The diagnosis of Zika virus infection is established via serology or
RT-PCR (algorithm 1 and table 2) [70]. (See "Zika virus infection: An overview".)
● Malaria – Malaria is characterized by fever, malaise, nausea, vomiting, abdominal pain, diarrhea, myalgia, and anemia. The
diagnosis of malaria is established by visualization of parasites on peripheral smear. (See "Malaria: Clinical manifestations
and diagnosis in nonpregnant adults and children".)
● Typhoid fever – Clinical manifestations of typhoid fever include fever, bradycardia, abdominal pain, and rash. The diagnosis
is established by stool and/or blood culture. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of
enteric (typhoid and paratyphoid) fever".)
● Leptospirosis – Leptospirosis is characterized by fever, rigors, myalgia, conjunctival suffusion, and headache. Less common
symptoms and signs include cough, nausea, vomiting, diarrhea, abdominal pain, and arthralgia. The diagnosis is established
via serology. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
● Parvovirus B19 – In children, parvovirus presents most commonly as a mild febrile illness characterized by an erythematous
malar rash followed by a lacy rash over the trunk and extremities. In adults, parvovirus may present as an acute arthritis
involving the small joints of the hands, wrists, knees, and feet, with or without a rash. The diagnosis may established via
serology or nucleic acid testing [79]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
● Acute HIV infection – A variety of symptoms and signs may occur in association with acute HIV infection; the most common
findings are fever, lymphadenopathy, sore throat, rash, myalgia/arthralgia, and headache. Other manifestations include
painful mucocutaneous ulceration and aseptic meningitis. Diagnostic testing consists of an HIV immunoassay (ideally, a
combination antigen/antibody immunoassay) and an HIV virologic (viral load) test. (See "Acute and early HIV infection:
Clinical manifestations and diagnosis".)
● Viral hepatitis – Causes of viral hepatitis include hepatitis A, B, C, D, and E. Hepatitis A and E are acute infections
transmitted by the fecal-oral route, whereas hepatitis B, C, and D can present acutely or chronically and are transmitted by
body fluids. They are distinguished via serology and PCR (see related topics).
● Rickettsial infection – Rickettsial infections with similar manifestations as DENV infection include African tick bite fever and
relapsing fever. African tick bite fever is observed among travelers to Africa and the Caribbean and is characterized by
headache, fever, myalgia, solitary or multiple eschars with regional lymphadenopathy, and generalized rash; the diagnosis is
established via serology. Relapsing fever is characterized by fever, headache, neck stiffness, arthralgia, myalgia, and
nausea; diagnostic tools include direct smear and polymerase chain reaction. (See "Other spotted fever group rickettsial
infections" and "Clinical features, diagnosis, and management of relapsing fever".)
● Sepsis due to bacteremia – Sepsis due to bacteremia may present with fever, tachycardia, and altered mental status;
diagnosis requires blood culture.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Dengue virus".)
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 5th to 6th 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 10th to 12th 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.)
● Basics topic (see "Patient education: Dengue fever (The Basics)")
SUMMARY
● The clinical manifestations of dengue range from self-limited dengue fever (DF) to dengue hemorrhagic fever (DHF) with
shock syndrome, which may carry a significant mortality rate if improperly managed. 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 (DENV) infection, some of which can be severe. (See 'Clinical manifestations' above.)
