Dengue Virus Infection Clinical Manifestations and Diagnosis UpToDate

10/3/23, 10:06 PM Dengue virus infection: Clinical manifestations and diagnosis - UpToDate
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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: Keri K Hall, MD, MS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2023.

This topic last updated: Oct 05, 2022.
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 DENVs, 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".)
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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 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].
In 2011, the WHO South-East Asia Regional Office published new guidelines for the prevention and control of dengue and
introduced the concept of the expanded dengue syndrome. The syndrome includes patients with severe organ involvement
(liver, kidney, brain, or heart) but without evidence of plasma leakage. Prolonged shock, comorbidities, and/or coinfections were
cited as common risk factors [11].
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 [12-16]. The WHO issued additional documents on dengue management in
2011 and 2012 [17,18].
WHO 1997 classification — In 1997, the WHO published a classification scheme describing three categories of symptomatic
infection: DF, DHF, and DSS [4]. (See 'Classification schemes' above.)
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 DHF [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 [19]. (See 'Dengue shock
syndrome' below.)
The criteria for DHF comprise a narrow definition that does not encompass all patients with clinically severe or complicated
DENV infections [5,20]. (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. It is estimated that the tourniquet test is positive in 80 percent of patients with dengue [7].
• 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 is 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 WHO 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 DENV infection includes 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 [21].
Clinically apparent dengue is more common among adults [22]; among children, most infections are asymptomatic or
minimally symptomatic [23,24]. 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 [25].
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 [20,26,27]. (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 [28].
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 (DF) includes febrile and recovery 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 recovery 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 [28-30]. 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 (ie, pain with eye movement), and joint pain occur in 60 to 70 percent of cases [24]. 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 [24]. 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 [5,7,31]. 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 [32,33]. Other less frequent manifestations included
hematemesis (15 to 30 percent), heavy menstrual bleeding (40 percent of women), melena (5 to 10 percent), epistaxis (10
percent), or hematuria [34]. 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
[29]. Facial puffiness, petechiae (on the skin and/or palate), and bruising (particularly at venipuncture sites) may be observed
[35]. 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 [31,36]. 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 [30].
Leukopenia and thrombocytopenia (≤100,000 cells/mm3) are common [29,30,37-40]. 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 [30,37]. 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 [32,33,41]. (See 'Dengue with warning signs' above and 'Critical phase'
below.)
Critical phase — The vast majority of infections that progress to a critical phase result from second DENV infections that occur
more than 18 months after a resolved 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
[37]. 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 [42]. 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 [43].
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.
Recovery phase — During the recovery 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 recovery 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 [44-48].
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 [44,47]. In addition, abdominal pain (occasionally mimicking an acute
abdomen) has been described as a clinical manifestation in case series [49,50].
Neurologic manifestations associated with DENV infection include encephalopathy and seizures; permanent neurologic
sequelae have been described [44,45,51-53]. In case series, the frequency of these manifestations is approximately 1 percent
[46]. Clinical manifestations include fever, headache, and lethargy; some patients may have no characteristic features of DENV
infection [45]. In such cases, the diagnosis has been supported by serologic testing, culture, or detection by polymerase chain
reaction in cerebrospinal fluid [45]. Other neurologic syndromes that have been reported to be potentially associated with
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DENV infection include stroke, acute pure motor weakness, mononeuropathies, polyneuropathies, Guillain-Barré syndrome,
and transverse myelitis [45,46,48,54].
Cardiovascular manifestations (including myocardial impairment, arrhythmias, and, occasionally, fulminant myocarditis) have
been described in patients with DENV infection [55-57]. One study including 81 patients with DENV in Brazil noted elevated
levels of troponin or B-type natriuretic peptide in 15 percent of cases [56]. 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 [58]. Reports of histologic findings of myocarditis at autopsy have been notable for detection of DENV antigens in
cardiomyocytes [56,59].
Acute kidney injury (AKI) has been reported in up to 3 percent of dengue cases [60-63]. Mechanisms of AKI may include shock,
rhabdomyolysis, glomerulonephritis, and acute tubular necrosis [64].
Retinal vasculitis and hemophagocytic lymphohistiocytosis have been described in association with DENV infection [65-67].
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 [68,69].
Secondary hemophagocytic lymphohistiocytosis is a potentially fatal hyperinflammatory condition and has been recognized in
cases of severe dengue [70,71].
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 vaccination are discussed separately. (See "Dengue virus infection: Prevention and treatment".)
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) [72]. (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 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) [73-75].
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 recovery 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 the DENVs, the diagnostic approach is
