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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):

● Retro-orbital or ocular pain

● Myalgia and/or bone pain

● Arthralgia

● 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 mm 3 or less) – This number represents a direct count using a phase-contrast microscope (normal is 200,000 to 500,000 per mm 3 ). 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 mm 3 ).

● 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

● Headache, eye pain, muscle ache, or joint pain

● 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:

• 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/mm 3 ) 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/mm 3 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" .)

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 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th 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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  • Patient Care & Health Information
  • Diseases & Conditions
  • Dengue fever

Dengue (DENG-gey) fever is a mosquito-borne illness that occurs in tropical and subtropical areas of the world. Mild dengue fever causes a high fever and flu-like symptoms. The severe form of dengue fever, also called dengue hemorrhagic fever, can cause serious bleeding, a sudden drop in blood pressure (shock) and death.

Millions of cases of dengue infection occur worldwide each year. Dengue fever is most common in Southeast Asia, the western Pacific islands, Latin America and Africa. But the disease has been spreading to new areas, including local outbreaks in Europe and southern parts of the United States.

Researchers are working on dengue fever vaccines. For now, in areas where dengue fever is common, the best ways to prevent infection are to avoid being bitten by mosquitoes and to take steps to reduce the mosquito population.

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Many people experience no signs or symptoms of a dengue infection.

When symptoms do occur, they may be mistaken for other illnesses — such as the flu — and usually begin four to 10 days after you are bitten by an infected mosquito.

Dengue fever causes a high fever — 104 F (40 C) — and any of the following signs and symptoms:

  • Muscle, bone or joint pain
  • Pain behind the eyes
  • Swollen glands

Most people recover within a week or so. In some cases, symptoms worsen and can become life-threatening. This is called severe dengue, dengue hemorrhagic fever or dengue shock syndrome.

Severe dengue happens when your blood vessels become damaged and leaky. And the number of clot-forming cells (platelets) in your bloodstream drops. This can lead to shock, internal bleeding, organ failure and even death.

Warning signs of severe dengue fever — which is a life-threatening emergency — can develop quickly. The warning signs usually begin the first day or two after your fever goes away, and may include:

  • Severe stomach pain
  • Persistent vomiting
  • Bleeding from your gums or nose
  • Blood in your urine, stools or vomit
  • Bleeding under the skin, which might look like bruising
  • Difficult or rapid breathing
  • Irritability or restlessness

When to see a doctor

Severe dengue fever is a life-threatening medical emergency. Seek immediate medical attention if you've recently visited an area in which dengue fever is known to occur, you have had a fever and you develop any of the warning signs. Warning signs include severe stomach pain, vomiting, difficulty breathing, or blood in your nose, gums, vomit or stools.

If you've been traveling recently and develop a fever and mild symptoms of dengue fever, call your doctor.

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Dengue fever is caused by any one of four types of dengue viruses. You can't get dengue fever from being around an infected person. Instead, dengue fever is spread through mosquito bites.

The two types of mosquitoes that most often spread the dengue viruses are common both in and around human lodgings. When a mosquito bites a person infected with a dengue virus, the virus enters the mosquito. Then, when the infected mosquito bites another person, the virus enters that person's bloodstream and causes an infection.

After you've recovered from dengue fever, you have long-term immunity to the type of virus that infected you — but not to the other three dengue fever virus types. This means you can be infected again in the future by one of the other three virus types. Your risk of developing severe dengue fever increases if you get dengue fever a second, third or fourth time.

Risk factors

You have a greater risk of developing dengue fever or a more severe form of the disease if:

  • You live or travel in tropical areas. Being in tropical and subtropical areas increases your risk of exposure to the virus that causes dengue fever. Especially high-risk areas include Southeast Asia, the western Pacific islands, Latin America and Africa.
  • You have had dengue fever in the past. Previous infection with a dengue fever virus increases your risk of severe symptoms if you get dengue fever again.

Complications

Severe dengue fever can cause internal bleeding and organ damage. Blood pressure can drop to dangerous levels, causing shock. In some cases, severe dengue fever can lead to death.

Women who get dengue fever during pregnancy may be able to spread the virus to the baby during childbirth. Additionally, babies of women who get dengue fever during pregnancy have a higher risk of pre-term birth, low birth weight or fetal distress.

In areas of the world where dengue fever is common, one dengue fever vaccine (Dengvaxia) is approved for people ages 9 to 45 who have already had dengue fever at least once. The vaccine is given in three doses over the course of 12 months.

The vaccine is approved only for people who have a documented history of dengue fever or who have had a blood test that shows previous infection with one of the dengue viruses — called seropositivity. In people who have not had dengue fever in the past (seronegative), receiving the vaccine appears to increase the risk of severe dengue fever and hospitalization due to dengue fever in the future.

Dengvaxia is not available for travelers or for people who live in the continental United States. But in 2019, the U.S. Food and Drug Administration approved the vaccine for people ages 9 to 16 who have had dengue fever in the past and who live in the U.S. territories of American Samoa, Guam, Puerto Rico and the U.S. Virgin Islands — where dengue fever is common.

Prevent mosquito bites

The World Health Organization stresses that the vaccine is not an effective tool on its own to reduce dengue fever in areas where the illness is common. Preventing mosquito bites and controlling the mosquito population are still the main methods for preventing the spread of dengue fever.

If you live in or travel to an area where dengue fever is common, these tips may help reduce your risk of mosquito bites:

  • Stay in air-conditioned or well-screened housing. The mosquitoes that carry the dengue viruses are most active from dawn to dusk, but they can also bite at night.
  • Wear protective clothing. When you go into mosquito-infested areas, wear a long-sleeved shirt, long pants, socks and shoes.
  • Use mosquito repellent. Permethrin can be applied to your clothing, shoes, camping gear and bed netting. You can also buy clothing made with permethrin already in it. For your skin, use a repellent containing at least a 10% concentration of DEET.
  • Reduce mosquito habitat. The mosquitoes that carry the dengue virus typically live in and around houses, breeding in standing water that can collect in such things as used automobile tires. You can help lower mosquito populations by eliminating habitats where they lay their eggs. At least once a week, empty and clean containers that hold standing water, such as planting containers, animal dishes and flower vases. Keep standing water containers covered between cleanings.
  • AskMayoExpert. Viral hemorrhagic fever. Mayo Clinic; 2019.
  • Dengue. Centers for Disease Control and Prevention. https://www.cdc.gov/dengue/index.html. Accessed Oct. 26, 2020.
  • Dengue and severe dengue. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue. Accessed Oct. 26, 2020.
  • Ferri FF. Dengue fever. In: Ferri's Clinical Advisor 2021. Elsevier; 2021. https://www.clinicalkey.com. Accessed Oct. 26, 2020.
  • Wilder-Smith A, et al. Dengue. The Lancet. 2019; doi:10.1016/S0140-6736(18)32560-1.
  • Thomas SJ, et al. Dengue virus infection: Prevention and treatment. https://www.uptodate.com/contents/search. Accessed Oct. 30, 2020.

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presentation in dengue

Dengue Hemorrhagic Fever/Dengue Shock Syndrome

  • Symptoms and Signs |
  • Diagnosis |
  • Treatment |
  • Key Points |
  • More Information |

Dengue hemorrhagic fever is a variant presentation of dengue infection that occurs primarily in children < 10 years living in areas where dengue is endemic. Dengue hemorrhagic fever, which has also been called Philippine, Thai, or Southeast Asian hemorrhagic fever, frequently requires prior infection with the dengue virus.

Dengue hemorrhagic fever is an immunopathologic disease; dengue virus–antibody immune complexes trigger release of vasoactive mediators by macrophages. The mediators increase vascular permeability, causing vascular leakage, hemorrhagic manifestations, hemoconcentration, and serous effusions, which can lead to circulatory collapse (ie, dengue shock syndrome).

Symptoms and Signs of Dengue Hemorrhagic Fever

Dengue hemorrhagic fever often begins with abrupt fever and headache and is initially indistinguishable from classic dengue. Warning signs that predict possible progression to severe dengue include

Severe abdominal pain and tenderness

Persistent vomiting

Hematemesis

Epistaxis or bleeding from the gums

Black, tarry stools (melena)

Lethargy, confusion, or restlessness

Hepatomegaly, pleural effusion, or ascites

Marked change in temperature (from fever to hypothermia)

Circulatory collapse and multiorgan failure, called dengue shock syndrome, may develop rapidly 2 to 6 days after onset.

Bleeding tendencies manifest as follows:

Usually as purpura, petechiae, or ecchymoses at injection sites

Sometimes as hematemesis, melena, or epistaxis

Occasionally as subarachnoid hemorrhage

Bronchopneumonia with or without bilateral pleural effusions is common. Myocarditis can occur.

Mortality is usually < 1% in experienced centers but otherwise can range to up 30%.

Diagnosis of Dengue Hemorrhagic Fever

Clinical and laboratory criteria

Dengue hemorrhagic fever is suspected in children with World Health Organization–defined clinical criteria for the diagnosis:

Sudden fever that stays high for 2 to 7 days

Hemorrhagic manifestations

Hepatomegaly

Hemorrhagic manifestations include at least a positive tourniquet test and petechiae, purpura, ecchymoses, bleeding gums, hematemesis, or melena. The tourniquet test is done by inflating a blood pressure cuff to midway between the systolic and diastolic blood pressure for 15 minutes. The number of petechiae that form within a 2.5-cm diameter circle are counted; > 20 petechiae suggests capillary fragility.

Complete blood count, coagulation tests, urinalysis, liver tests, and dengue serologic tests should be done. Coagulation abnormalities include

Thrombocytopenia (≤ 100,000 platelets/mcL [≤ 100 x 10 9 /L])

A prolonged prothrombin time (PT)

Prolonged activated partial thromboplastin time (PTT)

Decreased fibrinogen

Increased amount of fibrin split products

There may be hypoproteinemia, mild proteinuria, and increases in aspartate aminotransferase (AST) levels.

Serological diagnosis can be made using the IgM capture enzyme-linked immunosorbent assay (MAC-ELISA). Combined with the dengue virus RNA amplification test, it can provide a diagnosis within the first 1 to 7 days of illness. The plaque reduction neutralization test (PRNT) is specific and sensitive. Titers in acute and convalescent phase serum samples can reliably establish dengue virus infection and may indicate the specific dengue virus type involved. The PRNT requires live dengue viruses for the test and is labor-intensive and expensive. Many laboratories are not able to do the PRNT.

Patients with World Health Organization-defined clinical criteria plus thrombocytopenia ( ≤ 100,000/mcL [≤ 100 x 10 9 /L]) or hemoconcentration (Hct increased by ≥ 20%) are presumed to have the disease (see the Centers for Disease Control and Prevention's Dengue Virus: Clinical Guidance ).

Treatment of Dengue Hemorrhagic Fever

Supportive care

Patients with dengue hemorrhagic fever require intensive treatment to maintain euvolemia. Both hypovolemia (which can cause shock) and overhydration (which can cause acute respiratory distress syndrome) should be avoided. Urine output and the degree of hemoconcentration can be used to monitor intravascular volume.

No antivirals have been shown to improve outcome.

Dengue hemorrhagic fever occurs primarily in children

Dengue hemorrhagic fever may initially resemble classic dengue fever, but certain findings (eg, severe abdominal pain and tenderness, persistent vomiting, hematemesis, epistaxis, melena) indicate possible progression to severe dengue.

Diagnose based on specific clinical and laboratory criteria.

Maintaining euvolemia is crucial.

More Information

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

Centers for Disease Control and Prevention: Dengue Virus: For Healthcare Providers : Information on prevention, clinical presentation, diagnosis, and treatment, as well as how to distinguish COVID-19 from dengue

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Clinical Presentation and Platelet Profile of Dengue Fever: A Retrospective Study

1 Department of General Medicine, Sree Balaji Medical College and Hospital, Chennai, IND

N. Anuradha

Viknesh p anbalagan.

Background: Dengue fever (DF) is a mosquito-borne viral illness carried worldwide by Aedes aegypti and Aedes albopictus mosquitoes. The aim of the present study was to observe the different clinical presentations of dengue fever and the platelet profile analysis in DF patients.

Methods: This retrospective study was performed on 130 diagnosed patients with dengue fever, aged over 14 years. Data collection included patient age, gender, clinical manifestations, hematocrit, platelet count, and evidence of plasma leakage.

Results: Most of the patients belong to the 21-30 year age group, with a greater number of males compared to females. The common presentation of dengue fever was fever and myalgia, observed in 100% and 95.3% of the patients, respectively. A platelet count of less than 1,00,000 was observed in 77% of patients, whereas decreased total leukocyte count (TLC) and hematocrit were observed in 52.3% and 40% of patients, respectively. About 46.15% of patients had bradycardia on examination. Pleural effusion and ascites were found in 20.7% and 15.3% of patients, respectively.

Conclusion: Patients presenting with fever, hemorrhagic symptoms, or signs of plasma leakage should be promptly suspected, timely diagnosed and managed on the grounds of dengue fever.

Introduction

Dengue fever (DF) is an acute, self-limiting systemic viral illness caused by the dengue virus (Flaviviridae), spread globally by the mosquitoes Aedes aegypti and Aedes albopictus [ 1 ]. The World Health Organization (WHO) listed DF as one of the top ten global health risks. The dengue virus infects an estimated 390 million people each year, with 96 million showing clinical symptoms. In the previous decade, the number of cases in Southeast Asia has grown [ 2 ]. In tropical and sub-tropical nations, DF is a public health issue. Epidemics are growing increasingly common in India, burdening the public health system's limited resources. In India, the epidemic of dengue patients has increased in the past. Dengue epidemics in India are cyclical and spread geographically into rural regions, and cycle all sorts of serotypes in the population [ 3 ]. Specific clinical criteria identify dengue cases; however, they can appear with various symptoms. DF is a mysterious disease, including the virus-vector and host-virus relationships and a wide range of clinical manifestations [ 4 ].

Dengue infection manifests itself in a variety of ways, from mild febrile fever (DF) to severe hemorrhagic diseases like dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [ 5 ]. The deadliest variants of this disease, DHF and DSS, have been documented in India from Delhi, Calcutta, and Chennai [ 6 ]. Over the decade following the first epidemic, there has been a temporal change in the prevalence of various clinical symptoms. The change in the clinical presentation was thought to be caused by shifting serotypes (DEN-1, 2, 3, and 4) throughout outbreaks and re-infection. In addition, detailed serotype data for each occurrence is yet unavailable [ 7 ].

Antipyretics and pain relievers treat DF asymptomatically to relieve muscle and bone discomfort. Severe instances may necessitate hospitalization as well as enough hydration. The febrile phase of DF is marked by a high fever, headache, myalgia, body soreness, vomiting, joint pain, temporary rash, and modest bleeding symptoms such as petechiae, ecchymosis at pressure sites, and venipuncture bleeding [ 8 ]. The patient's risk of progressing to severe dengue (SD) is increased in the following critical phase, defined by plasma leakage that can lead to shock and fluid buildup (ascites or pleural effusion) with severe bleeding without respiratory difficulty and severe organ damage [ 9 ].

Acute liver failure, encephalopathy with convulsions, renal dysfunction, and lower gastrointestinal hemorrhage are all examples of unusual presentations. The clinico-epidemiologic characteristics of dengue infection have already been studied in several publications [ 10 ]. Patients with dengue fever who presented to the outpatient or emergency departments of a tertiary care hospital in an urban environment were assessed for their clinical and hematological profiles. The aim of the present study was to observe the different clinical presentations of dengue fever and the platelet profile analysis in DF patients.

Materials and methods

The present observational study was conducted at a tertiary care hospital over 24 months during the dengue fever season between 2019 and 2021. All patients presenting to the outpatient department with complaints of fever and clinical features of dengue with a positive test (dengue NS1) were included in this study. The study was conducted in accordance with the ethical principles following approval from the Medical Review and Ethical Committee (Registration No. ECR/719/Inst/TN/2015/RR-21). Written informed consent was obtained from every volunteer before clinical trial participation. The study includes all the patients meeting the inclusion criteria who gave consent from the dengue ward of the hospital; male and female patients above 14 years of age with bleeding manifestations and thrombocytopenia with platelet count (less than or equal to 100,000/μL). Patients with other viral or bacterial infections after a routine lab test and those who refused to participate in the survey were excluded from the study.

Data collection

At the time of presentation, the following information was collected: age, gender, clinical presentation, duration of fever, myalgia, joint pain, vomiting, rash, bleeding, hepatomegaly, headache, and shock, along with plasma leakage evidence such as ascites, pleural effusion, presence of petechiae, positive tourniquet test, other bleeding manifestations, hematocrit, and platelet count. Based on the presence of clinical symptoms, patients were classified as having dengue fever without warning signals (DF), dengue fever with warning signs (DFWS), or severe dengue (SD). The data were tabulated and presented as numbers (percentages).

All the patients were successfully enrolled in the study. Most of the patients were in the age group of 21-30 years (60), followed by 31-40 years (30), 15-20 years (22), 41-50 years (11), and 51-60 years (7). Out of all patients, 80 (62%) patients were males. The severity of dengue increased in 22% of patients with DHF and 6% with DSS. Male patients predominated in the DHF and DSS categories (20 and 6%). Relatively lower female patients were observed in groups DHF (8%) and DSS (2%) (Table ​ (Table1). 1 ). Among the patients, all were diagnosed with fever (100%), myalgia (95.3%), headache (79.20%), as well as joint pain (76.90%), which were observed in higher frequencies. Shock (93.80%), bleeding (78.40%), and hepatomegaly (75%) were not observed in most of the patients. Hess was observed only in 26.1% of patients.

DF: dengue fever, DHF: dengue hemorrhagic fever, DSS: dengue shock syndrome.

Among the patients, all were diagnosed with fever (100%), myalgia (95.3%), headache (79.20%), as well as joint pain (76.90%), which was observed in higher frequencies. Shock (93.80%), bleeding (78.40%), and hepatomegaly (75%) were not observed in most of the patients. Hess was observed only in 26.1% of patients (Table ​ (Table2 2 ).

ABD: Abdomen.

On analyzing the hematological parameters, 77% of patients had a platelet count of less than 1,00,000 cu. mm. (Table ​ (Table3). 3 ). The total leukocyte count (TLC) was less than 4000 and more than 11,000 in 51% and 3%, respectively. However, 46% of patients had normal TLC. The hematocrit level was less than 40 in 68 (52.3%), between 40-45 in 37 (28.4%), and more than 45 in 25 (19.2%) patients (Table ​ (Table3). 3 ). In 60 (46.15%) patients, bradycardia was observed (Table 3 ).

Among the evidence of plasma leakage, 20.7% was reported with pleural effusion, followed by ascites (15.3%), pedal edema (9.2%), and shock (6.15%) (Table ​ (Table4 4 ).