● Classic DF is an acute febrile illness accompanied by headache, retro-orbital pain, and marked muscle and bone 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 'Dengue
fever' above.)
● DHF is the most serious manifestation of DENV infection and can be associated with shock. The four cardinal features of
DHF include increased vascular permeability, fever, hemorrhagic manifestations, and marked thrombocytopenia (100,000
cells/mm3 or lower). (See 'Dengue hemorrhagic fever' above.)
● Plasma leakage is the most specific and life-threatening feature of DHF 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.)
● Hemorrhagic manifestations of DENV infection can range from spontaneous petechiae to profuse bleeding. Severe bleeding
sometimes occurs in the absence of plasma leakage. (See 'Dengue fever' above and 'Dengue hemorrhagic fever' above.)
● The diagnosis of acute DENV infection is based mainly on clinical signs and symptoms in patients exposed to dengue by
residence in or travel to a dengue-endemic country or region. In settings where serologic assays are available, we favor use
of an acute-phase serum sample for use in an immunoglobulin (Ig)M immunoassay 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 nonstructural protein 1 antigen by enzyme-linked immunosorbent assay (ELISA). (See 'Diagnosis'
above.)
● If the clinical suspicion of DENV 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 DENV by hemagglutination inhibition assay or IgG ELISA. If
other diagnoses are being entertained, testing should be considered. (See 'Diagnosis' above.)
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REFERENCES
1. Simmons CP, Farrar JJ, Nguyen vV, Wills B. Dengue. N Engl J Med 2012; 366:1423.
2. Guzman MG, Harris E. Dengue. Lancet 2015; 385:453.
3. Kularatne SA. Dengue fever. BMJ 2015; 351:h4661.
4. World Health Organization. Dengue haemorrhagic fever: Diagnosis, treatment, prevention and control, 2nd edition. WHO, G
eneva 1997. http://apps.who.int/iris/bitstream/10665/41988/1/9241545003_eng.pdf (Accessed on December 07, 2016).
5. 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 Trop Med Hyg 2004; 70:172.
6. Wichmann O, Gascon J, Schunk M, et al. Severe dengue virus infection in travelers: risk factors and laboratory indicators. J
Infect Dis 2007; 195:1089.
7. Srikiatkhachorn A, Gibbons RV, Green S, et al. Dengue hemorrhagic fever: the sensitivity and specificity of the world health
organization definition for identification of severe cases of dengue in Thailand, 1994-2005. Clin Infect Dis 2010; 50:1135.
8. Anderson KB, Chunsuttiwat S, Nisalak A, et al. Burden of symptomatic dengue infection in children at primary school in
Thailand: a prospective study. Lancet 2007; 369:1452.
9. World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention and control, New edition. WHO: Genev
a 2009. http://www.who.int/tdr/publications/documents/dengue-diagnosis.pdf?ua=1 (Accessed on December 07, 2016).
10. Srikiatkhachorn A, Rothman AL, Gibbons RV, et al. Dengue--how best to classify it. Clin Infect Dis 2011; 53:563.
11. Zakaria Z, Zainordin NA, Sim BL, et al. An evaluation of the World Health Organization's 1997 and 2009 dengue
classifications in hospitalized dengue patients in Malaysia. J Infect Dev Ctries 2014; 8:869.
12. Horstick O, Jaenisch T, Martinez E, et al. Comparing the usefulness of the 1997 and 2009 WHO dengue case classification:
a systematic literature review. Am J Trop Med Hyg 2014; 91:621.
13. Nujum ZT, Thomas A, Vijayakumar K, et al. Comparative performance of the probable case definitions of dengue by WHO
(2009) and the WHO-SEAR expert group (2011). Pathog Glob Health 2014; 108:103.
14. Gan VC, Lye DC, Thein TL, et al. Implications of discordance in world health organization 1997 and 2009 dengue
classifications in adult dengue. PLoS One 2013; 8:e60946.