summarized in the figure ( algorithm 1 and table 2) [76]. (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 DENV 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 DENV 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 [77]. 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 [78]. 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: Epidemiology, clinical manifestations, and diagnosis" and "Lassa fever" and "Crimean-
Congo hemorrhagic fever" and "Kidney 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 [79-81].
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 [82-84]. The diagnosis of Zika virus infection is established via serology or RT-
PCR ( algorithm 1 and table 2) [76]. (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 rapid antigen test or 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 "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical
manifestations, and diagnosis".)
● 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 be
established via serology or nucleic acid testing [85]. (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.
● Influenza – Symptoms of influenza virus infection include abrupt onset of fever, headache, myalgia, and malaise,
accompanied by manifestations of respiratory-tract illness, such as cough, sore throat, and rhinitis. The diagnosis is
established via molecular testing of a nasopharyngeal specimen; other diagnostic tools are also available. (See "Seasonal
influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in children: Clinical features and
diagnosis".)
● Coronavirus disease 2019 (COVID-19) – Symptoms of COVID-19 include fever, cough, and/or dyspnea; other features,
including upper respiratory tract symptoms, myalgias, diarrhea, and loss of senses of smell or taste are also common.
Laboratory manifestations may include lymphopenia and elevated liver enzymes. The diagnosis is established via
molecular testing of a nasopharyngeal specimen; other diagnostic tools are also available. (See "COVID-19: Clinical
features" and "COVID-19: Diagnosis".)
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
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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 AND RECOMMENDATIONS
● Clinical manifestations – The three clinical phases of dengue are febrile phase, critical phase, and recovery phase. The
critical phase is not seen in all infections. (See 'Phases of infection' above.)
• Febrile phase – The febrile phase usually lasts three to seven days. (See 'Febrile phase' above.)
- Symptoms – Fever is nearly universal and is typically ≥38.5°C. Other common, acute symptoms include headache,
retro-orbital pain, and marked myalgia and arthralgia. A transient macular rash may develop two to five days after
onset of fever ( picture 1 and picture 2).
- Physical examination – Findings may include rash, conjunctival injection, pharyngeal erythema, and hemorrhagic
features (eg, petechiae, ecchymoses, vaginal or gastrointestinal bleeding). A tourniquet test (performed by
inflating a blood pressure cuff on the arm to midway between systolic and diastolic blood pressures for five
minutes) usually reveals petechiae one to two minutes after deflating the cuff ( picture 3).
- Laboratory findings – Typical findings include leukopenia, thrombocytopenia, and elevated aminotransferases.
• Critical phase – At defervescence, a small proportion of patients (usually children and young adults) develop plasma
leakage, bleeding, shock, and organ impairment or failure, which usually lasts 24 to 48 hours. The extent of plasma
leakage varies, and mild plasma leakage is not always associated with shock or organ failure. (See 'Critical phase'
above.)
- Warning signs – Signs of impending critical illness include persistent vomiting, severe abdominal pain, tender
hepatomegaly, pleural effusion, ascites, mucosal bleeding, and lethargy or restlessness. Physical examination may
reveal narrowed pulse pressure followed by hypotension and shock. Laboratory findings may include a high or
increasing hematocrit (≥20 percent from baseline), a rapid decrease in platelets, increased activated partial-
thromboplastin time, and decreased fibrinogen levels. (See 'Dengue with warning signs' above.)
The vast majority of infections that progress to a critical phase result from a second DENV infection with a different
DENV type than the first infection and occurs more than 18 months after a first infection. (See 'Critical phase' above and
"Dengue virus infection: Pathogenesis", section on 'Prior dengue exposure'.)
• Recovery phase – During the recovery phase, plasma leakage and hemorrhage resolve, vital signs stabilize, and
accumulated fluids are resorbed. A pruritic confluent, erythematous eruption with small islands of unaffected skin may
appear ( picture 1). The recovery phase typically lasts two to four days, but adults may have profound fatigue for
days to weeks after recovery.
● Diagnosis – Diagnosis is often made clinically although laboratory diagnostic testing allows confirmation of disease.
• Clinical diagnosis – A provisional diagnosis is based on typical clinical manifestations (fever, headache, nausea,
vomiting, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, positive tourniquet test,
leukopenia) coupled with exposure to a dengue-endemic country or region. (See 'Clinical approach' above.)
• Confirmatory diagnostic tests (see 'Laboratory testing' above) –
- Detection of viral protein or genome – Polymerase chain reaction (PCR) to detect viral genomes and antigen
tests are typically positive during the first week of illness.
- Serology ( figure 2) – Virus-specific IgM positivity develops around the fourth day of illness and is widely used to
make a presumptive diagnosis. The diagnosis may be confirmed via IgM seroconversion between paired acute and
recovery phase (obtained 10 to 14 days after the acute phase) specimens; a diagnosis of acute DENV infection may
be established by a significant rise in antibody levels as specified by the test).
Virus-specific IgG positivity generally develops slowly but may occur as early as seven days after onset of illness.
Baseline IgG positivity may be present in individuals with prior Dengue virus infection or vaccination.
● Differential diagnosis – Alternative diagnoses include other viral hemorrhagic fevers, some of which require strict
infection control measures. Other infections to be considered include Chikungunya or Zika virus ( table 3), malaria,
typhoid fever, leptospirosis, acute HIV infection, rickettsial infection, and sepsis due to bacteremia. (See 'Differential
diagnosis' above.)
● Immunized individuals – Immunized individuals may present with attenuated disease. Those without prior Dengue
infection may be at increased risk of severe disease if natural infection occurs following vaccination. Issues related to
dengue vaccine are discussed separately. (See "Dengue virus infection: Prevention and treatment".)
Use of UpToDate is subject to the Terms of Use.
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Topic 3025 Version 47.0
GRAPHICS
Dengue hemodynamic assessment
Prolonged/profound
Stable circulation Shock (DHF Grade III)* ¶
shock (DHF Grade IV)* ¶
Heart rate Normal Tachycardia Severe tachycardia or