The present study was conducted to find out various clinical and laboratory parameters of dengue patients attending our hospital. The study aims to have a detailed clinico-hematologic profile of dengue disease so that prompt management of needy patients can be done. The study was conducted on 130 seropositive patients with confirmed dengue fever. Mostly, the disease was observed among young males between 21 and 30 years of age. The most commonly observed syndrome was DF compared to DHF and DSS. However, the most common manifestations were fever and myalgia, observed in 100% and 95.3% of the patients, respectively. On laboratory analysis of hematological parameters, the study revealed that 77% of patients had thrombocytopenia and 51% suffered from leukopenia. Moreover, a hematocrit of less than 40 was observed among 60 patients (52.3%). Bradycardia was found in 60 (46.15%) of the patients. Pleural effusion and ascites were recorded as the most common plasma leakage symptoms.

The present study found that the DF type of dengue is more common in men in their second decade of life. Several investigations have found comparable infection dominance in male patients. The studies relate the commonness to the relatively higher exposure rates of the virus in men [ 11 , 12 ]. Dengue fever is categorized as DF, DHF, or DSS, depending on the severity of the clinical manifestations [ 11 ]. These results were relatable to those published earlier that recorded a higher incidence of DF (65.2%) compared to DHF (34%) and DSS (0.79%) among 756 dengue patients studied [ 13 ].

Patients with classic dengue fever, arthralgia, myalgia, retro-orbital discomfort, rash, and hemorrhagic signs with or without shock frequently appear with a triad of symptoms. In recent years, respiratory symptoms, gastrointestinal problems, a low platelet count, and abnormal liver function tests have all been reported as signs of dengue fever. Over the decade following the first epidemic, there has been a temporal change in the prevalence of various clinical symptoms [ 14 ]. A likely triad of manifestations was observed in our study, with fever and myalgia dominating with other less common indexes: headache, joint pain, vomiting, abdominal pain, rash, hepatomegaly, bleeding, and shock. Fever as a significant index was reported in outbreaks in 2010 and 2018 [ 14 ].

The current study observed a lower Hess value (26.1%) that was not relatable to the confirmed dengue cases. In a parallel analysis, a very low percent tested positive for Hess among a large proportion of patients confirmed with dengue [ 14 ]. This demonstrates that the tourniquet test is specific but not sensitive for diagnosing dengue fever. For other tropical illnesses, the tourniquet test is not included in the case definition [ 15 ]. Due to a low platelet count and increased capillary permeability, hemorrhagic manifestation is one of the consequences of DF [ 16 ]. This was evident in most of our patients; 77% recorded a lower platelet count. On the present duty, we couldn't find any patients with bleeding symptoms and a positive tourniquet test. Most of the patients in our study had neutropenia and our findings correlate with the study of Singh et al., who also observed similar low TLC counts [ 17 ]. An inconsistency in the TLC of dengue patients was also noted, similar to our study [ 18 ]. This research also implicates that virus-induced destruction or suppression of myeloid progenitor cells may cause leukopenia in dengue fever. Bradycardia, one of the major dengue manifestations, was found to occur in 46.15% of patients. A similar relatively lower bradycardia occurrence was reported [ 19 ]. Transitions to plasma leakage, which resulted in respiratory distress syndrome and organ failure, were seen more frequently and were thought to predict increased case fatality among dengue patients [ 20 ]. Pleural effusion and ascites were the most common bleeding manifestations as per our study. A likely occurrence of ascites, as well as pleural effusion in dengue patients, was reported [ 21 ].

Limitations

This study used a limited sample size since it was conducted in a single outpatient clinic. However, because of the low rate of clinics receiving only people from the neighborhood, this small sample was kept for such a long period. In addition, there was no information on whether the infection was primary or secondary and the dengue serotype. Cross-sectional research involving many centers and tertiary hospitals, with a bigger sample size and the entire general population, might yield more helpful conclusions.

Conclusions

Dengue fever is a serious endemic disease, particularly in developing countries. The present study address common clinical and hematological manifestations of dengue fever together with other syndromes. Fever and myalgia were found to be the most common symptoms in dengue-affected patients. Furthermore, the study emphasizes that by knowing the various clinico-hematological manifestations of dengue fever, timely measures of management and treatment can be undertaken.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study. Sree Balaji Medical College and Hospital issued approval ECR/719/Inst/TN/2015/RR-21

Animal Ethics

Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

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  • Published: 18 August 2016

Dengue infection

  • Maria G. Guzman 1 ,
  • Duane J. Gubler 2 ,
  • Alienys Izquierdo 1 ,
  • Eric Martinez 1 &
  • Scott B. Halstead 3  

Nature Reviews Disease Primers volume  2 , Article number:  16055 ( 2016 ) Cite this article

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  • Dengue virus
  • Viral epidemiology
  • Viral host response
  • Viral infection
  • Viral pathogenesis

Dengue is widespread throughout the tropics and local spatial variation in dengue virus transmission is strongly influenced by rainfall, temperature, urbanization and distribution of the principal mosquito vector Aedes aegypti . Currently, endemic dengue virus transmission is reported in the Eastern Mediterranean, American, South-East Asian, Western Pacific and African regions, whereas sporadic local transmission has been reported in Europe and the United States as the result of virus introduction to areas where Ae. aegypti and Aedes albopictus , a secondary vector, occur. The global burden of the disease is not well known, but its epidemiological patterns are alarming for both human health and the global economy. Dengue has been identified as a disease of the future owing to trends toward increased urbanization, scarce water supplies and, possibly, environmental change. According to the WHO, dengue control is technically feasible with coordinated international technical and financial support for national programmes. This Primer provides a general overview on dengue, covering epidemiology, control, disease mechanisms, diagnosis, treatment and research priorities.

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Introduction.

Dengue is currently one of the world's most important neglected tropical diseases 1 and its incidence has increased >30-fold in recent decades alongside the geographical expansion of the Aedes vector mosquitoes and dengue viruses (DENVs) 2 , 3 . Transmission of DENVs occurs in Eastern Mediterranean, American, South-East Asian, Western Pacific and African regions, with new cases occurring and spreading to non-endemic areas in the United States and Europe. Dengue epidemics impose high costs to health services, to families and to the economic systems of affected countries 1 .

The term ‘dengue viruses’ groups four genetically and antigenically related viruses that are known as serotypes 1–4, each of them grouped into genotypes. Infection by any of the four serotypes can result in a range of clinical manifestations for which the timing or sequence of infections can be an important determinant of disease severity and course 4 . Dengue illness is clinically classified as either dengue with or without warning signs or severe dengue 2 ( Fig. 1 ). This classification was launched by the WHO in 2009 for the purpose of improving clinical management. The assessment of warning signs is designed to permit the early identification of patients with more-severe disease manifestations who require supportive therapy. Dengue illness can also be divided into three separate phases: the acute (febrile) phase, the critical (plasma leakage) phase and the convalescent or reabsorption phase ( Box 1 ). The 2009 classification replaced the previous 1997 WHO system that addressed and underscored the two pathological phenomena associated with the disease: plasma leakage and abnormal haemostasis. Under this classification, patients were designated as having either dengue fever — a nonspecific febrile illness and the most common manifestation of DENV infection — or dengue haemorrhagic fever and dengue shock syndrome (DHF/DSS) — a combination of plasma leakage and coagulopathy, sometimes accompanied by bleeding that can lead to a rapid fall in blood pressure and consequently to circulatory shock and organ impairment 3 ( Box 1 ).

figure 1

The criteria for dengue with or without warning signs and for severe dengue. Dashed arrows indicate that not all patients progress to severe dengue. * Important when there is no sign of plasma leakage. ‡ Requires strict observation and medical intervention. ALT, alanine aminotransferase; AST, aspartate aminotransferase. From Ref. 2 . Adapted with permission, from WHO/TDR, Dengue Guidelines for Diagnosis, Treatment, Prevention and Control — New Edition, World Health Organization and Special Programme for Research and Training in Tropical Diseases, WHO Press, Figure 1.4, 2009.

PowerPoint slide

This Primer provides special emphasis on the epidemiology, diagnosis, clinical management, pathogenic mechanisms and control of dengue. Research priorities are also discussed.

Box 1: Key clinical terms

Acute phase

Characterized by high fever that is driven by high viral loads (viraemia)

Critical phase

Characterized by plasma leakage into the abdominal and pleural cavities, which becomes evident at the end of the febrile (acute) stage of illness (days 3–6)

Warning signs that announce shock are usually present

Convalescent phase

Involves both cessation of plasma leakage and reabsorption of leaked fluids

Dengue or dengue fever

A nonspecific febrile illness that is characterized by fever and the presence of two or more other symptoms, such as headache, rash, retro-orbital or ocular pain and myalgia

Most patients have a satisfactory resolution without signs of severity or warning signs (referred to as dengue without warning signs according to the 2009 WHO classification)

Dengue haemorrhagic fever

Characterized by increased vascular permeability, plasma leakage, bleeding, thrombocytopaenia and fever (according to the 1997 WHO classification)

The term and concept are not included in the revised 2009 WHO classification nor are they recommended for triage of patients because it is not necessarily associated with severity, among other reasons

Dengue with warning signs

At the end of the febrile period, some patients have signs or symptoms that are suggestive of important fluid loss associated with capillary leakage (for example, severe abdominal pain), announcing the imminence of shock and indicating that fluid replacement is urgently required (according to the 2009 WHO classification)

Severe dengue

Circulatory shock or respiratory distress associated with severe plasma leakage, severe bleeding or severe organ involvement (frequently myocarditis, encephalitis and severe hepatitis) with or without shock or bleeding (according to the 2009 WHO classification)

Epidemiology

Transmission.

DENVs are maintained in an endemic–epidemic cycle involving humans and mosquitoes in crowded tropical urban centres. These viruses are fully adapted to humans, and the highly domesticated principal vector mosquito Aedes aegypti emerged long ago from sylvatic cycles involving non-human primates and canopy-dwelling Aedes mosquitoes in the rainforests of Asia and Africa 4 . Although these cycles still exist, their public health importance is uncertain. Ae. aegypti was introduced to the Americas during the slave trade in the 1600s and spread worldwide as the shipping industry expanded. This species lives in intimate association with and feeds on humans, rests in their homes and lays its eggs in man-made water containers. The average female mosquito lives for approximately 1 week, but some females can live for ≥2 weeks 5 .

The female mosquito becomes infected when she takes a blood meal during the acute febrile and viraemic phase of illness. During the extrinsic incubation period, the virus first infects midgut cells and then disseminates to replicate in numerous mosquito tissues, ultimately infecting the salivary glands 5–12 (generally 8–10) days later, a process that is influenced by ambient temperature, the viral strain and the competence of the mosquito. Once the salivary glands are infected, the mosquito is infective and can transmit the virus to another person during blood-feeding 4 . The mosquito remains infective for life and can infect every person it subsequently feeds on or probes while trying to feed. The time from infection to onset of illness (the intrinsic incubation period) in humans ranges from 3 to 14 days, with an average of 4–7 days 4 , 6 ( Fig. 2 ). Vertical transmission can occur when the infected female mosquito transmits the virus through the eggs to her offspring, but the epidemiological importance of this mode of transmission is uncertain 4 .

figure 2

An Aedes aegypti mosquito can become infected by feeding on a person in the viraemic phase of infection. During the extrinsic phase of the cycle, dengue viruses first infect mosquito midgut cells and other tissues before disseminating to the salivary glands. An infected mosquito can then transmit the dengue virus to several humans as it feeds or attempts to feed. Once infected, it takes an average of 4–7 days for the onset of symptoms and for a person to become capable of transmitting dengue virus to a new mosquito. Both symptomatic and asymptomatic individuals can transmit dengue virus to mosquitoes.

Global burden of disease

Although DENVs achieved distribution throughout the tropics in the eighteenth and nineteenth centuries, during the twentieth and twenty-first centuries, globalization enabled their more-rapid spread and the introduction of multiple viral serotypes into permissive areas, resulting in most tropical regions becoming hyperendemic (that is, with multiple viral serotypes co-circulating). This rapid spread began with a pandemic of dengue in South-East Asia in the 1950s that was associated with regional economic and urban growth after World War II. Epidemic activity dramatically accelerated in the 1970s and 1980s, leading to a global geographical expansion of viruses and mosquito vectors, and the consequent widespread DENV transmission across the tropics and subtropical areas 4 , 7 ( Fig. 3 ). This geographical expansion resulted in increased frequency and magnitude of epidemics and increased frequency of severe disease ( Fig. 4 ). The principal drivers of this twentieth century pandemic were global trends, such as human population growth, urbanization, modern transportation, global trade and the absence of effective mosquito control in endemic countries 4 , 7 – 11 . The geographical spread and increased epidemic activity in the 1970s coincided with the jet airplane becoming a principal mode of human travel 4 , 8 . This development led to more-frequent epidemics followed by clinically silent or undetected transmission during inter-epidemic periods. Large cities tend to be hyperendemic, with co-circulation of all four serotypes. Epidemics might occur when herd immunity to one of the four serotypes wanes and/or when a new epidemic strain of virus emerges or is introduced. Although not documented, an increase or change in vector competence of the mosquito population might also influence epidemic transmission.

figure 3

The global evidence consensus, risk and burden of dengue is shown with evidence consensus on complete absence (dark green) through to complete presence (dark red) of dengue. Adapted from Ref. 10 , Nature Publishing Group.

figure 4

The number of locations that reported dengue between 1960 and 2012 are shown. An increasing trend is apparent in the number of locations reporting dengue, with higher figures in American and Asian regions. The figure shows the number of occurrence points by date recorded in mapping exercises; it is neither a prevalence nor an incidence metric, but an audit of data sources per year. Adapted from Ref. 301 , Nature Publishing Group.

Recent best estimates of dengue disease burden suggest that over half of the world's population (3.6 billion people) live in areas that place them at risk of DENV infection 12 , with 390 million overall DENV infections, 96 million symptomatic infections 10 , 2 million cases of severe disease 12 and 21,000 deaths per year 13 . The highest incidence of DENV infection occurs in Asia where children between 5 and 15 years of age are primarily infected, followed by the American tropics where the modal age of infection is 19–40 years, depending on the country 8 . Dengue rates in Africa are unknown 14 because many outbreaks and cases might be misattributed to malaria 15 . During the past 40 years, a steady increase in dengue epidemic activity in Africa has been noted, as well as in the isolated islands of the Pacific and Indian Oceans 4 , 8 , 14 .

As with disease burden, the economic consequences of dengue are not well studied. However, estimates of disability-adjusted life years have shown dengue to be in the same order of magnitude or higher as most of the major infectious diseases, such as upper respiratory infections and hepatitis B virus infection 16 . Recent estimates of direct and indirect costs resulting from DENV infections are considerable, averaging US$2.2 billion per year in the Americas between 2000 and 2007, US$1.2 billion in South-East Asia per year between 2001 and 2010 and US$76 million in Africa per year 17 , 18 . A recent study estimates the annual global cost of dengue at US$8.9 billion 19 . These are conservative estimates and are subject to many uncertainties.

Mechanisms/pathophysiology

Dengue viruses.

The viral genome . DENVs belong to the genus Flavivirus of the Flaviviridae family. The four serotypes are enveloped, spherical viral particles with a diameter of approximately 500 Å 20 . The genome of each serotype comprises approximately 11 kb of positive-sense, single-stranded RNA that encodes ten proteins. The three structural proteins encoded by the genome are the membrane (M) protein, envelope (E) protein and capsid (C) protein; the non-structural (NS) proteins are NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5.

Structure and function of the E protein and M protein . The delivery of the DENV genome into the host cytoplasm is a multistep process that begins with fusion of the viral membrane with the host plasma membrane, followed by endocytosis of the virus into an endosome and then pH-dependent fusion of the viral and endosomal membranes ( Fig. 5 ). The inside of the virus particle is formed by RNA complexed with capsid proteins and is surrounded by a lipid bilayer membrane that contains externally anchored M protein and E protein, which together orchestrate host–viral interactions during entry. The E protein is arranged on the surface of DENVs as 90 tightly packed monomers that lie flat against the membrane and facilitates viral entry into host cells by binding to cellular receptors and mediating the fusion of viral and cellular membranes 21 , 22 . Of its three domains (DI–DIII), DIII of the E protein is responsible for binding to host receptors and several mutations have been identified in this domain that affect receptor binding 21 – 23 . The hinge that connects DI to DII is highly flexible and is used to manoeuver DII in the low pH environment of the endosome, leading to the exposure of the DII fusion loop. This fusion loop then interacts with the endosomal membrane to facilitate fusion of the virus with the endosomal membrane and release of viral RNA into the host cell 24 . Upon release from infected cells, new DENV particles can either contain processed surface M protein, and therefore be infective or ‘mature’, or retain the uncleaved precursor form of the M (prM) protein on its surface and thereby remain in an ‘immature’ form. Some viral particles can have a mixture of M protein and prM protein on their surface and these particles may or may not be infective.

figure 5

Mature viral particles attach to host cells by the binding of the envelope (E) protein to unknown receptors. Viral entry is achieved through receptor-mediated endocytosis. Inside the host cell, pH-dependent rearrangement of the E protein facilitates fusion of the viral and endosomal membranes to release the nucleocapsid, which disassembles to release the capped viral genomic RNA. The genomic RNA is then translated into a long polyprotein, which is autocatalytically cleaved by the non-structural 2B (NS2B) or NS3 viral protease and host proteases into individual proteins. The released NS proteins are targeted to the site of replication on endoplasmic reticulum (ER)-derived vesicle packets to initiate transcription. NS1 is initially expressed in association with the ER; the monomer is modified by the addition of high mannose carbohydrate (CHO) moieties, resulting in membrane association. A subset of dengue virus (DENV) NS1 acquires glycosyl-phosphatidylinositol (GPI). Both membrane-bound NS1 and GPI-anchored NS1 are trafficked to the cell surface via an unknown pathway, where they have been shown to associate with lipids such as cholesterol. Some of the cell surface-associated NS1 can be previously secreted NS1 that has bound directly to cell surface glycosaminoglycans (GAGs). Some NS1 can also be secreted from host cells. Meanwhile, the precursor form of the membrane (M) protein (prM) and the E protein are embedded into the ER membrane and enclose the newly formed nucleocapsid as it buds into the ER lumen to form an immature particle. This particle is trafficked via the secretory pathway, in which the low pH of the trans -Golgi network causes substantial rearrangement of the prM and E proteins that permits the cleavage of prM by furin protease to form the mature M protein. The virion is released from the host cell with the release of the pr peptide (dashed arrow). A subset of viral particles are released with prM still intact and are unable to infect new host cells. + and – signs indicate positive-sense and negative-sense RNA, respectively. C, capsid; DC-SIGN, dendritic cell-specific ICAM3-grabbing non-integrin; UTR, untranslated region. Adapted from Ref. 302 , Nature Publishing Group.