15. Wieten RW, Vlietstra W, Goorhuis A, et al. Dengue in travellers: applicability of the 1975-1997 and the 2009 WHO
classification system of dengue fever. Trop Med Int Health 2012; 17:1023.
16. World Health Organization Regional Office for Southeast Asia. Comprehensive guidelines for prevention and control of den
gue and dengue haemorrhagic fever. Revised and expanded version. SEARO Technical Publication Series, New Delhi, Indi
a 2011.
17. World Health Organization. Handbook for clinical management of dengue. WHO, Geneva 2012. https://apps.who.int/iris/bits
tream/handle/10665/76887/9789241504713_eng.pdf?sequence=1&isAllowed=y (Accessed on September 13, 2016).
18. Rigau-Pérez JG, Laufer MK. Dengue-related deaths in Puerto Rico, 1992-1996: diagnosis and clinical alarm signals. Clin
Infect Dis 2006; 42:1241.
19. Deen JL, Harris E, Wills B, et al. The WHO dengue classification and case definitions: time for a reassessment. Lancet
2006; 368:170.
20. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature 2013; 496:504.
21. SABIN AB. Research on dengue during World War II. Am J Trop Med Hyg 1952; 1:30.
22. 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.
23. Cobra C, Rigau-Pérez JG, Kuno G, Vorndam V. Symptoms of dengue fever in relation to host immunologic response and
virus serotype, Puerto Rico, 1990-1991. Am J Epidemiol 1995; 142:1204.
24. L'Azou M, Moureau A, Sarti E, et al. Symptomatic Dengue in Children in 10 Asian and Latin American Countries. N Engl J
Med 2016; 374:1155.
25. Anderson KB, Gibbons RV, Cummings DA, et al. A shorter time interval between first and second dengue infections is
associated with protection from clinical illness in a school-based cohort in Thailand. J Infect Dis 2014; 209:360.
26. Montoya M, Gresh L, Mercado JC, et al. Symptomatic versus inapparent outcome in repeat dengue virus infections is
influenced by the time interval between infections and study year. PLoS Negl Trop Dis 2013; 7:e2357.
27. Fukusumi M, Arashiro T, Arima Y, et al. Dengue Sentinel Traveler Surveillance: Monthly and Yearly Notification Trends
among Japanese Travelers, 2006-2014. PLoS Negl Trop Dis 2016; 10:e0004924.
28. Trofa AF, DeFraites RF, Smoak BL, et al. Dengue fever in US military personnel in Haiti. JAMA 1997; 277:1546.
https://nebulosa.icesi.edu.co:2104/contents/dengue-virus-infection-clinical-manifestations-and-diagnosis/print?search=dengue&source=search… 10/23
29. Leder K, Torresi J, Brownstein JS, et al. Travel-associated illness trends and clusters, 2000-2010. Emerg Infect Dis 2013;
19:1049.
30. Cao XT, Ngo TN, Wills B, et al. Evaluation of the World Health Organization standard tourniquet test and a modified
tourniquet test in the diagnosis of dengue infection in Viet Nam. Trop Med Int Health 2002; 7:125.
31. Díaz A, Kourí G, Guzmán MG, et al. Description of the clinical picture of dengue hemorrhagic fever/dengue shock
syndrome (DHF/DSS) in adults. Bull Pan Am Health Organ 1988; 22:133.
32. Guzmán MG, Kourí G, Martínez E, et al. Clinical and serologic study of Cuban children with dengue hemorrhagic
fever/dengue shock syndrome (DHF/DSS). Bull Pan Am Health Organ 1987; 21:270.
33. Cunha BA, Apostolopoulou A, Sivarajah T, Klein NC. Facial Puffiness in a Returning Traveler From Puerto Rico:
Chikungunya, Dengue Fever, or Zika Virus? Clin Infect Dis 2016; 63:1264.
34. Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005; 353:924.
35. Kalayanarooj S, Vaughn DW, Nimmannitya S, et al. Early clinical and laboratory indicators of acute dengue illness. J Infect
Dis 1997; 176:313.
36. Potts JA, Rothman AL. Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic
populations. Trop Med Int Health 2008; 13:1328.
37. Halstead SB. Dengue. Lancet 2007; 370:1644.
38. Tanner L, Schreiber M, Low JG, et al. Decision tree algorithms predict the diagnosis and outcome of dengue fever in the