bradycardia
Blood pressure Normal Normal systolic pressure but Severe hypotension or

rising diastolic pressure undetectable blood pressure
(narrowing pulse 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 Nonpregnant patients Pregnant women
antibodies virus 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
Positive (either assay) ¶ ≥10 ≥10 Recent flavivirus infection ◊ Flavivirus infection, timing
Any result <10 <10 No evidence of dengue or Zika No evidence of dengue or Zika
virus infection § virus infection §
Positive dengue virus assay, Not performed Presumptive recent dengue Presumptive dengue virus
negative Zika virus assay virus infection infection, timing cannot be
determined
Positive Zika virus assay, negative Not performed Presumptive recent Zika virus Presumptive Zika virus infection,
dengue 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 Not performed Presumptive recent flavivirus Presumptive flavivirus infection,
virus assay not performed infection ◊ timing cannot be determined
Positive Zika virus assay, dengue Not performed Presumptive recent flavivirus Presumptive flavivirus infection,
virus assay not performed infection ◊ timing cannot be determined
Negative (both assays) Not performed No evidence of dengue or Zika No evidence of dengue or Zika
virus infection § virus infection §
Negative dengue virus assay, Zika Not performed No evidence of dengue virus No evidence of dengue virus
virus assay not performed infection § infection §
Negative Zika virus assay, dengue Not performed No evidence of Zika virus No evidence of Zika virus
virus assay not performed infection § infection §
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 infection compared with dengue and chikungunya
Features Dengue Chikungunya Zika
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 Patent Holder: USG/Army [Pan-flavivirus, chikungunya, Zika virus]. Grant/Research/Clinical Trial Support:
Congressionally Directed Medical Research Programs [Dengue human infection model]; Department of Defense [Dengue human infection
model]; Janssen [Dengue antiviral study]; Merck [Dengue patient reported outcome]; National Institute on Drug Abuse [Heroin vaccine study];
National Institutes of Health P01 [Dengue]; Pfizer [COVID vaccine trial]; Pfizer [Influenza vaccine trial]. Consultant/Advisory Boards: Clover
[COVID]; EdJen [Vaccines]; Isosavax [COVID]; Merck [Dengue]; Moderna [Zika]; Pfizer [Vaccines]; PrimeVax [Dengue]; Rheonix [Chief Medical
Officer, Board of Directors]; Sanofi Pasteur [Vaccines]; Takeda [Dengue]; Vaxxinity [COVID]. Other Financial Interest: Azimuth Biologics [Co-
founder, chief medical officer. New start up, pre-clinical, pre-revenue, University spin out, funded with NY state grant]; Cormac Life Sciences,
LLC [Veteran-owned small business]; Phairify [Director of Strategy & Cofounder]. All of the relevant financial relationships listed have been
mitigated. Alan L Rothman, MD Consultant/Advisory Boards: Moderna [Prevention and treatment of dengue virus infections]; Takeda
[Prevention and treatment of dengue virus infections]. All of the relevant financial relationships listed have been mitigated. Anon
Srikiatkhachorn, MD No relevant financial relationship(s) with ineligible companies to disclose. Siripen Kalayanarooj, MD No relevant
financial relationship(s) with ineligible companies to disclose. Martin S Hirsch, MD No relevant financial relationship(s) with ineligible
companies to disclose. Keri K Hall, MD, MS No relevant financial relationship(s) with ineligible companies 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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10/3/23, 10:06 PM Dengue virus infection: Clinical manifestations and diagnosis - UpToDate

Official reprint from UpToDate®

Dengue virus infection: Clinical manifestations and diagnosis

Literature review current through: Sep 2023.

● 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:

● 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:

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

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

SUMMARY AND RECOMMENDATIONS

• Confirmatory diagnostic tests (see 'Laboratory testing' above) –

Use of UpToDate is subject to the Terms of Use.

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

Dengue hemodynamic assessment

Heart rate Normal Tachycardia Severe tachycardia or

Blood pressure Normal Normal systolic pressure but Severe hypotension or

Respiratory rate Normal Tachypnea Hyperpnea or Kussmaul

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.

Δ Pulse pressure is systolic pressure minus diastolic pressure.

Graphic 109848 Version 2.0

Rash in dengue fever

Courtesy of Alan Rothman, MD.

Graphic 97534 Version 2.0

Dengue virus infection

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

Graphic 97996 Version 1.0

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

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

Features Dengue Chikungunya Zika

Fever +++ +++ ++

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