Structure and function of the NS proteins . The NS proteins are involved in viral replication and packaging, processes that are closely linked to host endoplasmic reticulum (ER) and secretory pathway function ( Fig. 5 ). NS1 is a 46 kDa glycoprotein that exists in three forms: the ER-resident form; the membrane-anchored form; and the secreted form. NS1 is initially synthesized as a soluble monomer and becomes associated with the membrane after dimerization in the lumen of the ER 25 . The crystal structure of NS1 has recently been determined and revealed exposed hydrophobic domains in the dimer that probably mediate this membrane association 26 . Intracellular NS1 participates in early viral RNA replication and is found in virus-induced vesicular compartments that house the viral replication complexes 27 . NS1 is also transported to the cell surface, where it either remains associated with the cell membrane or is secreted (sNS1) as a soluble, lipid-associated hexameric species. sNS1 can be detected in the blood of infected patients from the first day of symptoms and circulates at levels in the ng per ml to mg per ml range during the acute phase of infection 28 , and blood levels of sNS1 correlate with peak viraemia and disease severity in secondary DENV infection 28 . Several studies have suggested that sNS1 is a key mediator of dengue pathogenesis. For instance, highly purified recombinant NS1 (rNS1) devoid of bacterial endotoxin activity directly activates mouse macrophages and human peripheral blood mononuclear cells via Toll-like receptor 4 (TLR4), leading to the induction and release of pro-inflammatory cytokines and chemokines. In addition, in in vitro and in vivo models of vascular leakage, exposure to NS1 resulted in the disruption of endothelial cell monolayer integrity 29 , 30 . The key features of NS1 and of the other DENV NS proteins are detailed in Table 1 .

Locus of DENV infection in vivo

Overview of infection . During mosquito feeding, DENV is inoculated into the dermis and epidermis, and some virus is also injected directly into the bloodstream. In the skin, this delivery results in the infection of macrophages, dendritic cells and Langerhans cells. These infected cells can migrate from the initial site of infection to lymph nodes, which triggers the recruitment of monocytes and macrophages that then become subsequent targets of DENV infection. As a result, the number and variety of cells infected with DENV increases and the infection can become disseminated throughout the lymphatic system with the infection of cells of the mononuclear lineage, including blood-derived monocytes, myeloid dendritic cells and splenic and liver macrophages 31 , 32 .

Determination of infected cells in vivo. The identification of sites of DENV infection in vivo is problematic because many of the stains that are used to visualize dengue viral antigens do not discriminate between intracellular antigens that have been phagocytosed and those that are indicative of active viral invasion and replication. For this reason, to identify sites of DENV infection, it is crucial to use probes for DENV-specific RNA, negative-sense RNA or for NS proteins, which are produced at sites of viral replication or assembly. The few studies that have been published using these markers have detected DENV infection in monocytes that are present in the blood and macrophages from the liver, skin, spleen and thymus 33 , 34 . In addition, sites of infection can also be identified through the detection of viral particles. Peripheral blood monocytes from patients with dengue have been found to harbour DENVs 35 , and immature skin dendritic cells support the growth of DENVs 36 .

Although dengue viral particles or antigens have been shown to localize to neurons, microglia and endothelial cells in the human central nervous system (CNS) 37 , no evidence of DENV replication was found in the CNS when a sensitive viral RNA amplification method was applied to samples from patients who had died as a result of DENV infection 38 . Moreover, no DENV antigens were detected in CNS tissue from 13 children who had died from DHF/DSS 33 .

DENV can also infect the liver, resulting in apoptosis of hepatocytes 39 , and when apoptotic DENV-infected hepatocytes are engulfed by Kupffer cells, they form Councilman bodies — the classic histopathological finding in the livers of those with dengue and yellow fever. Results from studies that attempted to culture DENVs in explanted human tissue, primary human cells and human cell lines suggest that DENV1 is unable to replicate in mature Kupffer cells. By contrast, primary hepatocytes and hepatocyte cell lines were successfully infected but underwent apoptosis shortly after 40 , 41 . Although DENV infection imparts considerable damage to the liver, infection of this organ might not make a considerable contribution to the distribution or maintenance of acute infection 33 .

Host receptors of DENV entry . DENVs are capable of infecting many different cell types in vitro , including epithelial cells, endothelial cells, hepatocytes, muscle cells, dendritic cells, monocytes, bone marrow cells and mast cells. Despite the ability to infect these cells with DENVs in a laboratory setting, their roles in dengue pathogenesis and the cellular receptors involved in their infection remain unknown. Although candidate receptors — such as heparan sulfate, dendritic cell-specific ICAM3-grabbing non-integrin, macrophage mannose receptor 1, heat shock protein 70 (HSP70) and HSP90 — have been described for in vitro systems, their contribution to infection in humans is not established 42 .

Infection and response

Four main factors control DENV disease response along a response continuum: immune status, virus strain, genetic status and age ( Fig. 6 ).

figure 6

Four main factors control dengue virus (DENV) disease response along a response continuum: immune status, virus strain, genetic status and age. Individuals at risk of a secondary infection are at a higher risk of severe disease through the antibody-dependent enhancement phenomenon, with a higher production of virus. Genetic dengue susceptibility favours disease severity. For example, white individuals have been found to have a higher chance of developing severe disease than black individuals. Younger age is associated with disease severity in individuals experiencing a secondary infection. The association of each serotype and genotype to disease severity, epidemic potential and efficiency transmission could be influenced by the differences among them, but also by other conditions such as host immunity, the ability of the vector to become infected and to disseminate the virus to humans, among others. FcγR, Fcγ receptor.

Immune status . Infection with any DENV serotype results in long-term homotypic immunity (that is, immunity against the serotype causing the infection) with a short period of heterotypic immunity (that is, immunity against another serotype) 43 , 44 . Only a small fraction of circulating antibodies in monotypic-immune individuals (that is, those only immune to one viral serotype) neutralize homologous DENV. Polyclonal antibodies are directed against several epitopes; some are directed against quaternary epitopes located at the hinge region between DI and DII of the E protein on the surface of intact virions 45 , 46 . Immediately after an individual's first DENV infection, antibodies might neutralize heterotypic DENVs in in vitro assays. Over the next few months, antibodies become increasingly specific to the DENV serotype that is causing the infection 47 . These in vitro changes in neutralizing antibody specificity correlate with in vivo observations. Monotypic-immune humans demonstrate an initial short period of cross-protection against infection with heterotypic DENVs (approximately 2 months) and a longer period of protection against severe disease (approximately 2 years) caused by heterotypic DENV infections 47 . Recently, a class of strong broadly cross-neutralizing antibodies was recovered and characterized 48 , 49 . Whether these antibodies are preferentially selected during second heterotypic DENV infections and contribute to pan-DENV protection are unknown. Neutralizing antibodies circulate for a lifetime and are thought to explain the observed long-lasting protection against re-infection with homotypic DENVs 50 , 51 .

The majority of circulating antibodies are non-neutralizing and are directed against various antigens on the E protein and the prM protein. In the absence of blocking by type-specific neutralizing antibodies, non-neutralizing antibodies usually enhance the entry of any DENV into Fc receptor-bearing cells. This phenomenon is called antibody-dependent enhancement (ADE) 52 , 53 and makes DENVs unique among human viral infections, in that pre-infection partial immunity to one or more DENV (so-called sensitization) upgrades disease severity. As such, severe dengue and DHF/DSS occur most often in individuals with monotypic immunity during a second heterotypic DENV infection. Severe cases also occur (infrequently) in primary infections. By contrast, third and fourth DENV infections are typically mild or asymptomatic 54 , 55 .

In dengue-endemic countries, DHF/DSS also occurs during primary infections in infants born to mothers who are immune to DENV. These mothers circulate antibodies from two or more lifetime DENV infections that occurred before pregnancy 56 – 58 . As discussed above, these individuals develop broad neutralizing antibodies and are usually protected against severe disease with heterotypic DENV strains 55 , 59 . Epidemiological data from many countries indicate that these multitypic antibodies protect infants from dengue illness for several months after birth 60 , 61 . Then, the concentration of these neutralizing maternal antibodies eventually falls below a protective threshold, with most antibodies having a half-life of approximately 40 days. For a short period, if the infant is infected with DENV, severe disease mediated by ADE may occur owing to the presence of maternal non-neutralizing antibodies.

In addition to serotype-specific immunity, the interval between an individual's first DENV infection and subsequent infections might be an important determinant of disease severity. For example, in a comparison of groups of identical age, DHF occurred at an eightfold higher rate in those whose secondary DENV2 infections were separated by 20 years than those whose secondary infection was 4 years after their first. A possible reason why severe disease rates increase with longer intervals between infections might be related to the steady decline in heterotypic neutralization of DENV2 by DENV1 antibodies 62 . A second phenomenon sometimes observed in dengue is that infection sequences that were previously benign can suddenly become pathogenic. For example, in Tahiti in 2001, DHF occurred in children 4–13 years of age who contracted DENV1 infections, even though they had previously been infected with DENV2 4–5 years earlier 63 . By contrast, during the 1980 Rayong (Thailand) epidemic, no severe disease accompanied secondary DENV1 infections, even though they comprised 37.5% of all secondary DENV infections 64 , indicating that, although infection sequence is important, a secondary infection with DENV1 does not necessarily cause severe disease.

The relative contribution of antibodies versus T cells to protection against dengue is not well understood, although there is growing evidence that both components are required to prevent infection, overt disease and severe disease 65 – 67 . For example, recent studies on naturally infected humans and infection of humanized mice indicate that T cells contribute to protection against severe disease associated with heterotypic secondary DENV infections 68 . Effective CD8 + T cell immunity is largely mediated by epitopes on NS proteins, their respective contribution varying between different DENV serotypes 69 .

Viral serotypes . Although all four DENV serotypes are transmitted by Aedes mosquitoes and, in principle, cause the same clinical manifestations and show similar patterns of systemic dissemination, there are some biological differences between them 60 , 70 . Indeed, associations between particular serotypes or genotypes and disease severity, epidemic potential and the efficiency of transmission have been described, but these associations could be influenced by factors other than intrinsic viral characteristics, such as host immunity, the ability of the mosquito vector to become infected and to transmit the virus to humans, and the conditions (which are not well known) that support the displacement of one genotype by another 71 – 73 .

The hypothesis that some DENVs have greater ‘virulence’ and epidemic potential than others was introduced in the 1970s 61 , 74 . The DENV polyprotein demonstrates 30% divergence between the four serotypes, and several genotypes within each serotype show different geographical distributions 71 . Some data indicate that genetic changes in DENVs might directly affect transmission potential in mosquitoes or disease expression in infected humans. For example, some studies have shown that DENV2 of Asian origin replicates to higher titres in human dendritic cells, infects Ae. aegypti mosquitoes more efficiently and is transmitted at a higher rate than American DENV2 strains 75 , 76 . In addition, some strains of DENV3 replicate at a higher rate in mosquitoes than other DENV3 strains, leading to the capacity to displace established DENV3 strains 68 , 77 . Similarly, when DENV4 was introduced to Puerto Rico, it caused three major epidemics in 1982, 1986 and 1998; the latter two epidemics were each associated with a clade (that is, a monophyletic group of the same genotype) change in the circulating virus 78 , 79 . Similar clade changes associated with endemic and epidemic transmission have been observed with DENV2 in the South Pacific 74 , 80 and DENV3 in Sri Lanka 81 , 82 . To date, most of the genetic changes associated with epidemic potential have resulted in amino acid changes in NS proteins.

Several pathogenesis studies have been performed on patients with dengue who were clinically classified as having either dengue fever or DHF/DSS 3 . Although both dengue fever and DHF/DSS can be associated with any serotype, some sequences of infection have been associated with severe disease at a higher frequency than others 83 . In addition, some serotypes may be associated with DHF/DSS during a secondary infection but result predominantly in mild or asymptomatic infections during primary infections. Furthermore, there is no evidence that severe dengue regularly accompanies primary infections of susceptible individuals. In this context, DENVs are not inherently ‘virulent’ but are instead conditionally virulent. That condition is usually the presence of pre-infection circulating DENV antibodies, as discussed above 73 . For example, in the very ‘clean’ epidemiological setting of the Santiago de Cuba DENV2 epidemic of 1997, susceptible individuals of all ages who were infected by the DENV2 Asian genotype primarily developed subclinical disease. By contrast, individuals who contracted a secondary infection with DENV2 after first having a DENV1 infection almost always experienced overt disease (the overt to subclinical disease ratio was nearly 1). Similar observations have been reported for primary DENV4 infections 84 .

Of interest is the possibility that, during the course of epidemics, there is a rapid selection of DENV neutralization escape mutants or of mutations that affect the ability of certain DENVs to cause infections that involve different degrees of ADE 85 . In support of this possibility, in three Cuban epidemics, month-to-month increases were observed in the proportion of severe secondary DENV cases compared with mild cases as well as in case fatality rates. For example, in the 1997 DENV2 outbreak in Santiago de Cuba, there was an emergence of severe disease that was accompanied by a stable amino acid switch in NS1 (Ref. 86 ). Somewhat similar increases in severity of secondary DENV2 infections have been described in Taiwan and Nicaragua; these were associated with several mutations, including changes in the structure of the DENV 3′ untranslated region (UTR) 87 , 88 . Although the precise mechanisms of the rapid acquisition of increased fitness of DENVs are unknown, suspicions increasingly point to improved viral survival during interactions with the human innate immune system 89 .

Host genetics . As with most infectious diseases, host factors, many of which are measured by proxy genetic markers, can control the outcome of infection through mechanisms that are not yet fully understood. Some host factors that affect the outcome of DENV infection have been well documented. For example, an unidentified gene that is present in black individuals moderates the clinical severity of secondary DENV infections, and studies have shown that the rates of DHF/DSS were lower in infected black patients than in white patients with the same secondary DENV2 infection experience 90 , 91 . Table 2 includes some human leukocyte antigen (HLA) and non-HLA genes that are linked with increased susceptibility or resistance to dengue 92 – 102 .

Patient age and sex . Age affects dengue disease expression in a contradictory manner. The disease severity that accompanies a first DENV infection is directly related to age. In susceptible young children, first DENV infections are usually occult or mild, whereas adults experiencing a first DENV infection often develop dengue fever. More complicated outcomes are observed in the elderly or in those with chronic diseases, such as diabetes mellitus, chronic obstructive pulmonary disease or cardiovascular disease 2 . Bleeding phenomena are common in both the elderly and those with comorbidities. Menorrhagia has been observed in adult women during primary DENV infections and gastrointestinal bleeding has been observed in individuals with peptic ulcer disease. The risk of progressing to DHF/DSS in sensitized individuals varies inversely with age. When an entire population (people ≥3 years of age) was exposed to identical rates of secondary DENV2 infection, DHF rates were more than fivefold higher in children than in adults 103 . This observation can probably be explained by intrinsic host susceptibility to vascular permeability that accompanies a secondary DENV infection 104 , 105 . Indeed, healthy children have been reported to have a higher capillary fragility than adults. The greater density and surface area of growing microvessels in childhood could be the reason for why children have this higher microvascular permeability 106 , 107 . The outcome of secondary DENV infections is also controlled by sex, with girls >4 years of age having higher rates of DSS than boys of any age 59 , 86 .

Pathophysiology

Acute DENV infections are expressed along a continuum from inapparent to undifferentiated fever, to an acute febrile viral exanthema and finally to a complex of physiological abnormalities that affects multiple systems, including the liver, blood coagulation, complement, haematopoiesis and the vascular systems.

Vascular permeability . Dengue vascular permeability syndrome, which was historically known as DHF/DSS, includes the abnormalities that affect the vascular system. Several studies have shown that there is a range of capillary permeability and plasma leakage affecting most individuals with overt dengue illnesses, rather than distinct pathological mechanisms underlying DHF/DSS. For example, endothelial cell damage by infection or extensive cell death does not seem to be responsible for the increase in vascular permeability associated with dengue 33 , 108 . Indeed, patients who are recovering from DHF regain normal endothelial function relatively quickly, implying that whatever causes vascular permeability is more reversible than endothelial damage, and might include one or more soluble mediator 109 . In addition, increased microvascular permeability has been reported in patients with DHF/DSS at or around the time they experience defervescence (a decrease in increased temperature) 109 , 110 , indicating that vascular permeability is not directly correlated with peak viraemia that usually occurs on the first day after the onset of fever. A mild increase in microvascular permeability has been observed in infected volunteers experiencing dengue fever, indicating that dengue disease severity occurs across a continuum 111 , 112 .

Recent studies on myeloid cells, both in vitro and in mice, indicate that NS1 induces vascular leakage and activation of TLR4, resulting in the production of inflammatory cytokines 29 , 30 . These studies suggest that circulating DENV NS1 triggers endothelial barrier dysfunction, which causes increased permeability of human endothelial cells in vitro . These findings open a new window of opportunity for dengue drug and vaccine development 29 , 30 .

Thrombocytopaenia . Thrombocytopaenia results from transient bone marrow suppression and increased peripheral destruction of platelets during the febrile and early convalescent phases of the disease, and results in platelet counts as low as 5,000 per ml (compared with approximately 200,000 platelets per ml in healthy individuals) 113 , 114 . Whereas thrombocytopaenia occurs commonly across a wide range of infectious diseases, severe thrombocytopaenia accompanies clinically significant vascular permeability during acute DENV infections. Remarkably, in the bone marrow, early suppression of the production of all blood cell types occurs during the early febrile phase of DENV infection 115 , 116 . A possible explanation for this suppression comes from studies on lymphocytic choriomeningitis virus infection. Here, in infected laboratory animals, bone marrow suppression was mediated by interferon-α (IFNα) production 117 . Towards the end of the febrile period of a DENV infection, the bone marrow cells recover to normal density and diversity, leaving only a residual megakaryocyte arrest that can be observed in autopsy studies 118 .

Coagulopathy . The impaired haemostasis that accompanies DHF/DSS involves a series of alterations in the coagulation system that disrupts the regulation of clot formation. For example, an increase in activated partial thromboplastin time (APTT; which measures time to clot formation) and a reduction in the level of fibrinogen (a factor that promotes clot formation) are fairly consistent findings in DHF/DSS 119 – 121 . The evidence that haemorrhage in dengue is caused by classic disseminated intravascular coagulation is under debate 120 . The concentration of procoagulant markers is increased in some DHF/DSS cases, but this increase is usually mild and is accompanied by a considerable reduction in the concentration of anticoagulant proteins.

Factors that might contribute to these alterations include secreted viral effectors. Recent reports have shown that NS1 binds to thrombin in vivo to form NS1–thrombin complexes. In addition, in vitro , rNS1 inhibits prothrombin activation and prolongs APTT in human platelet-deficient plasma 122 . Release of heparan sulfate or chondroitin sulfate (molecules similar in structure to heparin that mimic its function as an anticoagulant), which are possibly sheared off by NS1 from the glycocalyx, can also contribute to altered haemostasis 112 .

In most patients, coagulopathy is relatively minor and resolves within a few days. In some children with severe shock, these minor derangements are compounded by the effects of prolonged hypotension and tissue hypoxia. Major bleeding occurs by erythrocyte extravasation in the gastrointestinal tract.