early phase of illness. PLoS Negl Trop Dis 2008; 2:e196.
39. Khor BS, Liu JW, Lee IK, Yang KD. Dengue hemorrhagic fever patients with acute abdomen: clinical experience of 14
cases. Am J Trop Med Hyg 2006; 74:901.
40. Srikiatkhachorn A, Krautrachue A, Ratanaprakarn W, et al. Natural history of plasma leakage in dengue hemorrhagic fever:
a serial ultrasonographic study. Pediatr Infect Dis J 2007; 26:283.
41. Ferreira BDC, Correia D. Ultrasound Assessment of Hepatobiliary and Splenic Changes in Patients With Dengue and
Warning Signs During the Acute and Recovery Phases. J Ultrasound Med 2019; 38:2015.
42. Chhour YM, Ruble G, Hong R, et al. Hospital-based diagnosis of hemorrhagic fever, encephalitis, and hepatitis in
Cambodian children. Emerg Infect Dis 2002; 8:485.
43. Solomon T, Dung NM, Vaughn DW, et al. Neurological manifestations of dengue infection. Lancet 2000; 355:1053.
44. Carod-Artal FJ, Wichmann O, Farrar J, Gascón J. Neurological complications of dengue virus infection. Lancet Neurol
2013; 12:906.
45. Neeraja M, Iakshmi V, Teja VD, et al. Unusual and rare manifestations of dengue during a dengue outbreak in a tertiary
care hospital in South India. Arch Virol 2014; 159:1567.
46. Verma R, Sahu R, Holla V. Neurological manifestations of dengue infection: a review. J Neurol Sci 2014; 346:26.
47. Pires Neto Rda J, de Sá SL, Pinho SC, et al. Dengue infection in children and adolescents: clinical profile in a reference
hospital in northeast Brazil. Rev Soc Bras Med Trop 2013; 46:765.
48. Misra UK, Kalita J, Syam UK, Dhole TN. Neurological manifestations of dengue virus infection. J Neurol Sci 2006; 244:117.
49. Araújo FM, Araújo MS, Nogueira RM, et al. Central nervous system involvement in dengue: a study in fatal cases from a
dengue endemic area. Neurology 2012; 78:736.
50. Sahu R, Verma R, Jain A, et al. Neurologic complications in dengue virus infection: a prospective cohort study. Neurology
2014; 83:1601.
51. Li HM, Huang YK, Su YC, Kao CH. Risk of stroke in patients with dengue fever: a population-based cohort study. CMAJ
2018; 190:E285.
52. Yacoub S, Griffiths A, Chau TT, et al. Cardiac function in Vietnamese patients with different dengue severity grades. Crit
Care Med 2012; 40:477.
53. Miranda CH, Borges Mde C, Matsuno AK, et al. Evaluation of cardiac involvement during dengue viral infection. Clin Infect
Dis 2013; 57:812.
54. Yacoub S, Wertheim H, Simmons CP, et al. Cardiovascular manifestations of the emerging dengue pandemic. Nat Rev
Cardiol 2014; 11:335.
55. Kirawittaya T, Yoon IK, Wichit S, et al. Evaluation of Cardiac Involvement in Children with Dengue by Serial
Echocardiographic Studies. PLoS Negl Trop Dis 2015; 9:e0003943.
56. 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.
57. Lee IK, Liu JW, Yang KD. Clinical characteristics, risk factors, and outcomes in adults experiencing dengue hemorrhagic
fever complicated with acute renal failure. Am J Trop Med Hyg 2009; 80:651.
58. Laoprasopwattana K, Pruekprasert P, Dissaneewate P, et al. Outcome of dengue hemorrhagic fever-caused acute kidney
injury in Thai children. J Pediatr 2010; 157:303.
59. Basu G, Chrispal A, Boorugu H, et al. Acute kidney injury in tropical acute febrile illness in a tertiary care centre--RIFLE
criteria validation. Nephrol Dial Transplant 2011; 26:524.
60. Huang SY, Lee IK, Liu JW, et al. Clinical features of and risk factors for rhabdomyolysis among adult patients with dengue
virus infection. Am J Trop Med Hyg 2015; 92:75.
61. Chan DP, Teoh SC, Tan CS, et al. Ophthalmic complications of dengue. Emerg Infect Dis 2006; 12:285.
62. Tan LH, Lum LC, Omar SF, Kan FK. Hemophagocytosis in dengue: comprehensive report of six cases. J Clin Virol 2012;
55:79.
63. Sharp TM, Gaul L, Muehlenbachs A, et al. Fatal hemophagocytic lymphohistiocytosis associated with locally acquired
