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Dengue virus infection: Clinical manifestations and diagnosis

Dengue virus infection: Clinical manifestations and diagnosis
Literature review current through: Jan 2024.
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".)

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 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 — 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 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".)

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Topic 3025 Version 49.0

References

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