Complement activation . The complement system becomes activated to control DENV infection, and this activation contributes to pathogenesis through interaction with the coagulation system. In classic studies on complement in children with DHF/DSS, temporal and peak production of complement split products correlated with blood fibrinogen levels and thrombocytopaenia 123 . Complement activation has been described in detail in a 6-month-old infant with DSS during a primary DENV infection 124 . Most studies on complement activation in dengue have centred on patients with secondary DENV infections and have led to the conclusion that complement activation was mediated via the classical pathway by circulating immune complexes. By contrast, studies on complement activation in infants experiencing a primary DENV infection have implicated the alternative pathway in activating complement during infection. Indeed, in children experiencing a secondary DENV infection, NS1 might be responsible for activating complement by the alternative pathway 122 .

Liver enlargement . Liver enlargement and dysfunction are common during DENV infection, with liver enlargement having a significantly stronger association with DHF/DSS than with dengue fever (55% compared with 18%; P < 0.01) 125 . For instance, one study in Thailand showed that hepatomegaly was observed in a high percentage of all children admitted with serologically confirmed severe dengue 126 – 128 . Liver enlargement seems to occur for two reasons: generalized oedema due to vascular permeability and an inflammatory response that occurs after infection of hepatocytes by DENVs. However, almost no cellular inflammatory response was observed in livers from patients who died as a result of DENV infection, reinforcing the observation that liver damage might be caused by apoptosis, as discussed above.

Despite the prevalence of liver enlargement, jaundice in dengue illness, even in DSS, is rare 125 , 129 . By contrast, changes in liver enzyme levels, which are markers of liver dysfunction, are common. Aspartate aminotransferase and alanine aminotransferase blood levels are increased in 60–90% of children with DHF. The increase in the levels of the transaminases was shown to be mild to moderate in one study, but a small group of patients (7–10%) had transaminase levels that were tenfold higher than the upper limit of normal. In this study, co-infection with hepatitis B virus or hepatitis C virus was not related to liver enzyme changes, and liver enzyme levels were significantly higher in patients with prolonged shock 130 . Finally, this study also demonstrated that the levels of serum bilirubin, alkaline phosphatase and gamma-glutamyl transpeptidase were raised in 7%, 16% and 83% of patients, respectively.

Models of vascular permeability in dengue . Many researchers attribute vascular permeability to a lethal ‘cytokine storm’ caused by overactive T cells, heterologous T cell responses or defective T cell responses (original antigenic sin) 131 – 133 . Other hypotheses to explain this phenomenon posit that circulating immune complexes activate complement or that immune responses to DENV proteins cross-react with host systems to generate short-lived immune or autoimmune DHF/DSS 134 – 136 . However, none of these explanations can account for why infants who have never previously experienced DENV infection develop severe dengue disease. Alternatively, capillary leakage might be caused by factors produced in target cells that are directly related to DENV infection 137 – 142 . However, this hypothesis does not fit with the observation that, although target cells are infected throughout the course of infection, the onset of vascular permeability is delayed to the time of defervescence.

The onset of thrombocytopaenia, altered haemostasis, complement activation, liver damage and detectable vascular permeability before defervescence suggest that DHF/DSS might result from a factor or factors that circulate throughout the acute illness, which exceeds a threshold at defervescence. DENV virions and NS1 circulate throughout the acute phase. As discussed above, NS1 interacts with the complement system, can extend APTT and several lines of evidence support the notion that NS1 contributes to vascular permeability. Indeed, APTT values are the strongest correlate of vascular permeability in patients with dengue illness 143 . Moreover, it has been known for several decades that antibodies against DENV NS1 protect against lethal dengue disease in animal models 144 . Perhaps then, terminal T cell-mediated cytolysis of DENV-infected cells releases a bolus of cell-bound NS1 to surpass a threshold resulting in vascular permeability 145 . Finally, the mechanisms that underlie peak vascular permeability during defervescence in dengue remain unclear, but intensified research efforts might uncover these in the future.

Diagnosis, screening and prevention

Signs and symptoms.

Dengue is a dynamic illness, despite its short duration (no more than 1 week in nearly 90% of cases). Its clinical expression can change as the days go by and can also worsen suddenly. Dengue illness can evolve into three phases: the acute febrile phase — observed in most of the patients — and the critical and the recovery (convalescent) phases 2 ( Box 1 ).

Fever occurs during the acute febrile stage and is generally the first clinical manifestation of illness with a variable intensity. It is associated with headache and vomiting, as well as body pains. In children, fever is frequently the only clinical manifestation or is associated with rash and/or unspecific digestive symptoms. The pharynx can become reddened, but other signs and symptoms of the respiratory system are not frequent or clinically significant. Slight abdominal pain and diarrhoea can occur; diarrhoea more frequently occurs in patients who are <2 years of age and in adults. In general, compared with children, adolescents and adults show a ‘flu-like syndrome’ (including malaise, headache and body pains) with more prominent digestive symptoms than respiratory symptoms, if any. During the febrile stage, leukocyte counts are usually decreased. Petechiae (small spots on the skin caused by broken capillaries) or ecchymosis (large subcutaneous bleeding spots) can be present, with or without thrombocytopaenia. After 2–5 days, these symptoms can be followed by rapid clinical deterioration. Most patients with dengue recover after defervescence; however, the clinical state of some patients worsens when the fever drops. Thus, the period during which the fever subsides indicates the beginning of the critical phase.

The critical phase coincides with the leakage of plasma that can lead to shock, which is characterized by coldness in the teguments, weak pulse, delayed capillary filling, tachycardia, oliguria and hypotension. Shock is caused by low blood volume (hypovolaemia). At the beginning, not all clinical signs of shock are observed, and, in this setting, shock can be detected by a narrowing of the differential arterial tension or pulse pressure (a difference of ≤20 mmHg between the maximum or systolic arterial tension and the minimum or diastolic arterial tension). At this stage, patients usually have a flushed face, a warm trunk, cold and clammy extremities, diaphoresis (sweating), slow venous filling, restlessness, irritability, pain in the upper and middle abdomen and decreased urinary output. In addition, patients might also exhibit signs of impaired haemostasis, including scattered petechiae on the forehead and extremities, spontaneous ecchymoses, easy bruising and bleeding at venipuncture sites, and circumoral and peripheral cyanosis (blue skin discolouration). Gastrointestinal bleeding occurs in <10% of patients and usually follows a period of uncorrected hypotensive shock. Patients with shock also experience rapid and potentially laboured breathing, a weak pulse and have a rapid heartbeat that sounds ‘thready’. Finally, their livers are usually firm, tender and can become enlarged to 4–6 cm below the costal margin, the haematocrit level is increased and the platelets — which were decreasing progressively — reach their lowest count. In those who recover, this critical phase lasts for 24–36 hours and is followed by a rapid convalescence.

Convalescence can involve complications, such as encephalopathy, bradycardia, ventricular extarsystoles and, rarely, myocarditis and encephalitis.

According to the 2009 WHO clinical classification, a patient can have dengue with or without warning signs or severe dengue ( Fig. 1 ), highlighting that severity is considered as the second step of the same disease. In other words, dengue can be considered to be a single disease entity that is both systemic and dynamic.

Diagnostic approaches

Detection of viraemia . DENV viraemia is detectable 24–48 hours before fever onset and continues for 5–6 days ( Fig. 7 ). During this period, infective virus, its specific RNA and the NS1 protein can be detected in patient blood, serum and plasma, and also in tissues from fatal cases 146 . Virological, molecular and serological methods are used to confirm DENV infection for epidemiological surveillance and clinical diagnosis.

figure 7

Viraemia, non-structural 1 (NS1) antigen and antibodies change over time; thus, different diagnostic tests will be appropriate depending on the stage of infection. ELISA, enzyme-linked immunosorbent assay; RT, reverse transcription. Adapted from Ref. 153 , Nature Publishing Group.

Anti-DENV IgM antibody detection is the most widely used test in routine practice 147 . Anti-DENV IgM titres in sera from patients in the acute phase of disease are measured to serologically confirm infection, whereas patients in convalescence are identified through IgM and IgG seroconversion by comparing antibody titres in paired acute and convalescent sera 146 , 148 . For patients who are suspected of having dengue, a presumptive diagnosis can be made by the detection of anti-IgM antibodies in samples collected at day 6 of acute symptoms. Commercial kits for IgM or IgG detection in enzyme-linked immunosorbent assay (ELISA) and less-sensitive rapid test formats are available 149 , 150 .

Reverse transcription PCR (RT-PCR), real-time RT-PCR, DENV isolation in mosquito cell lines and by mosquito inoculation facilitate confirmation and identification of the agent virologically. Although virus isolation and identification is highly specific, it has a relatively low sensitivity and is resource-consuming and time-consuming. By contrast, DENV RNA detection provides a rapid, sensitive and specific method for virological diagnostic confirmation. NS1 protein detection provides a window of opportunity for early aetiological diagnosis. The sensitivity and specificity of DENV NS1 detection depend on the infecting serotype, the timing of sample collection and the parity of DENV infection (primary versus secondary), as well as the format of the test 151 , 152 .

Box 2 shows the interpretation of dengue tests and Table 3 summarizes the WHO recommended diagnostic tests according to laboratory surveillance level 2 , 153 . Whereas all of these methods can be used to establish aetiological diagnosis, bedside rapid tests for antigen, antibody or simultaneous antigen and antibody detection are preferable if they are of satisfactory sensitivity and specificity.

The recent introduction and extension of two new arboviruses in dengue-endemic countries of the American region — chikungunya (an alphavirus detected at the end of 2013 in the Caribbean island of St Martin) and Zika (a flavivirus detected in May 2015 in Brazil) — impose new challenges for the diagnosis of dengue and the arbovirus in general. The diagnosis of any of these viruses is based on RNA and/or IgM detection. However, the duration of viraemia is different between these infections, antibody cross-reaction is observed between DENV and Zika virus (which belong to the same viral family: Flaviviridae ) and commercial, adequately evaluated kits for serology are needed for chikungunya virus and Zika virus infections. To face this emergency, the network of Arbovirus National Laboratories of the American region (RELDA; formerly the Dengue Laboratory Network of the Americas) conducted by the Pan American Health Organization (PAHO), recommended a new diagnostic algorithm for DENV, Zika and chikungunya viruses. In the first step, DENV, chikungunya and Zika viral RNA is detected by real-time PCR in acute samples. If available, IgM serology on serum samples collected from individuals with clinically suspected DENV infection or Zika virus infection should be tested by IgM Capture ELISA to both DENV and Zika virus. If positive to both viruses, a secondary flavivirus infection should be considered 154 .

Considering this new epidemiological situation, it is expected that dengue and flavivirus diagnostic guidelines will change with new algorithms according to the epidemiological situation and more-sensitive and specific as well as better evaluated commercial kits for serology.

Identification of patients at risk of severe disease . As DENV infections can result in severe and life-threatening illness, identifying which patients are at risk of an outcome that requires supportive interventions is important. Differentiating this group from the thousands of mild cases during outbreaks is a major medical challenge; simple and inexpensive strategies are urgently needed. The 2009 WHO classification system for the identification of patients at risk of severe disease is summarized in Fig. 1 (Ref. 155 ).

Biomarkers for dengue prognosis that are under evaluation include a high level of viraemia and NS1 protein, the level of microparticles that are produced as a consequence of apoptotic cell death and cellular activation, the level of some immune-response mediators, such as IL-1 receptor-like 1 (IL1RL1; also known as ST2), tumour necrosis factor (TNF), TNF-related apoptosis-inducing ligand (TRAIL), and some biochemical alterations, but to date none have been approved for routine practice 156 , 157 . However, as part as the routine laboratory follow-up of a suspected dengue case, a full blood count should be done at the first patient visit. A decreasing white blood cell count makes a diagnosis of dengue very likely, whereas plasma leakage is suggested by a rapid decrease in platelet count, mainly if it is associated with a rising haematocrit level. Fluid accumulation, which can be detected by X-ray or ultrasonography, is a conclusive warning sign of plasma leakage. In addition, laboratory findings during the critical stage of illness that vary according to the severity of vascular permeability include prolonged bleeding time, increased APTT, thrombocytopaenia, increased levels of liver enzymes, activated complement with high levels of C3a and C5a, fibrin split products and low levels of fibrinogen. Chest X-ray is the best method for detecting pleural effusions, and abdominal sonograms can detect gallbladder wall thickening and ascites 2 , 158 . Patients should also be closely monitored for signs of shock.

Daily monitoring of the clinical warning signs to detect early progression from mild to severe illness remains the most useful method to prevent fatal disease 2 , and serial ultrasonographic studies could be better than existing markers, such as the haematocrit level, to identify patients who are at risk of developing severe dengue who merit intensive monitoring 159 . Clinical algorithms have also been proposed for both dengue case identification and dengue prognosis, but none are in routine use 160 – 162 .

Classification systems . There are somewhat competing views in the field as to the optimal approach for the clinical classification of patients with dengue and the identification of warning signs of severe disease, and several reviews and position papers regarding the usefulness of the 2009 WHO system compared with the 1997 WHO system have been published 163 , 164 . Prospective clinical studies developed in Asian and Latin-American countries have concluded that the 2009 WHO dengue classification system may be better at detecting severe DENV infection cases compared to the previous WHO classification system 165 – 167 . Others have argued that the revised 2009 WHO classification has a high sensitivity for identifying severe dengue and is easy to apply 168 ; some consider the 2009 system to be promising from both research and clinical perspectives 169 . Indeed, the 2009 classification system has greater discriminatory power for detecting patients who are at risk of progression to severe disease and those who need hospitalization than the 1997 classification 170 . Furthermore, the 2009 system is simple to use for triage and case management according to disease severity, even in primary care settings 171 , and for disease surveillance. It also reflects the natural course of dengue illness from mild to severe disease and covers all clinical manifestations 172 . A formal expert consensus was reached in La Habana, Cuba, in 2013 with dengue experts from the Americas 173 , where a decrease in disease lethality after the introduction of the revised classification was evident 174 .

That said, through the analysis of retrospective data, some investigators have found that warning signs are not as useful in adults as they are in children 175 , and have argued that the current recommended predictors of severe dengue are, therefore, limited 176 . Others have put forward that there is a need for a more precise definition of warning signs to enable optimal triaging for accurate identification of patients who require hospitalization 177 . In addition to these critiques, one study described that both the 1997 and the 2009 WHO classification systems show high sensitivity but lack specificity 178 , and that the 2009 system requires refined definitions of severe bleeding and organ impairment to improve its clinical relevance 179 . A major ongoing clinical study, coordinated by one of the three large European Union-funded consortia that are currently working on dengue research themes, might address some of these issues 180 . Finally, since the introduction of the revised criteria, a high number of patients have been admitted to hospital or placed under clinical observation during dengue epidemics. This increase is probably owing more to traditional hospital-based methods of managing patients with dengue than to the 2009 WHO classification system, a conclusion that is supported by the fact that this increase in clinical intervention can be alleviated through the participation of trained primary care health units, which the WHO is trying to facilitate 181 .

Although the 2009 WHO classification is more applicable to clinical and epidemiological purposes than the 1997 classification, debate continues regarding its usefulness for pathogenesis research 182 . In particular, some have argued that the dengue fever, DHF and DSS classifications were more capable of correctly identifying cases of plasma leakage than the 2009 system, and that this identification served as a useful predictor of disease severity that was directly related to the main underlying model of pathogenesis. However, in a separate study, the same authors concluded that the 1997 system misclassified a substantial proportion of patients 183 . Specifically, only 68% of patients who were in need of clinical intervention were classified as having DHF and, therefore, in using this system, it could be inferred that 32% of severe cases would be missed. One of these studies has been analysed by a group of experts 184 , who concluded that the revised classification reflects clinical severity in real time, which is something that clinicians have wanted for some time, and with its simplified structure will facilitate effective triage and patient management and also allow collection of improved comparative surveillance data.

Box 2: Interpretation of dengue diagnostic tests

Dengue virus infection is confirmed if any of the following test results are produced:

RT-PCR or real-time RT-PCR are positive

Positive virus culture

Positive NS1 test

IgM seroconversion *

IgG seroconversion

A presumptive dengue diagnosis is made if either of the following test results are produced:

Positive IgM in a single serum sample *

High titre of IgG in a single serum sample tested by haemagluttination inhibition assay or ELISA (≥1,280) *

ELISA, enzyme-linked immunosorbent assay; NS1, non-structural 1 protein; RT, reverse transcription. * The recent introduction and expansion of Zika virus infection into dengue-endemic countries impose a further diagnostic challenge. IgM antibodies in patients with secondary dengue virus infection can cross-react with Zika virus. For this reason, the Pan American Health Organization recommends IgM detection to both dengue virus and Zika virus antigens. Samples that are IgM positive against dengue virus or Zika virus antigens individually are considered a primary infection of dengue virus or Zika virus, respectively, whereas samples that are positive against both viruses are considered a presumptive flavivirus infection. Similarly, specific IgG cross-reaction can be observed with Zika virus antigens. For a more specific serological diagnosis, neutralization assays to both viruses are recommended 154 .

Vaccine-based prevention

The mechanisms of protective dengue immunity are not well understood. Neutralizing antibodies against viruses serve as the most commonly used correlate of protection. As discussed above, antibodies produced during an infection provide lifelong protection to the homologous virus but short-lived protection against the other three serotypes 185 . Most neutralizing antibodies recognize the E protein, and high DENV neutralizing antibody titres in mice and monkeys have been correlated with protection 186 . However, there is no proof that protection is always associated with neutralizing antibodies, as evidenced by the absence of protection against DENV2 in some vaccinated individuals who have appreciable levels of circulating neutralizing antibody 187 , 188 . Different antibody responses, such as antibody-dependent cell-mediated cytotoxicity and complement fixation, might also correlate with antibody-mediated protection against DENVs 189 , 190 . Moreover, T cell-mediated functions might correlate with protection in vivo . In general, CD4 + T cells can control viral infection through various mechanisms, including the production of antiviral and inflammatory cytokines, cytotoxic killing of infected cells, the enhancement of CD8 + T cell and B cell responses and the promotion of immune memory responses. Similarly, CD8 + T cells also act through the production of pro-inflammatory cytokines, such as TNF and IFNγ, and can be directly cytotoxic to viral infected cells 191 , 192 .

The development of safe and fully protective dengue vaccines faces several challenges: ideally, the vaccine should protect against the four serotypes; long-term protection is required otherwise an individual might become susceptible to breakthrough infection and enhanced disease owing to waning and non-protective immunity (that is, a dengue vaccine could lead to DHF/DSS through ADE if immunity is not sustained or is partial); there is no animal model that exactly replicates human dengue disease; although DENV neutralizing antibodies protect in some circumstances, the full correlates of protection are not known; and vaccine candidates need to be evaluated in the context of changing patterns of transmission intensity and circulating viruses.

Several DENV vaccines are currently under development, including some in phase III safety and efficacy testing. One that has completed phase III efficacy testing is under registration in several countries ( Table 4 ). These vaccines are outlined below.