dengue virus infection - New Mexico and Texas, 2012. MMWR Morb Mortal Wkly Rep 2014; 63:49.
64. Thein TL, Ng EL, Yeang MS, et al. Risk factors for concurrent bacteremia in adult patients with dengue. J Microbiol
Immunol Infect 2017; 50:314.
65. Trunfio M, Savoldi A, Viganò O, d'Arminio Monforte A. Bacterial coinfections in dengue virus disease: what we know and
what is still obscure about an emerging concern. Infection 2017; 45:1.
66. Kalayanarooj S, Chansiriwongs V, Nimmannitya S. Dengue patients at the Children’s Hospital, Bangkok: 1995-1999 review.
Dengue Bulletin 2002; 26:33.
67. Guzman MG, Jaenisch T, Gaczkowski R, et al. Multi-country evaluation of the sensitivity and specificity of two
commercially-available NS1 ELISA assays for dengue diagnosis. PLoS Negl Trop Dis 2010; 4.
68. Hunsperger EA, Muñoz-Jordán J, Beltran M, et al. Performance of Dengue Diagnostic Tests in a Single-Specimen
Diagnostic Algorithm. J Infect Dis 2016; 214:836.
69. Huits R, Soentjens P, Maniewski-Kelner U, et al. Clinical Utility of the Nonstructural 1 Antigen Rapid Diagnostic Test in the
Management of Dengue in Returning Travelers With Fever. Open Forum Infect Dis 2017; 4:ofw273.
70. Sharp TM, Fischer M, Muñoz-Jordán JL, et al. Dengue and Zika Virus Diagnostic Testing for Patients with a Clinically
Compatible Illness and Risk for Infection with Both Viruses. MMWR Recomm Rep 2019; 68:1.
71. Plennevaux E, Moureau A, Arredondo-García JL, et al. Impact of Dengue Vaccination on Serological Diagnosis: Insights
From Phase III Dengue Vaccine Efficacy Trials. Clin Infect Dis 2018; 66:1164.
72. Jessie K, Fong MY, Devi S, et al. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry
and in situ hybridization. J Infect Dis 2004; 189:1411.
73. Taraphdar D, Sarkar A, Mukhopadhyay BB, Chatterjee S. A comparative study of clinical features between monotypic and
dual infection cases with Chikungunya virus and dengue virus in West Bengal, India. Am J Trop Med Hyg 2012; 86:720.
74. Lee VJ, Chow A, Zheng X, et al. Simple clinical and laboratory predictors of Chikungunya versus dengue infections in
adults. PLoS Negl Trop Dis 2012; 6:e1786.
75. Mohd Zim MA, Sam IC, Omar SF, et al. Chikungunya infection in Malaysia: comparison with dengue infection in adults and
predictors of persistent arthralgia. J Clin Virol 2013; 56:141.
76. Villamil-Gómez WE, González-Camargo O, Rodriguez-Ayubi J, et al. Dengue, chikungunya and Zika co-infection in a
patient from Colombia. J Infect Public Health 2016; 9:684.
77. Waggoner JJ, Gresh L, Vargas MJ, et al. Viremia and Clinical Presentation in Nicaraguan Patients Infected With Zika Virus,
Chikungunya Virus, and Dengue Virus. Clin Infect Dis 2016; 63:1584.
78. Silva MMO, Tauro LB, Kikuti M, et al. Concomitant Transmission of Dengue, Chikungunya, and Zika Viruses in Brazil:
Clinical and Epidemiological Findings From Surveillance for Acute Febrile Illness. Clin Infect Dis 2019; 69:1353.
79. Di Paola N, Mesquita FS, Oliveira DBL, et al. An Outbreak of Human Parvovirus B19 Hidden by Dengue Fever. Clin Infect
Dis 2019; 68:810.
Topic 3025 Version 42.0
GRAPHICS
Dengue hemodynamic assessment
Prolonged/profound shock
Stable circulation Shock (DHF Grade III)* ¶
(DHF Grade IV)* ¶
Heart rate Normal Tachycardia Severe tachycardia or bradycardia
Blood pressure Normal Normal systolic pressure but rising Severe hypotension or undetectable
diastolic pressure (narrowing pulse blood pressure
pressure Δ)
Postural hypotension
Respiratory rate Normal Tachypnea Hyperpnea or Kussmaul respirations
Urine output Normal Reducing trend Oliguria or anuria
Consciousness level Clear, lucid Clear, lucid Restless, combative
Capillary refill Brisk (≤2 seconds) Prolonged (>2 seconds) Very prolonged
Extremities Warm, pink Cool Cold, clammy, mottled skin
Peripheral pulse volume Good volume Weak, thready Feeble or absent
DHF: dengue hemorrhagic fever.

* The World Health Organization has established the following grading system for severity of dengue hemorrhagic fever:
DHF Grade I – Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma leakage.
DHF Grade II – DHF Grade I plus spontaneous bleeding.
DHF Grade III – DHF Grade I or DHF Grade II plus narrowing pulse pressure or hypotension.
DHF Grade IV – DHF Grade III plus profound shock with undetectable blood pressure and pulse.
Dengue shock syndrome consists of DHF Grade III and DHF Grade IV.
¶ Shock due to plasma leakage often presents with a narrow pulse pressure or elevated diastolic pressure with preserved systolic pressure, whereas shock due to
bleeding often presents with hypotension or low systolic pressure. Other causes of shock must also be considered (such as hypoglycemia, excessive vomiting, or
bacterial coinfection).
Δ Pulse pressure is systolic pressure minus diastolic pressure.
Modified from: Centers for Disease Control and Prevention. Dengue case management. Available at: http://www.cdc.gov/dengue/resources/dengue-clinician-
guide_508.pdf (Accessed on September 15, 2016).
Graphic 109848 Version 2.0
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.
Dengue virus infection
Maculopapular eruption on the back of a patient with dengue virus infection.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
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.
Laboratory tests for diagnosis of dengue virus infection
Comparative merits of laboratory methods for diagnosis of dengue infection.
Ig: immunoglobulin.
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Microbiology. Peeling RW, Artsob H, Pelegrino JL, et al.
Evaluation of diagnostic tests: Dengue. Nat Rev Microbiol 2010; 8:S30. Copyright © 2010. www.nature.com/nrmicro.
Dengue antibody response in primary and secondary infection
RNA: ribonucleic acid; NS1: nonstructural protein 1; Ig: immunoglobulin.
Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Microbiology. Peeling RW, Artsob H, Pelegrino JL, et al. Evaluation of
diagnostic tests: Dengue. Nat Rev Microbiol 2010; 8:S30. Copyright © 2010. www.nature.com/nrmicro.
Approach to diagnostic testing for dengue and Zika virus infection in symptomatic nonpregnant individuals
with risk for infection with both viruses
Specimen and test selection: Dengue and Zika virus NAATs, IgM antibody testing, and PRNTs should be performed on serum. Some NAATs also can be
performed on plasma, whole blood, cerebrospinal fluid, or urine, and some antibody tests can be performed on plasma, whole blood, or cerebrospinal fluid.
Laboratories might choose to perform dengue and Zika virus NAATs and IgM antibody testing simultaneously rather than sequentially, or to perform dengue
virus nonstructural protein-1 testing instead of dengue virus NAAT.
Indications to repeat assay(s): If the patient's illness has epidemiologic or clinical significance (eg, first case of local transmission in area, new
transmission mode, or unusual clinical syndrome), repeat a positive NAAT on newly extracted RNA from the same specimen. For indeterminate IgM antibody
test results, repeat IgM antibody testing or perform PRNT on the same specimen. In areas where PRNTs are not performed, report the indeterminate results
and request a second serum specimen for IgM antibody testing.
Interpretation of results: Dengue and Zika virus IgM antibodies can be detected in serum for months following infection. The specific timing of infection
cannot be determined. Data on the epidemiology of viruses known to be circulating at the location of exposure and clinical findings should be considered
when interpreting the results of serologic diagnostic testing.
NAAT: nucleic acid amplification test; IgM: immunoglobulin M; PRNT: plaque reduction neutralization test.
Reproduced from: Sharp TM, Fischer M, Muñoz-Jordán JL, et al. Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for
infection with both viruses. MMWR Recomm Rep 2019; 68:1.
Interpretation of dengue and Zika virus diagnostic test results
Dengue and Zika virus NAATs Interpretation