Live attenuated vaccines . Live attenuated vaccines have numerous advantages, including the ability to induce an immune response that mimics the response to natural infection, the induction of robust B cell and T cell responses and the ability to confer lifelong immune memory. Live attenuated vaccines can be produced at relatively low cost and might be effective after one dose 186 . Early dengue vaccine efforts focused on passaging wild-type DENV strains through various types of primary cells or cell lines, including primary dog kidney (PDK) and African green monkey kidney (GMK) cells. Passaging of DENV in vitro renders it less virulent in humans and was investigated in two series of work.

In the first series, vaccine strains from each serotype obtained by passage through PDK cells or primary GMK cells were selected and tested in monovalent, bivalent, trivalent and tetravalent vaccinations in Thai adults 193 . Of the tetravalent recipients, only one of ten seroconverted to all four serotypes, and neutralizing antibody responses were directed primarily against DENV3. Subsequently, several tetravalent vaccine formulations were tested and the dominant neutralizing antibody response was still against DENV3 (Refs 194 , 195 ). Following on from these studies, the DENV3 vaccine strain was re-derived genetically, grown in Vero cells and tested in volunteers 196 . All recipients had adverse reactions and the trial was halted 186 .

In the second series, different formulations of the tetravalent vaccine were tested in monkeys and flavivirus-naive adults and children 197 , 198 . The formulations were improved to reduce the reactogenicity and increase the immunogenicity 199 , 200 . These new formulations were safe and moderately effective, and the authors recommend that studies in a larger number of adults and then in children are warranted 186 .

Another attenuation strategy is the targeted mutagenesis of 3′ UTR regions of DENV RNA 201 . The viral 3′ UTR is approximately 450 nucleotides long and comprises four defined domains: domain A; domains A2 and A3, which seem to work as enhancers for viral RNA replication; and domain A4 and the 3′ stem loop, which are essential elements for viral replication 202 . The deletion was created by the removal of nucleotides 172–143 from the 3′ UTR. This deletion, designated Δ30, has been shown to attenuate DENV1 and DENV4 in rhesus monkeys and to inhibit dissemination of DENVs in mosquitoes 203 , 204 . Monovalent and tetravalent preparations have been given to human volunteers and produced good immune responses 205 . A phase I trial investigated a single dose of four different formulations of a live tetravalent vaccine in flavivirus-naive volunteers. The vaccines were well tolerated, produced no severe adverse events and only one dose induced a good neutralizing antibody response in 75–90% of the individuals 206 . One of these tetravalent DENV vaccines was licensed to several vaccine developers 207 and entered large-scale phase III efficacy trials in Brazil following a small human challenge trial conducted in the United States. A single dose of the dengue vaccine TV003 fully protected 21 vaccinated volunteers against infection in a virus challenge study, whereas 20 unvaccinated controls all developed an infection 208 .

In addition, a candidate tetravalent dengue vaccine (called CYD-TDV) has been developed, via the insertion of the prM and E genes of the four DENV serotypes into the genetic backbone of the 17D yellow fever vaccine virus 209 . Two ChimeriVax phase III trials were conducted in >30,000 children in five Asian and five American countries. Overall efficacy in the Asian trial was 56.5% and 60.8% in the American trial 187 , 188 . In addition, a reduction in severe complications was reported with a vaccine efficacy of >80% against DHF. These vaccines seem to boost immune responses and protect individuals who have had one previous DENV infection and are, therefore, at risk of ADE. However, these vaccines failed to protect seronegative individuals against clinical infection with all four DENV serotypes, and a group of young vaccinated children had higher rates of hospitalized breakthrough DENV infections than controls 210 . Children who were ≤5 years of age when vaccinated experienced a DENV disease resulting in hospitalization at five times the rate of controls. The aetiology of disease in placebo and vaccinated children that results in hospitalization during a DENV infection, while clinically similar, are of different origin. The implications of the observed mixture of DENV protection and enhanced disease in CYD vaccinees is under study 211 . CYD-TDV seems to protect people who have been infected once and, accordingly, are at risk of severe disease. But, conversely, it puts people who were susceptible to a first infection at risk of severe disease. Even so, the vaccine is approved in Mexico, the Philippines and Brazil.

Another vaccine construct has been developed by substituting the prM and E genes of DENV2 PDK-53 with those of wild-type DENV1, DENV3 or DENV4 (Ref. 212 ). Three different formulations of these tetravalent vaccine (DENVax) were tested in monkeys, and all vaccinated monkeys developed neutralizing antibodies against all four serotypes after one or two doses 213 . On the basis of these results, phase I and phase II trials were carried out to evaluate different vaccination regimens, formulations and alternative routes of immunization 214 . The vaccine was well tolerated in children and adults 1.5–45 years of age, irrespective of prior dengue exposure; mild injection-site symptoms were the most common adverse events. DENVax induced a neutralizing antibody response and seroconversion to the four DENVs, as well as cross-reactive T cell-mediated responses that could be necessary for a broad protection against dengue illness 215 . Currently, phase III trials of the vaccine have been initiated in several Asian countries.

Following on from live attenuated vaccines, another generation of vaccine candidates, including subunit vaccines, inactivated vaccines, DNA vaccines and viral vector vaccines, is being launched.

Subunit vaccines . The advantages of protein vaccines compared with live attenuated vaccines are that they are safe, the induction of a balanced immune response to the four DENV serotypes should be feasible and the immunization schedule can be accelerated, reducing the risk of incomplete immunity and the potential for ADE. However, these vaccines require the use of adjuvants and multiple doses to achieve optimal immunogenicity, and they may not be as efficient as live attenuated vaccines at inducing long-lasting immunity 186 .

The protein target of subunit vaccine development for dengue has been the E glycoprotein, as the majority of neutralizing epitopes on the DENV virion are located in this protein. Recombinant E protein has been produced using Escherichia coli , baculovirus and insect cells, yeast and mammalian cells 216 – 219 . Truncated recombinant E protein subunits (80E) of each serotype were obtained in a Drosophila melanogaster Schneider 2 cell expression system and were found to induce neutralizing antibody responses in mice and in non-human primates 220 . A phase I trial of the DENV1-80E vaccine candidate has been completed 221 and a phase I trial of a tetravalent formulation began in 2012 (Ref. 222 ). The subunit vaccine might be an important component in a prime–boost vaccine regimen.

Domain III-capsid (DIII-C) is a novel candidate vaccine containing viral fragments that might potentially induce neutralizing antibodies and cell-mediated immunity. DIII-C has been evaluated in Balb/c mice and Vervet monkeys 223 , 224 . In animal models, DIII-C has been shown to induce a serotype-specific immune response in terms of both antiviral antibodies and cellular immune response with partial protective efficacy 225 . This candidate is at an advanced stage of preclinical development.

Inactivated vaccines . Vaccination with inactivated vaccines ideally should induce a balanced immune response without the viral interference (wherein the replication of one virus can inhibit the generation of a balanced immune response against all four serotypes as it can interfere with the replication of the other serotypes) that can occur with live attenuated vaccines. In addition, there is no risk of viral replication or reversion to wild-type virus. Inactivated vaccines are less effective in inducing long-lasting immunity than live attenuated vaccines, so multiple doses and adjuvants are needed for optimal immunogenicity in unprimed individuals. A dengue inactivated vaccine might be useful as part of a heterologous prime–boost vaccine regimen 186 .

A dengue purified formalin-inactivated vaccine (DPIV) is being developed and has been shown to be immunogenic in rhesus macaques. A phase I trial began in 2011, and two phase I trials of a tetravalent candidate began in 2012 in a dengue-primed population and in a non-endemic area 186 .

DNA vaccines . DNA vaccination results in antigen expression by both major histocompatibility complex (MHC) class I and MHC class II, leading to the activation of CD4 + and CD8 + T cells, as well as an antibody response. In addition, DNA vaccines are non-replicating and, therefore, safer than live attenuated vaccines, with low reactogenicity. Other advantages include low cost, ease of production and temperature stability 186 . Most of the DNA vaccine-based approaches in dengue have focused on eliciting immune responses to the prM protein and the E protein in mice and monkeys 186 . DNA vaccines based on the NS1 protein have also been tested in mice 226 , 227 , and another DNA vaccine, based on the expression of DENV1 prM, E and NS1 proteins, induced better protection than a DNA vaccine without NS1 (Ref. 228 ). Further advances in DNA vaccination may lead to a successful DENV vaccine.

Viral vector vaccines . Several viral vector platforms, including vaccinia virus, adenovirus and alphavirus vectors, have been explored as delivery vehicles for DENV antigens. Viral vector dengue vaccine candidates are focused on eliciting and evaluating anti-E protein antibody responses. No viral vector vaccine has advanced to clinical phase I testing 186 .

Vector control-based prevention

As the twentieth century dengue pandemic expanded over the past 40 years, prevention and control of the disease relied solely on mosquito control, as there was no licensed vaccine. However, as evidenced by the increasing global disease burden and expanding geographical distribution of both the viruses and the mosquito vectors, it is clear that mosquito control, as used in most countries, has failed to control dengue 229 – 231 ( Fig. 3 ). The reasons for this failure are complex and a detailed discussion is beyond the scope of this Primer. Briefly, after the successes of the American hemispheric Ae. aegypti and global malaria eradication programmes in the 1950s and 1960s 232 , there was widespread complacency about vector-borne diseases in general, and dengue in particular 229 . Moreover, dengue was not considered a major public health problem by policy makers who controlled budgets because epidemics were intermittent and mortality was low. This led to a redirection of resources and a lack of commitment to dengue control on the part of permissive countries and to deteriorating public health infrastructure 233 . Finally, limitations placed on the use of effective insecticides, such as dichlorodiphenyltrichloroethane (DDT), and the improper use of mosquito control tools that were available were contributing factors to the failure.

There were two countries that, temporarily, were exceptions to this general failure: Singapore and Cuba. Singapore was one of the first countries in Asia to experience DHF in the 1960s 234 . A highly successful Ae. aegypti control programme, which prevented epidemic dengue in Singapore for nearly 20 years, was implemented in 1968. The programme had three main pillars: legislation that levied fines on individuals whose premises were found to be infested by Ae. aegypti mosquitoes; larval source reduction and control; and community outreach and education 235 . Although this programme is still functioning and effectively controlling Ae. aegypti , it has failed to prevent the re-emergence of epidemic DENV transmission in the past 20 years 236 . The reasons for this re-emergence are not fully understood, but are thought to be a combination of low herd immunity, high frequency introduction of DENVs from neighbouring endemic or epidemic countries that had not controlled the disease and a highly dense human population 236 , 237 .

The Cuban programme was initiated in 1981 during the first large epidemic of DHF in the Americas 237 , 238 . This programme was based on the same three pillars used in Singapore, but added a fourth pillar: extensive use of space spraying of pyrethroid and organophosphate insecticides to kill adult mosquitoes using ultra-low volume and thermal fogging machines 238 . Epidemic dengue was controlled in Cuba for almost 30 years, but this programme also ultimately failed because of economic problems and, as with Singapore, the introduction of DENVs from neighbouring endemic or epidemic countries that had not controlled dengue have occurred.

There are several important lessons to be learned from these experiences. First, sustainable dengue control cannot be achieved by individual countries or communities when they are surrounded by areas with endemic or epidemic dengue. Thus, effective sustainable programmes must be developed on a regional basis as clearly demonstrated by the American hemispheric eradication programme 231 , 239 . Second, sustainable control requires long-term commitment by endemic countries. Those countries must use their own resources instead of relying on international agencies whose funds might not be relied on with certainty 229 , 231 . Last, to be effective, mosquito control tools must be used properly by trained personnel 240 . Otherwise, dengue control efforts become a waste of time and money.

Fortunately, the future for dengue control using vector control looks brighter as there are numerous new tools in the development pipeline. A new organization, the Partnership for Dengue Control, has recently been formed to facilitate an integrated approach to dengue control 241 . As a global alliance of partners and stakeholders interested in controlling dengue, it will bring together the leading expertise in dengue and public health to design new strategies for dengue control by integrating new and existing mosquito control tools with vaccination. Recent expert consensus workshops have reviewed currently available mosquito control methods as well as those in the development pipeline that might become available in the next 5 years. Briefly, the reviews concluded that, for currently available tools, targeted indoor residual spraying with synthetic pyrethroid insecticides combined with larval control were the most likely to provide effective Ae. aegypti control, provided the methods were used properly. The new tools in the pipeline include new non-pyrethroid residual insecticides that can be used for the control of dengue as well as new uses for those insecticides. Thus, in addition to targeted indoor and outdoor spraying, these compounds, which may have a residual activity of ≥6 months, can also be used as spatial repellents, to treat curtains and other materials hanging in mosquito resting areas and in lethal ovitraps (devices that mimic natural mosquito breeding sites).

Other tools in the pipeline include biological ( Wolbachia ) and genetic (sterile males) control 241 – 243 . A strain of Wolbachia , a natural bacterial parasite of insects, has been adapted to Ae. aegypti . When infected, the female Ae. aegypti has a reduced lifespan and has increased resistance to infection with DENVs, both of which can decrease transmission. When released into a natural population of Ae. aegypti , the Wolbachia spreads via normal mating, ultimately infecting most individuals in that population. A major advantage of this method is that it provides sustainable control. The sterile male method uses a dominant lethal gene carried by male Ae. aegypti , which are released into the natural mosquito population. When the males carrying the lethal gene mate with wild-type female Ae. aegypti , the progeny die as larvae, therefore, reducing the population. The advantage of this method is rapid reduction of the mosquito population, but the disadvantage is that it is not sustainable. Both of these approaches are in advanced field trials in several countries in Asia, South America and Central America, with promising results 241 .

Unfortunately, none of these mosquito control methods are likely to be completely effective in controlling dengue if used alone, but if used in an integrated control programme with other synergistic mosquito control tools and vaccines, effective control might be achieved 241 .

Central health policy-making institutions of each country should have programmes aimed at avoiding dengue-related fatalities. Permanent capacity building is necessary 244 to ensure the adequate classification and supportive care of patients 245 . Moreover, judicious fluid management during the critical phase coupled with continuous monitoring 246 , reorganization of sanitary services during epidemics 247 and dengue research are all vital to improve outcomes for patients 248 . A very comprehensive review on case treatment and management can be found in the WHO Dengue Guidelines for Diagnosis, Treatment, Prevention and Control 2 . In general, more histopathological and virological studies are needed to define the causes and pathogenesis of all of the complications that can accompany dengue illness.

General approaches

No specific treatment for dengue is currently available; consequently, patients are provided with supportive care. As management decisions need to be made before a confirmed dengue diagnosis by serology or other tests, clinicians must rely on clinical and epidemiological data to decide whether to classify a patient as a suspected dengue case 249 . In the absence of an effective antiviral drug, the prescription of bed rest and abundant liquids by mouth can be pivotal in determining the outcomes of patients. Indeed, fluid intake during the 24 hours before being seen by a clinician has been significantly associated with decreased risk for hospitalization of patients with dengue fever 250 . Analgesic and antipyretic drugs, such as paracetamol (neither aspirin nor NSAIDs should be taken), can be prescribed at the usual dosage for children and adults. Bed nets or repellents to avoid mosquito bites should be used to prevent other cases at home and in the neighbourhood.

Fluid therapy is key to dengue management and is applied based on disease severity. In mild dengue, oral fluid therapy can be as effective as intravenous fluid replacement and there is no need for hospitalization. Nevertheless, the requirement for hospital admission must be made according to the analysis of each clinical case, and hospitalization might be required, for instance, when a patient has diabetes mellitus or other comorbidities or characteristics, such as in the case of pregnant women, newborns or the elderly 251 , 252 . Old age and comorbidities, such as cardiovascular disease, stroke, respiratory disease and renal disease, might contribute to the development of severe dengue 253 .

Capillary leakage and shock . Capillary leakage becomes evident at the end of the febrile stage (days 3–6) and increases during the next 24–48 hours. At defervescence, the identification of warning signs ( Fig. 1 ) has a greater discriminatory power for detecting patients who are at risk of progression to severe disease and those who need hospitalization 254 , as the 2009 WHO guidelines recommend 2 , 163 . Families also must be educated to identify the so-called warning signs of dengue shock when fever subsides 171 and, when available, patients should be monitored clinically for markers of severe disease risk. Warning signs are the clinical heralds that announce the imminence of shock. In this situation, the fluid lost from the circulatory system owing to capillary leakage must be replaced by immediately initiating intravenous fluid therapy, of which crystalloid solutions (volume expanding fluid replacements such as lactate Ringer solution) or physiological (normal) saline solution are recommended 255 . Therapy with fluid support should be continued, according to the clinical situation of the patient and their fluid balance. As a rule, most patients with dengue recover if they are stratified and managed according to WHO recommendations 167 , 173 , which are guidelines that are supported by recognized experts 9 .

Some patients have a poor clinical evolution and present with pronounced frank hypotension, mental confusion and worsening of the other signs 256 . In these cases, intravenous administration of crystalloid solutions should be continued according to the WHO recommendations 257 , 258 . If appropriate management is continued, most patients will recover and go on to require maintenance fluid therapy, which is calculated according to the clinical situation of the patient. For those who do not recover, colloids (volume expanding solutions that contain human albumin, gelatin or starch) can be administered as an alternative to crystalloid solutions.

Impaired haemostasis . The haemorrhages that can accompany dengue illness are multifactorial. Although haemorrhages can worsen outcomes for patients who experience DSS, they are not necessarily associated with capillary leakage and can occur at any moment of the critical phase or during the convalescent phase 259 . Nevertheless, haemorrhages are frequent complications of prolonged shock rather than a general dengue complication (such as disseminated intravascular coagulation) and, therefore, the best way to prevent major haemorrhages is to prevent shock or treat it quickly and appropriately. Risk factors for severe haemorrhage include the duration of shock and low-to-normal levels of haematocrit at shock onset, whereas platelet count is not predictive of bleeding and does not correlate with its severity 260 . A sudden decrease in the levels of haematocrit and haemoglobin without an improvement of the patient is a sign of silent haemorrhage. Bleeding most commonly occurs in the gastrointestinal system where it can manifest as haematemesis (the vomiting of blood) and/or melaena (black, tar-like faeces). Treatment of gastrointestinal bleeding involves transfusion with packed red blood cells. Intracranial or lung bleeding can also occur and these are associated with a poor prognosis that can sometimes involve multiple organ system failure 261 . Finally, thrombocytopaenia is frequently observed in the course of dengue illness, but there is currently no evidence to support the practice of prophylactic platelet transfusions, which are costly and sometimes harmful 262 .