Positive dengue virus assay, negative Zika virus assay Acute dengue virus infection
Positive Zika virus assay, negative dengue virus assay Acute Zika virus infection
Positive (both assays) Acute dengue and Zika virus coinfection
Negative (both assays) No evidence of dengue or Zika virus infection*
Dengue and Zika virus IgM Dengue Zika virus Nonpregnant patients Pregnant women
antibodies virus PRNT
PRNT
Positive (either assay) ¶ Δ ≥10 <10 Recent dengue virus infection Dengue virus infection, timing
cannot be determined
Positive (either assay) ¶ Δ <10 ≥10 Recent Zika virus infection Zika virus infection, timing cannot
be determined
Positive (either assay) ¶ ≥10 ≥10 Recent flavivirus infection ◊ Flavivirus infection, timing cannot be
determined
Any result <10 <10 No evidence of dengue or Zika virus No evidence of dengue or Zika virus
infection § infection §
Positive dengue virus assay, negative Zika Not performed Presumptive recent dengue virus Presumptive dengue virus infection,
virus assay infection timing cannot be determined
Positive Zika virus assay, negative dengue Not performed Presumptive recent Zika virus Presumptive Zika virus infection,
virus assay infection timing cannot be determined
Positive (both assays) Not performed Presumptive recent flavivirus Presumptive flavivirus infection,
infection ◊ timing cannot be determined
Positive dengue virus assay, Zika virus Not performed Presumptive recent flavivirus Presumptive flavivirus infection,
assay not performed infection ◊ timing cannot be determined
Positive Zika virus assay, dengue virus Not performed Presumptive recent flavivirus Presumptive flavivirus infection,
assay not performed infection ◊ timing cannot be determined
Negative (both assays) Not performed No evidence of dengue or Zika virus No evidence of dengue or Zika virus
infection § infection §
Negative dengue virus assay, Zika virus Not performed No evidence of dengue virus No evidence of dengue virus
assay not performed infection § infection §
Negative Zika virus assay, dengue virus Not performed No evidence of Zika virus infection § No evidence of Zika virus infection §
assay not performed
NAAT: nucleic acid amplification test; IgM: immunoglobulin M; PRNT: plaque reduction neutralization test.
* In the absence of testing to detect IgM antibodies, negative NAAT results might reflect collection after clearance of detectable viral RNA and does not rule out
infection.
¶ Includes presumptive positive, indeterminate, and equivocal IgM antibody results that are not resolved by retesting.
Δ IgM and PRNT antibody testing infrequently provide discordant results (eg, dengue virus IgM positive, Zika virus IgM negative with dengue virus PRNT titer
<10, Zika virus PRNT titer ≥10; or dengue virus IgM negative, Zika virus IgM positive with dengue virus PRNT titer ≥10, Zika virus PRNT titer <10). In such
cases, report results as "presumptive flavivirus infection" and request a second specimen for retesting.
◊ The patient should be clinically managed for possible dengue and Zika virus infection because they might have been infected with either or both viruses. Data
on the epidemiology of viruses known to be circulating at the location of exposure and clinical findings should be considered when interpreting the results.
§ In the absence of NAAT, negative IgM or neutralizing antibody testing in specimens collected ≤7 days after illness onset might reflect collection before the
development of a detectable antibody response and does not rule out infection.
Reproduced from: Sharp TM, Fischer M, Muñoz-Jordán JL, et al. Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk
for infection with both viruses. MMWR Recomm Rep 2019; 68:1.
Clinical features: Zika virus compared with dengue and chikungunya
Features Zika Dengue Chikungunya
Fever ++ +++ +++
Rash +++ + ++
Conjunctivitis ++ – +
Arthralgia ++ + +++
Inflammatory arthritis (characterized by prolonged morning stiffness) -- -- +++
Myalgia + ++ +
Headache + ++ ++
Hemorrhage – ++ –
Shock – + –
Adapted from: Centers for Disease Control and Prevention. Zika virus - What clinicians need to know? Clinician Outreach and Communication Activity (COCA) Call,
January 26, 2016. Available at: http://emergency.cdc.gov/coca/ppt/2016/01_26_16_zika.pdf (Accessed February 1, 2016).
Contributor Disclosures
Stephen J Thomas, MD Grant/Research/Clinical Trial Support: Congressionally Directed Medical Research Programs [Dengue human
infection model grant]; Janssen [Dengue human infection model study]; National Institute on Drug Abuse [Heroin vaccine study]; Department of
Defense [Dengue human infection model]; National Institutes of Health P01 [Dengue]. Consultant/Advisory Boards: Takeda [Dengue]; Merck
[Dengue]; Sanofi [Dengue]; PrimeVax [Dengue]; Tremeau Pharmaceuticals [Dengue]; Themisbio [Chikungunya]; Moderna [Zika]. Patent Holder:
USG/Army [Pan-flavivirus, chikungunya, Zika virus]. Equity Ownership/Stock Options: PrimeVax SAB membership [Cancer immunotherapy].
Other Financial Interests: Cormac Life Sciences, LLC [veteran owned small business]; Green Mark Partners [Director of Strategy &
Cofounder]. Alan L Rothman, MD Consultant/Advisory Boards: Merck [Prevention and treatment of dengue virus infections]. Anon
Srikiatkhachorn, MD Nothing to disclose Siripen Kalayanarooj, MD Nothing 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 a multi-
level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Dengue virus infection: Clinical manifestations and diagnosis

● Fever or history of acute fever lasting 2 to 7 days, occasionally biphasic

● Hemorrhagic tendencies evidenced by at least one of the following:

• Petechiae, ecchymoses, or purpura.

• Signs of plasma leakage such as pleural effusion, ascites, and hypoproteinemia.

● Rapid and weak pulse.

● Narrow pulse pressure (20 mmHg [2.7 kPa]) or manifested by:

• Cold, clammy skin and restlessness.

● Abdominal pain or tenderness

● Severe plasma leakage leading to:

• Fluid accumulation with respiratory distress

● Severe bleeding (as evaluated by clinician)

● Severe organ involvement:

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥1000 units/L

The differential diagnosis of DENV infection includes:

and diagnosis in nonpregnant adults and children".)

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

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

Use of UpToDate is subject to the Subscription and License Agreement.

2. Guzman MG, Harris E. Dengue. Lancet 2015; 385:453.

3. Kularatne SA. Dengue fever. BMJ 2015; 351:h4661.

34. Wilder-Smith A, Schwartz E. Dengue in travelers. N Engl J Med 2005; 353:924.

37. Halstead SB. Dengue. Lancet 2007; 370:1644.

Topic 3025 Version 42.0

Dengue hemodynamic assessment

Heart rate Normal Tachycardia Severe tachycardia or bradycardia

Respiratory rate Normal Tachypnea Hyperpnea or Kussmaul respirations

Urine output Normal Reducing trend Oliguria or anuria

Consciousness level Clear, lucid Clear, lucid Restless, combative

Extremities Warm, pink Cool Cold, clammy, mottled skin

Peripheral pulse volume Good volume Weak, thready Feeble or absent

DHF: dengue hemorrhagic fever.

Graphic 109848 Version 2.0

Rash in dengue fever

Courtesy of Alan Rothman, MD.

Graphic 97534 Version 2.0

Maculopapular eruption on the back of a patient with dengue virus infection.

Graphic 97996 Version 1.0

Courtesy of Siripen Kalayanarooj, MD.

Graphic 97567 Version 2.0

Laboratory tests for diagnosis of dengue virus infection

Comparative merits of laboratory methods for diagnosis of dengue infection.

Graphic 113221 Version 1.0

Dengue antibody response in primary and secondary infection

RNA: ribonucleic acid; NS1: nonstructural protein 1; Ig: immunoglobulin.

Graphic 113222 Version 1.0

Graphic 121614 Version 2.0

Interpretation of dengue and Zika virus diagnostic test results

Dengue and Zika virus NAATs Interpretation

Positive (both assays) Acute dengue and Zika virus coinfection

Negative (both assays) No evidence of dengue or Zika virus infection*

Graphic 121613 Version 1.0

Clinical features: Zika virus compared with dengue and chikungunya

Features Zika Dengue Chikungunya

Fever ++ +++ +++

Inflammatory arthritis (characterized by prolonged morning stiffness) -- -- +++

Graphic 106512 Version 3.0

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