Other complications of severe dengue . Cardiac, hepatic, respiratory and neurological complications can all accompany dengue illness. DENV infection has been shown to cause cardiac disease with clinical manifestations ranging from a mild increase of disease biomarkers to myocarditis and/or pericarditis, and patients with severe dengue might show evidence of systolic and diastolic cardiac impairment that predominantly affects the septum and right ventricular walls 263 . Patients with dengue and clinical cardiovascular manifestations have been tested for abnormalities in the biomarkers troponin I and the amino-terminal fragment of brain natriuretic peptide, and these patients have also been studied using echocardiography and cardiac MRI 264 . These studies have shown that DENV infection can induce the destruction of cardiac fibres, the absence of myocyte nuclei and the loss of striations 265 . Dengue myocarditis or myocardiopathy can occur alone, can be associated with other organ dysfunctions or can be a complication of DSS. As such, cardiac function should be carefully monitored and, where appropriate, the patient should be admitted to an intensive care unit and given inotrope therapy (such as dopamine and dobutamine), according to local guidelines 266 .

The capillary leakage involved in severe dengue can have consequences for the respiratory system. These can include pleural effusion and respiratory distress associated with pulmonary oedema, which can be worsened by over-hydration during fluid therapy 267 . To avoid respiratory distress, during fluid therapy, the balance of fluids must be monitored 246 , oxygen therapy is mandatory and in some cases mechanical ventilation should be initiated.

In cases of acute dengue hepatitis, patients might require liver support and a hepatic pre-coma regimen (in attempt to avoid hepatic encephalopathy). In addition, patients with dengue hepatitis might also require management of other associated complications, such as bleeding (using transfusion of blood rather than platelets or fresh frozen plasma). Metabolic complications, such as acidosis, hypoglycaemia and hypocalcaemia, could be important components of dengue severity, although not necessarily associated with severe liver dysfunction. Pancreatitis is an infrequent complication of DENV infection 268 , 269 .

Emerging therapies

A major unmet need in dengue management is a safe and effective antiviral drug 270 . Although some antiviral candidates have been tested in randomized controlled trials, the results have been poor 271 . In addition, a trial of chloroquine — which has had in vitro antiviral effects against DENV infection and has additional anti-inflammatory properties — did not show any significant effect on the duration of viraemia or on the clinical course of illness 272 .

An alternative approach to using antivirals to treat dengue is to modulate the immune system, as cytokines have been implicated in contributing to capillary leakage. Although corticosteroids can suppress the immune system and decrease inflammation, a study in patients with dengue demonstrated no effect of steroid use on clinical signs or symptoms. Similarly, statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors) were unable to produce anti-inflammatory or endothelial-stabilizing effects in those with dengue 273 . Modern bioinformatics and high-throughput screening approaches are being used to try to identify new antiviral molecules and drugs that could stabilize the endothelium and, therefore, prevent or reverse capillary leakage in dengue illness.

Quality of life

Effects of acute illness.

Patients with dengue usually visit the physician with a main complaint of an unexplained high fever and malaise, sometimes with rash, petechiae or other skin and mucosal bleeding and vomiting. As a rule, these patients cannot attend school or go to work for ≥1 week. Dengue (also named ‘breakbone disease’) is frequently a very painful disease and mainly produces abdominal pain, backache, headache and myalgias 274 . By contrast, myositis (muscle inflammation) and muscle weakness are distinctly uncommon manifestations of DENV infection. Patients with dengue who have myositis have high levels of creatine phosphokinase and could have respiratory muscle involvement, which sometimes requires mechanical ventilation 275 . Guillain–Barré syndrome should be considered in patients who present with myalgias and general weakness or progressive limb weakness after the acute illness 276 .

Long-term effects of infection

Although fever and acute illness usually resolve within 1 week (mainly in children but also in some adults), most adult patients take longer to recover. In some patients, some dengue symptoms last for 6 months after the acute phase. The most frequent symptoms that are present at 6 months after acute illness are weakness (27.6% of patients), headache (14.8% of patients) and arthralgias (10.6% of patients). One study showed that these symptoms had an irregular appearance, were inconsistent and were mostly related to physical or mental exertion 277 . The persistence of some dengue symptoms has even been demonstrated 2 years after the acute illness 278 . Liver enzymes can normalize 1 month after acute illness 279 or continue to be raised for a much longer duration as a marker of liver cytolysis 280 . Fatigue post-DENV infection can result in clinical disease beyond the acute phase of infection, which may be explained by the immune alterations that are triggered by the DENV 281 . Some immunocompetent patients who had experienced severe dengue among other infectious diseases have had an increase in lymphocyte count preceding clinical deterioration that included interstitial pneumonitis, airway obstruction, CNS disturbances and systemic capillary leak syndrome, all of which were thought to represent immunopathological tissue damage 282 .

Neurological, renal and haematological outcomes

Neurological features have had an increased frequency in patients with dengue who have been admitted to hospital. These can be categorized into dengue encephalopathy (which is caused by hepatic failure or metabolic disorders), encephalitis (which is caused by direct virus invasion), neuromuscular complications (such as Guillain–Barré syndrome or transient muscle dysfunctions) and neuro-ophthalmic manifestations. Other neurological symptoms, such as transitory post-dengue Parkinsonism have been reported following serologically confirmed DENV infection. Transient and permanent visual disturbances have also been reported 283 . Impaired vision caused by dengue-associated ocular inflammation is an emerging ophthalmic condition and often involves the posterior segment (dengue-related maculopathy). The prognosis for these patients is variable and, although they usually regain good vision, they can retain persistent partially altered vision (which is defined as partially altered vision even up to 2 years after the clinical resolution of the acute disease) 284 . The aetiology and mechanisms of these complications deserve careful study.

Renal manifestations are uncommon and include acute kidney injury, proteinuria, glomerulonephritis and haemolytic uraemic syndrome 285 .

Among haematological alterations, haemophagocytic lymphohistiocytosis (an inflammatory condition characterized by increased proliferation of activated lymphocytes and macrophages that are capable of phagocytosing red blood cells leading to severe anaemia) has been recognized as a dengue-associated condition 286 .

There have been major advances in vaccines, specific antiviral drug development and vector control activities in the past 10 years. Used effectively, these new tools will provide new opportunities to control the disease. New molecular diagnostic and antigen detection tests and a better understanding of pathogenic mechanisms will enable earlier diagnosis and more-effective clinical management. In addition, a better understanding of virus–vector interactions and the dynamics of DENV transmission along with the new vector control tools that are being developed should lead to more-effective prevention and control of the disease.

Several vaccine candidates are currently in clinical trials, with live attenuated vaccines being the most successful developed to date 287 . The impact of the vaccination should be estimated by also considering vaccine coverage, the epidemiological situation of dengue, genetic polymorphisms within populations, dengue immunity of the target population and vector control activities 288 . The introduction of a licensed dengue vaccine into national programmes represents a challenge. According to the epidemiological situation, countries should decide whether high-risk groups or the total population should be vaccinated, and in which age groups and regions where the vaccine should be introduced. Mathematical models could become a very useful tool for the understanding of population-wide dengue strategies 289 .

As of April 2016, Sanofi Pasteur completed phase III testing and received approval from the WHO's Scientific Advisory Group of Experts on Immunization. The company has licensed their three-dose tetravalent live attenuated CYD vaccine (Dengvaxia) in five countries (Brazil, El Salvador, Mexico, Paraguay and the Philippines) for use in individuals 9–45 years of age, 70% of whom should be circulating DENV antibodies 188 , 210 , 290 , 291 .

Despite these advances, dengue research is still a priority. In 2006, the Special Programme for Research and Training in Tropical Diseases and the WHO convened a Dengue Scientific Working Group with experts from 20 countries who reviewed existing knowledge on dengue and established the research priorities, which were organized into four main streams: research related to reducing dengue fatality rates and disease severity; research on transmission control through improved vector management; research related to primary and secondary prevention; and health policy research aimed at contributing to an adequate public health response. The objective was to provide information for policy makers and foster the development of more cost-effective strategies to reverse the epidemiological trend of dengue. Unfortunately, owing to the current complex global dengue epidemiology, after almost 10 years, this approach is yet to stop the spread and emergence of dengue 292 , 293 .

Today, there are many promising areas for research. Interdisciplinary studies of the interactions between the virus, the human and the mosquito vector are required for a better understanding of the illness pathogenesis, DENV transmission dynamics, vaccine and drug development, and better diagnostic tools. The integration of clinical and epidemiological data with basic research, genomic studies and the application of advanced technology (such as ‘omics’, nanotechnology, biosensors and molecular modelling, among others) should be supported. No less important are studies to define the social, environmental and other risk factors for DENV transmission. Box 3 summarizes the main research priorities and topics.

Recognizing the importance of dengue, several international initiatives are ongoing. As a result of these efforts, the WHO published the Global Strategy for Dengue Prevention and Control in 2012 with three main targets: to reduce mortality to 50% by 2020; to reduce morbidity to 25% by 2020; and to better study disease burden. This strategy relies on five technical elements: diagnosis and case management; integrated surveillance and outbreak preparedness; sustainable vector control; future vaccine implementation; and research 13 .

At present, some of the WHO efforts are to identify early warning signs of outbreaks, to implement a strategy for integrated vector management and to analyse issues related to dengue vaccine and vaccination 2 , 294 – 298 . Other international initiatives include the Dengue Vaccine Initiative, the Partnership for Dengue Control and the multi-country research projects International Research Consortium on Dengue Risk Assessment, Management and Surveillance, Dengue Research Framework for Resisting Epidemics in Europe, and Innovative Tools and Strategies for Surveillance and Control of Dengue, which are supported by the European commission, among others 241 , 299 , 300 .

Overall, the international multi-sector response, as outlined in the 2012 WHO Global Strategy 13 and the Partnership for Dengue Control, will be crucial to reversing the global dengue trend as well as addressing other emerging vector-borne diseases, such as chikungunya, Zika and yellow fever virus infections. This strategy should include improved vector control through strategies such as community-based interventions to reduce breeding sites, an increase in the scope and breadth of dengue surveillance, improved case management to reduce the case fatality rate, a vaccination strategy and, potentially, novel entomological approaches to reduce transmission by altering mosquito ecology or genetics.

Box 3: Dengue research priorities topics

Reduce disease severity and fatality rates

Evaluate the 2009 WHO classification in clinical practice

Identify and validate prognostic markers (warning signs and risk factors) for severe disease

Prepare guidelines for clinical management of severe cases

Study dengue and comorbidities, pregnancy and in the elderly

Develop new diagnostic methods for early clinical diagnosis and clinical differentiation to chikungunya virus and Zika virus infections, tests for dengue confirmatory diagnosis, evaluation of commercial kits and quality assurance for diagnosis

Implement training programmes in case management at the different levels of the health care system

Define the molecular mechanisms of dengue and severe dengue with special emphasis on plasma leakage, bleeding and dengue in infants

Investigate the mechanisms of virus–human and virus–mosquito cell interactions, including host genetic associations with dengue virus (DENV)

Study the protective and pathogenic immune responses in DENV infection and the mechanisms of antibody-dependent enhancement, as well as the relationship with Zika immunity

Investigate the association between genetic changes in DENV and phenotypic expression

Reduce transmission

Study of vector biology and ecology

Develop and evaluate new vector control tools

Introduce and evaluate a strategy for integrated vector management

Implement training programmes in vector control to strengthen capacity

Study temporal, virological and immunological variables associated with transmission dynamics in different epidemiological settings

Apply mathematical modelling and geographical information systems for evaluating transmission dynamics, predicting transmission patterns and developing control measures

Define and evaluate better vector indices for surveillance and epidemic responses

Improve methods to study insecticide resistance

Develop early warning indicators of dengue outbreaks and epidemics and effective response systems

Develop new vaccine candidates via research on various areas

Apply mathematical modelling to estimate the effect of vaccination and the interaction between vaccination and vector control

Define indicators for post-vaccination surveillance

Integrate vaccine introduction with effective mosquito control

Health policy research

Define the burden and cost of illness, including in Africa

Identify strategies for multi-sectorial and multi-country collaboration for addressing dengue, integrating all factors and efforts to diminish transmission

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Introduction (M.G.G.); Epidemiology (D.J.G.); Mechanisms/pathophysiology (S.B.H.); Diagnosis, screening and prevention (A.I., D.J.G., E.M. and M.G.G.); Management (E.M.); Quality of life (E.M.); Outlook (M.G.G.); Overview of Primer (M.G.G.).

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D.J.G. is a patent holder on the Takeda vaccine and a stock holder in the company. He has consulted for Takeda and Sanofi, and was on the Scientific Advisory Board of Novartis Institute for Tropical Diseases from 2003 to 2012. All other authors declare no competing interests.

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Guzman, M., Gubler, D., Izquierdo, A. et al. Dengue infection. Nat Rev Dis Primers 2 , 16055 (2016). https://doi.org/10.1038/nrdp.2016.55

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Peer-reviewed

Research Article

Diabetes mellitus as a risk factor for severe dengue fever and West Nile fever: A meta-analysis

Contributed equally to this work with: Hong-Zheng Lu, Yu-Zhuang Xie

Roles Data curation, Methodology, Writing – original draft

Affiliations Department of Pathogen Biology, the Key Laboratory of Microbiology and Parasitology of Anhui Province, the Key Laboratory of Zoonoses of High Institutions in Anhui, School of Basic Medical Sciences, Anhui Medical University, Hefei, China, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui China

Affiliation Department of Pathogen Biology, the Key Laboratory of Microbiology and Parasitology of Anhui Province, the Key Laboratory of Zoonoses of High Institutions in Anhui, School of Basic Medical Sciences, Anhui Medical University, Hefei, China

Roles Data curation

Roles Data curation, Funding acquisition

Affiliation Department of Tropical Medicine, College of Military Preventive Medicine, Army Medical University, Chongqing, China

Affiliation Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, China

Roles Supervision, Writing – review & editing

* E-mail: [email protected] (FD); [email protected] (D-QW); [email protected] , [email protected] (S-QD)

Affiliation National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention (Chinese Center for Tropical Diseases Research), National Health Commission Key Laboratory of Parasite and Vector Biology; WHO Collaborating Center for Tropical Diseases; National Center for International Research on Tropical Diseases, Shanghai, China

Roles Conceptualization, Funding acquisition, Methodology, Supervision, Writing – review & editing

ORCID logo

  • Hong-Zheng Lu, 
  • Yu-Zhuang Xie, 
  • Chen Gao, 
  • Ying Wang, 
  • Ting-Ting Liu, 
  • Xing-Zhe Wu, 
  • Fang Dai, 
  • Duo-Quan Wang, 
  • Sheng-Qun Deng

PLOS

  • Published: May 31, 2024
  • https://doi.org/10.1371/journal.pntd.0012217
  • Reader Comments

This is an uncorrected proof.

Fig 1

Dengue fever (DF) and West Nile fever (WNF) have become endemic worldwide in the last two decades. Studies suggest that individuals with diabetes mellitus (DM) are at a higher risk of developing severe complications from these diseases. Identifying the factors associated with a severe clinical presentation is crucial, as prompt treatment is essential to prevent complications and fatalities. This article aims to summarize and assess the published evidence regarding the link between DM and the risk of severe clinical manifestations in cases of DF and WNF.

Methodology/Principal findings

A systematic search was conducted using the PubMed and Web of Science databases. 27 studies (19 on DF, 8 on WNF) involving 342,873 laboratory-confirmed patients were included in the analysis. The analysis showed that a diagnosis of DM was associated with an increased risk for severe clinical presentations of both DF (OR 3.39; 95% CI: 2.46, 4.68) and WNF (OR 2.89; 95% CI: 1.89, 4.41). DM also significantly increased the risk of death from both diseases (DF: OR 1.95; 95% CI: 1.09, 3.52; WNF: OR 1.74; 95% CI: 1.40, 2.17).

Conclusions/Significance

This study provides strong evidence supporting the association between DM and an increased risk of severe clinical manifestations in cases of DF and WNF. Diabetic individuals in DF or WNF endemic areas should be closely monitored when presenting with febrile symptoms due to their higher susceptibility to severe disease. Early detection and appropriate management strategies are crucial in reducing the morbidity and mortality rates associated with DF and WNF in diabetic patients. Tailored care and targeted public health interventions are needed to address this at-risk population. Further research is required to understand the underlying mechanisms and develop effective preventive and therapeutic approaches.

Author summary

In our study, we investigated the association between diabetes mellitus (DM) and the risk of severe clinical manifestations in cases of dengue fever (DF) and West Nile fever (WNF). By analyzing 27 studies involving over 342,000 laboratory-confirmed patients, we found compelling evidence supporting a link between DM and an increased risk of severe complications in both DF and WNF. Moreover, DM was found to significantly raise the risk of mortality from these diseases.

Our findings emphasize the importance of early detection and appropriate management strategies for diabetic individuals residing in endemic areas. Healthcare providers should be vigilant in monitoring diabetic patients with febrile symptoms, as they are more susceptible to developing severe disease. Tailored care and targeted interventions are crucial to minimize the morbidity and mortality rates associated with DF and WNF in diabetic individuals.

These findings have significant implications for public health, highlighting the need for awareness campaigns and preventive measures aimed at diabetic individuals. Further research is needed to understand the underlying mechanisms and develop effective strategies for prevention and treatment. By addressing these issues, we can reduce the impact of DF and WNF on individuals with DM.

Citation: Lu H-Z, Xie Y-Z, Gao C, Wang Y, Liu T-T, Wu X-Z, et al. (2024) Diabetes mellitus as a risk factor for severe dengue fever and West Nile fever: A meta-analysis. PLoS Negl Trop Dis 18(5): e0012217. https://doi.org/10.1371/journal.pntd.0012217

Editor: Christopher M. Barker, University of California, Davis, UNITED STATES

Received: December 11, 2023; Accepted: May 14, 2024; Published: May 31, 2024

Copyright: © 2024 Lu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This research was supported by the National Natural Science Foundation of China (82102432 to SQD, 81971971 to YW) and the Anhui Provincial Natural Science Foundation Project (2108085QH347 to SQD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Flaviviridae are a family of small enveloped viruses comprising four genera: Flavivirus , Pegivirus , Pestivirus , and Hepativirus , which are host-specific and pathogenic, mostly infecting mammals and birds. Clinical signs of flaviviral infection range from asymptomatic to severe or fatal hemorrhagic fever or neurologic disease [ 1 ]. Many flaviviruses are transmitted through the bite of infected arthropod vectors, primarily the Aedes genus and Culex genus. Human-to-human transmission from infected blood and tissues is also possible [ 2 ]. Flaviviruses have caused serious public health problems over the past decades, with epidemics of dengue virus (DENV), Japanese encephalitis virus (JEV), West Nile virus (WNV), Zika virus (ZIKV), and yellow fever virus (YFV) occurring worldwide [ 3 ]. A study of DENV prevalence estimated that 3.9 billion people worldwide are at risk of DENV infection. Over the past 20 years, the number of dengue cases reported to the World Health Organization (WHO) has increased more than sevenfold, from 505,430 in 2000 to more than 2.4 million in 2010 and 5.2 million in 2019 [ 4 , 5 ]. WNV first appeared in the northeastern United States in 1999 and is now distributed throughout most of the United States and southern Canada [ 6 ].

Although most people infected with DENV and WNV present asymptomatically or with undifferentiated febrile illnesses, a small number of infected individuals develop acute fever that may progress to severe clinical manifestations such as hemorrhage, vascular leakage, and encephalitis [ 7 ]. Because dengue fever (DF) and West Nile fever (WNF) are characterized by dynamic clinical changes over time, it is of great practical importance to identify predictive factors that measure the evolution of the disease into severe illness in the early clinical stages [ 8 , 9 ]. Available evidence suggests that age, sex, genetic background, and comorbidities may adversely affect the clinical presentation of the infection [ 9 – 11 ]. However, current knowledge of the risk factors for both diseases is insufficient to predict whether a patient will develop more severe clinical symptoms or even die. Early indicators of dengue progression to a severe stage (including abdominal pain or pressure, bleeding from mucous membranes, liver enlargement of more than 2 centimeters, and erythrocyte pressurization accompanied by a rapid drop in platelet count) are described in the 2009 WHO dengue guidelines [ 12 ]. In areas where the disease has been prevalent for a long time, the monitoring cost of these indicators is high, and unnecessary medical resources may be wasted. In addition, some of the warning signs may appear after the disease has progressed, lacking sensitivity and clinical value [ 13 ]. For WNF, there is also a lack of a clinical presentation that has been shown to be specific enough to predict severe illness, and it is now generally accepted that preexisting chronic conditions such as obesity, asthma, diabetes mellitus (DM), and hypertension are risk predictors of severe illness in WNF [ 14 , 15 ]. Movement disorders (muscle spasms, Parkinson’s syndrome) in patients and multifocal chorioretinitis have also been reported to be predictive of the development of WNF [ 16 , 17 ].

When infection occurs, elucidating the factors influencing disease severity is critical to identifying populations at high risk for severe illness, and effective intervention programmes and individualized clinical surveillance practices should specifically target these populations. DM is a multifaceted disease involving chronic metabolic disorders and immune dysfunction that leads to a wide range of clinical complications [ 18 , 19 ]. Additionally, DM is one of the most common and efficient predictors of potential clinical deterioration of flaviviruses [ 20 , 21 ]. The purpose of this study was to systematically review the available literature on the course of DF and WNF diseases associated with DM, to further determine whether DM promotes flavivirus infections (DENV and WNV) and to assess the magnitude of its role in serious versus nonserious clinical outcomes of disease infections.

Literature search

For this systematic review and meta-analysis, we followed the protocol described in the PRISMA statement [ 22 – 24 ]. We searched two databases (PubMed, Web of Science) to access all relevant published articles as of August 1, 2023 describing the association between DM and DENV and WNV. We used the following keywords: (("diabetes") OR ("mellitus") OR ("glycuresis") OR ("alloxan diabetes") OR ("alloxandiabetes") OR ("maturity-onset diabetes")) AND (("mosquito") OR ("mosquito-borne disease") OR ("MBD") OR ("dengue") OR ("breakbone fever") OR ("DENV") OR ("classical dengues") OR ("West Nile")). Only publications in English were included in this study. Conference abstracts were not included due to the lack of detailed descriptions of the study methods, and thus, the subsequent quality assessment could not be performed.

Inclusion and exclusion criteria

Two investigators (HZ Lu and YZ Xie) reviewed the titles and abstracts independently to identify the potentially eligible studies, for which the full texts were retrieved, and further assessment by reviewing the full text was conducted to identify the eligible studies. All discrepancies were resolved by discussion with the third investigator (C Gao).

The inclusion criteria of the studies in this meta-analysis were as follows: (1) DENV and WNV were clearly defined in the text; (2) both experimental and control groups were patients; and (3) reliable case identification methods were available.

The exclusion criteria were as follows: (1) no available full text or no extracted data; (2) fewer than 3 cases in each study or animal/cell study; (3) data from before 2000; and [ 4 ] when there were multiple publications on the same population or based on overlapping data, the latest or the largest study was included.

Data extraction

The following data were independently extracted from the studies by two investigators (Y Wang and TT Liu): (1) information about the publication (article title, first author, year of publication, year of data, region, study design); (2) data acquisition methods and case identification methods; (3) number of participants in the experiment; and (4) criteria for case definition.

Case definitions

Combining the 1997 and 2009 WHO guidelines for the classification of critical illnesses, we classified dengue progression into two groups [ 5 , 12 ]:

(1) Based on routine clinical data collected by the WHO’s 1997 guidelines, these guidelines classify symptomatic dengue virus infections into three clinical categories: undifferentiated fever, DF, and denguehemorrhagic fever (DHF). DHF was further categorized into four severity levels, of which levels III and IV were defined as dengue shock syndrome (DSS). We refer to DHF/DSS as “severe clinical presentation of dengue”.

(2) Applying the WHO 2009 classification criteria for dengue, a severe dengue case is defined as a suspected dengue patient with one or more of the following diseases: (i) severe plasma leakage that leads to shock (dengue shock) and/or fluid accumulation with respiratory distress; (ii) severe bleeding; and (iii) severe organ impairment.

West Nile fever

We refer to those who developed West Nile Neuroinvasive Disease (WNND) as having a “severe clinical presentation of WNV”, such as cases of WN encephalitis (WNE), WN meningitis (WNM), poliomyelitis or acute flaccid paralysis, WNV-associated retinopathy (WNVR), chorioretinitis or fatal cases [ 15 , 25 – 31 ].

Quality assessment

The qualities of the included studies were assessed by the Newcastle Ottawa Quality Scale (NOS) [ 32 ]. This scale evaluates the quality of the study by 8 questions from three aspects, namely, adequate case definition; representativeness of the cases; selection of controls; definition of controls; comparability of cases and controls on the basis of the design or analysis; ascertainment of exposure; same method of ascertainment for cases and controls; and nonresponse rate. For each trial, the results of the assessment were given. The quality assessment was performed by two investigators independently (LHZ and GC), and discrepancies were resolved by discussion with the third investigator (DSQ).

Statistical analysis

Meta-analyses were performed using Stata 16.0. We used odds ratios as the “primary model” and used random-effects or fixed-effects meta-analysis across all studies. The results were visualized in forest plots. Subgroup analyses were used to address heterogeneity and variability in the dependent variable and age of patients in the control and experimental groups. Heterogeneity between studies was assessed by using the I 2 test, the chi-squared test and forest plots. Heterogeneity was considered statistically significant when the P value < 0.05 or I 2 values > 50% [ 33 , 34 ]. A random-effects model was used when heterogeneity was considered; otherwise, a fixed-effects model was used. In addition, sensitivity analyses were used to assess the robustness.

General characteristics of the included studies

In total, 1700 studies were retrieved from the database in the initial search, of which 278 were considered potentially eligible after reviewing the titles and abstracts. After reading the full text of the articles, 31 articles were eligible, of which 4 studies used the same dataset as the others, and 27 articles were included in this meta-analysis [ 15 , 20 , 25 – 31 , 35 – 52 ]. The processes of study screening are shown in Fig 1 , and the general characteristics of the included studies and the corresponding NOS scores are shown in Tables 1 and 2 . Of these 27 studies, 19 were studies on dengue, 1 study was only able to extract data on deaths [ 49 ], and the remaining 8 were studies on WNF. In addition, most of these studies were case–control studies based on hospital administrative records. Both dengue and WNF were diagnosed by ELISA or RT–PCR, whereas DM was mostly derived from case records or self-reported by patients, and nine of these studies did not report the source of the DM diagnosis. Seven studies on dengue defined severe illness according to the WHO 1997 criteria, 7 studies defined it according to the WHO 2009 criteria, and the remaining studies combined both criteria. Subsequently, we divided the severe cases of both diseases into DHF (8 studies) and DSS (2 studies) according to the WHO 1997 criteria, and the remaining 8 studies used the WHO 2009 criteria and therefore were not included in the subgroup analysis. WNF was classified as WNM (1 study), WNE (2 studies), and WNVR (1 study). Finally, we tried to extract mortality data to analyze the effect of DM on mortality. We extracted 10 studies from 27 studies, 6 studies on dengue and 4 studies on WNF( S1 Table ).

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https://doi.org/10.1371/journal.pntd.0012217.t001

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Risk of bias assessment

All 31 studies were evaluated by the NOS tool. Five data points scored 9, nine data points scored 8, four data points scored 7, and eight data points scored 6. The findings of the funnel plot were confirmed by Egger’s test, indicating no significant publication bias in the analysis except for the results of two studies on dengue ( P >0.05) ( Table 3 ).

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https://doi.org/10.1371/journal.pntd.0012217.t003

Effects of DM on dengue and WNF

Eighteen and 8 studies reported the effect of DM on dengue and West Nile fever severity, respectively. Heterogeneity tests showed a high degree of heterogeneity in the effect of DM on the two diseases, with I 2 ( P ) values of 76% ( P < 0.001) and 66% ( P = 0.003), respectively. Therefore, a random effects model was used to estimate the combined effect of DM on both diseases. The results showed that DM significantly increased the risk of severe dengue and WNF, with ORs of 3.39 (95% CI: 2.46, 4.68) and 2.89 (95% CI: 1.89, 4.41), respectively ( Table 3 and Figs 2 and 3 ). The funnel plot showed publication bias ( P <0.05) on the effect of DM on dengue fever, while there was no publication bias ( P <0.05) on WNF ( Table 3 and S1 , S2 , S3 and S4 Figs). Sensitivity analysis showed a significant change in the study results when two articles, Mallhi (2015) and Mirza (2016), were excluded, and the heterogeneity was reduced from 76% to 47%.

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The size of the black square corresponding to each study is proportional to the sample size, and the center of each square represents the OR. Horizontal line shows the corresponding 95% CI of the OR. Pooled OR is represented by hollow diamond.

https://doi.org/10.1371/journal.pntd.0012217.g002

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https://doi.org/10.1371/journal.pntd.0012217.g003

We then stratified dengue (DHF, DSS) and WNF (WNM, WNE, WNVR) by disease progression or clinical symptoms to estimate the effect of DM on both. The combined effect of DM on DHF (n = 8) (OR = 2.73, 95% CI: 1.68, 4.44) and DSS (n = 2) (OR = 7.29, 95% CI: 3.09, 17.20) was statistically significant in both classifications of dengue ( Table 3 and Fig 4 ). Among the 3 classifications of WNF, the combined effect of DM on WNE (n = 2) (OR = 3.29, 95% CI: 1.15, 9.40) and WNVR (n = 1) (OR = 11.00, 95% CI: 1.13, 106.84) was statistically significant, whereas WNM (n = 1) (OR = 1.15, 95% CI: 0.38, 3.49) did not show statistical significance ( Table 3 and Fig 5 ). We then extracted mortality data for subgroup analyses to analyze the impact of DM on mortality from both diseases. The results showed a statistically significant combined effect of DM on dengue deaths (n = 6) (OR = 1.95, 95% CI: 1.09, 3.52) and West Nile fever deaths (n = 4) (OR = 1.74, 95% CI: 1.40, 2.17) ( Table 3 and Fig 6 ). With the exception of all studies ( P = 0.006) and DHF ( P = 0.032), the funnel plot did not show publication bias in several stratified studies ( P >0.05) ( S5 , S6 , S7 , S8 , S9 and S10 Figs).

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Forest plot of denguehemorrhagic fever (A). Forest plot of dengue shock syndrome (B). The size of the black square corresponding to each study is proportional to the sample size, and the center of each square represents the OR. Horizontal line shows the corresponding 95% CI of the OR. Pooled OR is represented by hollow diamond.

https://doi.org/10.1371/journal.pntd.0012217.g004

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Forest plot of West Nile meningitis (A). Forest plot of West Nile encephawlitis (B). Forest plot of West Nile virus-associated retinopathy (C). The size of the black square corresponding to each study is proportional to the sample size, and the center of each square represents the OR. Horizontal line shows the corresponding 95% CI of the OR. Pooled OR is represented by hollow diamond.

https://doi.org/10.1371/journal.pntd.0012217.g005

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Forest plot of diabetes mellitus on death of dengu (A). Forest plot of diabetes mellitus on death of West Nile fever (B). The size of the black square corresponding to each study is proportional to the sample size, and the center of each square represents the OR. Horizontal line shows the corresponding 95% CI of the OR. Pooled OR is represented by hollow diamond.

https://doi.org/10.1371/journal.pntd.0012217.g006

In this meta-analysis, we found that having DM was a demographic risk factor for the progression of DF and WNF to severe disease. Additionally, the results of the subgroup analyses showed that differences in the dependent variable (deterioration or death) did not lead to changes in the conclusions.

Our study also suffers from a number of shortcomings that cannot be addressed at this time. Most of the studies selected were retrospective, had different clinical and laboratory diagnostic criteria and control groups and were heterogeneous in terms of exposure and outcome. Some studies only used ELISA for diagnosis, which may result in serological cross-reactivity [ 57 ]. Most patients with DM have other comorbidities (e.g., hypertension, coronary artery disease), and we were unable to assess the impact of DM on the conditions of DF and WNF in isolation. At the same time, the judgment and inclusion criteria of DM in these articles are not clear, and only three studies showed a specific typology of DM (type 2) [ 39 , 43 , 44 ]. The diagnosis of DM mostly comes from case records, and some patients report themselves. It is difficult to distinguish whether DM is diagnosed before, after or during the onset of infection. Based on the literature included, we found that the majority of WNF studies originated in the United States, which may be related to the repeated outbreaks of WNF in North America over the past decade, which have resulted in the continued spread of WNF in communities [ 58 – 60 ]. This strong geographic trend may lead to impeded extrapolation of results. Most of the studies in dengue have adopted the new case classification of the WHO in 2009 to improve case management in the clinical setting. However, a proportion of reports still used the 1997 version, which was developed by the WHO based on a model of DF in Thai children and lacked clarity in the description of the measurement of outcome endpoints [ 61 ].

DM has been listed as a significant predictor of flavivirus-caused disease in the past, and this is supported by the findings of our meta-analysis. The underlying pathophysiologic mechanisms regarding the role of DM in the progression of DF and WNF are not completely clear at this time. Lee et al. found that patients with difficult glycemic control (HbA1c >7%) had a higher risk of dengue exacerbation than diabetic patients with better glycemic control (both without additional comorbidities) [ 44 ]. Hyperglycemia in diabetic patients is thought to lead to immune response dysfunction, with suppression of cytokine production, defective phagocytosis, and immune cell dysfunction, in addition to the risk of natural barrier impairment due to neuropathy [ 62 , 63 ]. This provides more opportunities for viruses to invade. In addition, platelet activity is increased to varying degrees in both type 1 and type 2 diabetic patients [ 64 ]. Platelets can interact with neutrophils to promote their activation and release of platelet factor (CXCL4), which has been shown to significantly inhibit the interferon pathway and enhance DENV replication in cells both in vitro and in vivo [ 65 ]. In addition, there is some biological evidence that can prove that patients with DM who are infected with DENV and WNV are more likely to aggravate infection. A study has shown that blood sugar is conducive to DENV replication, and it promotes virus transmission in mosquitoes through AKT and TOR signaling [ 66 ]. Furthermore, the study reveals that mosquito cells incubated in a high glucose medium exhibit upregulated levels of DENV proteins NS1, NS5, E, and prM, as well as AKT signaling (AKT phosphorylation) and TOR signaling (S6K phosphorylation) [ 66 ]. Some articles have found that monocytes infected with DENV in type 2 DM increase the production of interleukin-4 (IL-4), interleukin-10 (IL-10) and granulocyte-macrophage colony stimulating factor (GM-CSF) [ 67 ]. According to records, T helper (Th) cells play an important role in the immune pathogenesis of DHF [ 68 ]. According to the type of cytokine produced during activation, Th cells are divided into Th1 and Th2 cells. Activated Th1 cells produce IFN-γ (interferon), IL-2 and IL-12, while Th2 cells produce IL-4, IL-5, IL-10 and IL-13 [ 69 ]. Among the various mechanisms of the pathogenesis of DF, it has been reported that in secondarily infected hosts, a high DENV load is indirectly associated with DHF [ 70 ], and the overwhelming activation of Th2 cytokines has been documented in the development of DHF in patients with primary and secondary infections with DF [ 68 , 71 ]. Specifically, in the Th2 cytokine spectrum, IL-4 is the most effective cytokine for inducing Th2 cell differentiation, and IL-10 is responsible for the anti-inflammatory response in host immune activity [ 72 ]. In addition, it has been reported that compared with mild DF patients, the serum GM-CSF of severe DF patients is significantly increased [ 73 ]. Our stratified analysis similarly confirms this observation, with the OR value for DSS (7.29) being significantly higher than that for DHF (2.73).

Mukesh Kumar and others performed experiments on WNV infection in diabetic mouse models. The diabetic mouse model showed a high susceptibility to WNV disease, showing higher tissue tropism and mortality than wild-type mice. This is related to WNV infection and increased inflammation in diabetic mice and severely impaired and delayed specific immune response, which is characterized by delayed induction of IFN-α (interferon), and the concentration of WNV-specific IgM and IgG antibodies decreased in viremia [ 74 ]. Later, they discovered that the presence of DM significantly changed the recruitment of white blood cells in the brain, resulting in failure to clear the WNV infection in the brains of diabetic mice [ 75 ]. These findings are consistent with our study, emphasizing the importance of researching the role of DM in DF and WNF infections, and highlighting that DM could worsen the symptoms and severity of these diseases. Thus, our study further supports the need to focus on DM in the management of DF and WNF infections, as well as the importance of individualized intervention measures for patients with DM.

In addition to dengue and WNF, several studies have shown the effect of DM on Zika virus disease, Japanese encephalitis, and yellow fever. Azar et al. demonstrated increased susceptibility of Aedes aegypti that fed on “diabetic” bloodmeals to ZIKV by in vitro and in vivo modeling of type II DM and suggested that the prevalence of type II DM in the population may have a significant impact on ZIKV transmission [ 76 ]. Ahlers et al. showed that mammalian insulin can trigger AKT and ERK signaling in mosquitoes, leading to the transcription of JAK/STAT-associated antiviral genes [ 77 ]. DM was one of the most common comorbidities in the study patients (9.94%), and patients with comorbid JEV had higher medical costs than patients without DM [ 78 ]. Studies have shown that JEV comorbid with DM significantly increased the risk of death by 2.47 times ( P <0.05) [ 74 ]. Our results indicate that diabetes has a statistically significant combined impact on dengue fever mortality (OR = 1.95) and West Nile fever mortality (OR = 1.74). Patients with YFV and DM had a higher case fatality rate (CFR) of 80% compared with 65% in patients without DM [ 79 ]. In addition, DM attenuates the YFV vaccine effect by reducing 2’,5’-oligoadenylate synthase levels. Basal 2’,5’-oligoadenylate activity increased several-fold in response to YFV vaccination. In DM subjects, this increase was significantly lower ( P = 0.025) [ 80 ]. Based on these reports, DM can be shown to increase the risk of adverse outcomes of mosquito-borne flavivirus infection [ 14 , 76 , 80 ].

Overall, studying DM for DF and WNF infections is important to reduce the burden of disease by guiding approaches to improve patient prognosis or differential case management. We provide evidence that the prevalence of DM is higher in severe cases of dengue and WNF infection than in nonsevere cases. This means that DM may exacerbate the symptoms of DF and WNF infections. A further study with more focus on DM, DENV and WNV is therefore suggested. Examples include longitudinal studies of DM, DF and WNF, i.e., the effect of blood glucose concentration on the clinical symptoms of the disease. In addition, standardized prospective cohort studies in areas with high rates of infection will help to better understand the etiological role of DM in serious disease outcomes and to evaluate the causal relationship between them. This study can also provide some warnings for doctors who have DENV or WNV patients. For example, when a DENV or WNV patient with DM appears, the doctor should promptly decide whether it needs close observation, adequate treatment or hospitalization, and when a patient with DF has severe clinical symptoms, the doctor should promptly ask about past medical history, especially the history of DM. Patients with DM living in areas with high rates of DENV and WNV infection should be given a higher level of attention after diagnosis.

Supporting information

S1 fig. egger’s test of dengue..

https://doi.org/10.1371/journal.pntd.0012217.s001

S2 Fig. Trim and fill analysis of dengue.

https://doi.org/10.1371/journal.pntd.0012217.s002

S3 Fig. Egger’s test of West Nile fever.

https://doi.org/10.1371/journal.pntd.0012217.s003

S4 Fig. Trim and fill analysis of West Nile fever.

https://doi.org/10.1371/journal.pntd.0012217.s004

S5 Fig. Egger’s test of dengue hemorrhagic fever.

https://doi.org/10.1371/journal.pntd.0012217.s005

S6 Fig. Trim and fill analysis of dengue hemorrhagic fever.

https://doi.org/10.1371/journal.pntd.0012217.s006

S7 Fig. Egger’s test of death of dengue.

https://doi.org/10.1371/journal.pntd.0012217.s007

S8 Fig. Trim and fill analysis of death of dengue.

https://doi.org/10.1371/journal.pntd.0012217.s008

S9 Fig. Egger’s test of death of West Nile fever.

https://doi.org/10.1371/journal.pntd.0012217.s009

S10 Fig. Trim and fill analysis of death of West Nile fever.

https://doi.org/10.1371/journal.pntd.0012217.s010

S1 Table. Data collection of the studies included in the meta-analysis.

https://doi.org/10.1371/journal.pntd.0012217.s011

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Sentinel Enhanced Dengue Surveillance System — Puerto Rico, 2012–2022

Surveillance Summaries / May 30, 2024 / 73(3);1–29

Zachary J. Madewell, PhD 1 ; Alfonso C. Hernandez-Romieu, MD 1 ; Joshua M. Wong, MD 1 ; Laura D. Zambrano, PhD 1 ; Hannah R. Volkman, PhD 1 ; Janice Perez-Padilla, MPH 1 ; Dania M. Rodriguez, MS 1 ; Olga Lorenzi, MS 1 ; Carla Espinet, MPH 1 ; Jorge Munoz-Jordan, PhD 1 ; Verónica M. Frasqueri-Quintana, MPH 2 ; Vanessa Rivera-Amill, PhD 2 ; Luisa I. Alvarado-Domenech, MD 2 ; Diego Sainz, MD 3 ; Jorge Bertran, MD 3 ; Gabriela Paz-Bailey, MD, PhD 1 ; Laura E. Adams, DVM 1 ( View author affiliations )

Introduction

Ethics statement, limitations, future direction, acknowledgments.

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Problem/Condition: Dengue is the most prevalent mosquitoborne viral illness worldwide and is endemic in Puerto Rico. Dengue’s clinical spectrum can range from mild, undifferentiated febrile illness to hemorrhagic manifestations, shock, multiorgan failure, and death in severe cases. The disease presentation is nonspecific; therefore, various other illnesses (e.g., arboviral and respiratory pathogens) can cause similar clinical symptoms. Enhanced surveillance is necessary to determine disease prevalence, to characterize the epidemiology of severe disease, and to evaluate diagnostic and treatment practices to improve patient outcomes. The Sentinel Enhanced Dengue Surveillance System (SEDSS) was established to monitor trends of dengue and dengue-like acute febrile illnesses (AFIs), characterize the clinical course of disease, and serve as an early warning system for viral infections with epidemic potential.

Reporting Period: May 2012–December 2022.

Description of System: SEDSS conducts enhanced surveillance for dengue and other relevant AFIs in Puerto Rico. This report includes aggregated data collected from May 2012 through December 2022. SEDSS was launched in May 2012 with patients with AFIs from five health care facilities enrolled. The facilities included two emergency departments in tertiary acute care hospitals in the San Juan-Caguas-Guaynabo metropolitan area and Ponce, two secondary acute care hospitals in Carolina and Guayama, and one outpatient acute care clinic in Ponce. Patients arriving at any SEDSS site were eligible for enrollment if they reported having fever within the past 7 days. During the Zika epidemic (June 2016–June 2018), patients were eligible for enrollment if they had either rash and conjunctivitis, rash and arthralgia, or fever. Eligibility was expanded in April 2020 to include reported cough or shortness of breath within the past 14 days. Blood, urine, nasopharyngeal, and oropharyngeal specimens were collected at enrollment from all participants who consented. Diagnostic testing for dengue virus (DENV) serotypes 1–4, chikungunya virus, Zika virus, influenza A and B viruses, SARS-CoV-2, and five other respiratory viruses was performed by the CDC laboratory in San Juan.

Results: During May 2012–December 2022, a total of 43,608 participants with diagnosed AFI were enrolled in SEDSS; a majority of participants (45.0%) were from Ponce. During the surveillance period, there were 1,432 confirmed or probable cases of dengue, 2,293 confirmed or probable cases of chikungunya, and 1,918 confirmed or probable cases of Zika. The epidemic curves of the three arboviruses indicate dengue is endemic; outbreaks of chikungunya and Zika were sporadic, with case counts peaking in late 2014 and 2016, respectively. The majority of commonly identified respiratory pathogens were influenza A virus (3,756), SARS-CoV-2 (1,586), human adenovirus (1,550), respiratory syncytial virus (1,489), influenza B virus (1,430), and human parainfluenza virus type 1 or 3 (1,401). A total of 5,502 participants had confirmed or probable arbovirus infection, 11,922 had confirmed respiratory virus infection, and 26,503 had AFI without any of the arboviruses or respiratory viruses examined.

Interpretation: Dengue is endemic in Puerto Rico; however, incidence rates varied widely during the reporting period, with the last notable outbreak occurring during 2012–2013. DENV-1 was the predominant virus during the surveillance period; sporadic cases of DENV-4 also were reported. Puerto Rico experienced large outbreaks of chikungunya that peaked in 2014 and of Zika that peaked in 2016; few cases of both viruses have been reported since. Influenza A and respiratory syncytial virus seasonality patterns are distinct, with respiratory syncytial virus incidence typically reaching its annual peak a few weeks before influenza A. The emergence of SARS-CoV-2 led to a reduction in the circulation of other acute respiratory viruses.

Public Health Action: SEDSS is the only site-based enhanced surveillance system designed to gather information on AFI cases in Puerto Rico. This report illustrates that SEDSS can be adapted to detect dengue, Zika, chikungunya, COVID-19, and influenza outbreaks, along with other seasonal acute respiratory viruses, underscoring the importance of recognizing signs and symptoms of relevant diseases and understanding transmission dynamics among these viruses. This report also describes fluctuations in disease incidence, highlighting the value of active surveillance, testing for a panel of acute respiratory viruses, and the importance of flexible and responsive surveillance systems in addressing evolving public health challenges. Various vector control strategies and vaccines are being considered or implemented in Puerto Rico, and data from ongoing trials and SEDSS might be integrated to better understand epidemiologic factors underlying transmission and risk mitigation approaches. Data from SEDSS might guide sampling strategies and implementation of future trials to prevent arbovirus transmission, particularly during the expansion of SEDSS throughout the island to improve geographic representation.

Dengue is an acute febrile viral illness transmitted by Aedes spp. mosquitoes and caused by four closely related dengue virus serotypes (DENV 1–4). DENV causes an estimated 390 million infections ( 1 ) and 40,500 deaths worldwide each year ( 2 ). In contrast to data suggesting that the prevalence of most communicable diseases is declining worldwide, dengue incidence and disease prevalence have been increasing over time, measured both by disability-adjusted life years and mortality attributed to dengue ( 2 – 4 ). The increased prevalence is most pronounced in Southeast Asia; dengue remains endemic in Puerto Rico, where large outbreaks typically occur in cycles of 3–7 years ( 5 ). The most recent epidemic in Puerto Rico occurred during 2012–2013, dominated by DENV-1; sporadic cases of DENV-4 also occurred. During 2010–2020, dengue was associated with approximately 30,000 confirmed and probable cases, including 584 severe cases, approximately 10,000 hospitalizations, and 68 deaths islandwide ( 6 ). The southern region of Puerto Rico, which includes Ponce, has historically had a higher incidence of dengue. Ponce is the fourth largest municipality on the island and experienced a substantial proportion of dengue cases during the 2012–2013 epidemic ( 7 ).

Suspected dengue cases have historically been reported to the Passive Dengue Surveillance System (PDSS), a system jointly managed by CDC and the Puerto Rico Department of Health (PRDH). These cases were reported based on clinical suspicion, followed by laboratory confirmation by PRDH. PDSS faces certain challenges (e.g., underreporting, limited testing of suspected cases, and incomplete clinical data), highlighting the need for complementary and timely surveillance methods. Dengue presents diagnostic challenges because its nonspecific symptoms overlap with those of other acute febrile illnesses (AFIs), emphasizing the need for reliable diagnostic tests. Surveillance systems are often limited by underdiagnosis and underreporting, thereby missing cases. In 2012, CDC transferred the operational responsibility of PDSS to PRDH and established the Sentinel Enhanced Dengue Surveillance System (SEDSS), a site-based active surveillance system used to monitor acute febrile and respiratory illnesses within certain emergency departments (EDs) ( 8 – 10 ). SEDSS was designed to diagnose and characterize dengue infections, along with arboviral and other respiratory viruses, accompanied by comprehensive demographic, syndromic, and clinical data. SEDSS addresses these challenges through enhanced surveillance and by providing comprehensive diagnostic testing for all patients with AFIs, allowing for capture of the full spectrum of case and disease prevalence. Since May 2012, SEDSS has demonstrated its adaptability, expanding its scope to cover emerging pathogens such as chikungunya virus (CHIKV) in 2014, Zika virus (ZIKV) in 2016, and SARS-CoV-2 in 2020. This real-time tracking capability has positioned SEDSS as a flexible and responsive sentinel system, and this report represents the first comprehensive summary of SEDSS data, marking a milestone in the reporting of these surveillance findings.

This report summarizes arboviral and respiratory illnesses among patients with AFIs seeking care at SEDSS sites from May 5, 2012, through December 31, 2022, and describes large outbreaks of dengue, chikungunya, Zika, and COVID-19 that occurred at different points during the surveillance period. This report also characterizes the relative prevalence of dengue warning signs and severe dengue in different age groups among laboratory-confirmed cases.

Surveillance Sites and Procedures

Data for this enhanced surveillance study were collected from patients with AFIs from hospitals participating in SEDSS from 2012 to 2022. Data collection adhered to a protocol approved by institutional review boards at CDC, Auxilio Mutuo, and Ponce Medical School Foundation with informed consent obtained from all participants. Recruitment for SEDSS began in May 2012 with two tertiary care facilities, two secondary care facilities, and one outpatient acute care clinic. During 2012–2015, SEDSS included three sites: 1) Saint Luke’s Episcopal Hospital (SLEH) in Ponce (SLEH-Ponce), a tertiary acute care hospital with 425 beds, an average of 50,000 patient visits per year, and 11,000 overall inpatient admissions per year; 2) SLEH-Guayama, a secondary acute care hospital with 116 beds, 40,000 patient visits per year, and 6,000 overall inpatient admissions per year; and 3) Hospital de La Universidad de Puerto Rico (UPR) in Carolina (UPR-Carolina), a secondary acute care teaching hospital with 250 beds, 55,000 medical visits per year, and 10,000 overall inpatient admissions per year ( 9 – 11 ). SLEH-Guayama participated from February 2013 to September 2015, UPR-Carolina operated from July 2013 to August 2015, and SLEH-Ponce continued participation through 2022. In 2016, Centro de Emergencia y Medicina Integrada (CEMI), an outpatient acute care clinic in Ponce registering approximately 1,700 annual clinic visits and 3,000 admissions joined the network. In November 2018, Auxilio Mutuo Hospital, a tertiary care facility in the San Juan-Caguas-Guaynabo metropolitan area (San Juan metro area) with 497 beds, 33,000 patient visits per year, and 8,000 overall inpatient admissions per year, was incorporated. The expansion to the San Juan metro area enhanced geographic representativeness, allowing the surveillance system to cover a broader and more diverse population within Puerto Rico.

Informational posters were available in hospital waiting rooms and hallways to inform the community about SEDSS. Potential participants were identified by triage nurses as any patient with an AFI defined by the presence of fever ≥100.4°F (≥38.0°C) for temperatures measured orally, ≥99.5°F (≥37.5°C) for temperatures measured rectally, and ≥101.3°F (≥38.5°C) for temperatures measured axillary at the time of triage or chief complaint of having a fever within the past 7 days. During the Zika epidemic (June 2016–June 2018), patients were eligible for enrollment in SEDSS if they visited a SEDSS site with either rash and conjunctivitis, rash and arthralgia, or fever ( 12 ). These criteria were applicable specifically during the Zika epidemic period to enhance Zika surveillance and are no longer part of the current eligibility criteria. Beginning in April 2020, patients reporting cough or dyspnea within the past 14 days (with or without fever) also were eligible for enrollment to better capture respiratory viruses ( 9 ). No age groups were excluded, although infants were only eligible for enrollment if they visited the hospital after their initial discharge after birth. All patients meeting the inclusion criteria were invited to participate in the study using convenience sampling. If a patient was incapacitated at the time of triage because of acute illness, the patient was only asked to participate after stabilization. All participants received an informational sheet about SEDSS and were enrolled after providing informed consent.

Data Collection

Data from SEDSS were collected through patient interview and medical record review at intake during patient enrollment on a case investigation form (CIF) and approximately 7–14 days later on a convalescent sample processing form (CSPF). The CIF included demographic information (e.g., name, age, sex, pregnancy status, and contact information), comorbidities (e.g., diabetes, hypertension, asthma, chronic kidney disease, and immunodeficiency), and clinical features (e.g., onset date, vital signs, signs, and symptoms). The CSPF contained comparable information to the CIF but added the date of the second specimen collection and indicators of AFI severity (e.g., hospitalizations and other clinic visits). Data were originally collected using paper copies of the CIF and CSPF and were transitioned to electronic data in 2020 using the Research Electronic Data Capture (REDCap) system (REDCap Consortium; version 5.20.11) ( 13 , 14 ).

Inpatient medical data for participants with AFIs who were admitted to the hospital from SLEH-Ponce, SLEH-Guayama, and Auxilio Mutuo Hospital also were collected using a separate form (Hospital Admitted Abstraction Form) and entered into REDCap to collect key clinical indicators of disease severity and progression. For admitted patients, these data included information on extent and nature of hemorrhage, plasma leakage (e.g., ascites and pleural and cardiac effusions), hematologic indicators of increased intravascular permeability (e.g., hematocrit and serum albumin levels), additional blood pressure and heart rate measures to assess shock, and indicators of severe organ involvement (e.g., liver impairment, meningitis, and encephalitis) ( 15 ). These data were subsequently merged with data entered from the SEDSS CIF and CSPF forms using medical record numbers.

Sample Collection, Laboratory Procedures, and Case Confirmation

Blood, nasopharyngeal (NP), and oropharyngeal (OP) specimens were collected at enrollment from eligible participants. Additional blood samples (e.g., serum and whole blood) also were collected during the convalescent phase. Participants were required to provide at least one sample (blood, OP, or NP) to participate. All participants had molecular testing for dengue, chikungunya (December 2013–April 2020), and Zika (December 2015–April 2020) viruses for specimens collected within 7 days of symptom onset. Before March 2016, DENV was detected by the CDC DENV-1–4 Real-Time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) Assay ( 16 ). During March 2016–April 2020, the CDC Trioplex Real-Time RT-PCR Assay was used to detect DENV, CHIKV, and ZIKV concurrently, followed by the CDC DENV-1–4 Real-Time RT-PCR Assay on any samples positive for DENV to determine serotype ( 17 ). After April 2020, the CDC DENV-1–4 Real Time RT-PCR Assay again was used as the primary assay to detect DENV. Serologic testing was done by immunoglobulin M (IgM) antibody capture enzyme-linked immunosorbent assay for anti-DENV, anti-CHIKV (December 2013–March 2019), and anti-ZIKV (December 2015–March 2019) antibodies for specimens collected >3 days after symptom onset ( 18 ). Molecular diagnostic testing of NP and OP specimens was done by RT-PCR on a panel of respiratory viruses including influenza A (IAV) and influenza B (IBV) viruses, human adenovirus (HAdV), respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza virus (HPIV) types 1 and 3, seasonal human coronavirus (HCoV [229E, OC43, NL63, and HKU1]) ( 18 , 19 ), and for SARS-CoV-2. For SARS-CoV-2, the RT-PCR assays used included the CDC Real-Time RT-PCR Panel for tests performed before December 2021 and the CDC Influenza SARS-CoV-2 Multiplex Assay for tests performed in December 2021 and later ( 20 , 21 ). HCoV testing was conducted consistently from 2012 to 2014 but was discontinued because of the viruses’ low frequency. However, sporadic testing based on clinical suspicion or exposure to known cases might have occurred throughout the study period. Molecular and serologic results were used to classify participants as having confirmed or probable CHIKV, DENV, or ZIKV infection using established guidance ( 22 , 23 ) ( Table 1 ).

Dengue warning signs and severe dengue were defined by the Pan American Health Organization ( 24 ), incorporating available clinical indicators from SEDSS intake and follow-up forms and abstracted inpatient medical records. Dengue warning signs were defined by abdominal pain or tenderness, persistent vomiting, pleural or pericardial effusion or ascites, mucosal bleeding, restlessness, or hepatomegaly ( 15 ). Severe dengue was defined as severe plasma leakage or shock, severe bleeding, or severe organ impairment ( 15 ).

Descriptive frequencies of AFI cases were reported by selected characteristics, including year, days post onset, age group, sex, ED encounter, physician diagnosis, clinical disposition, and chronic conditions. These characteristics also were reported by arboviral infection status (confirmed and probable DENV, ZIKV, and CHIKV) and respiratory virus infection (confirmed IAV, IBV, RSV, HAdV, HPIV-1, HPIV-3, HMPV, HCoV, and SARS-CoV-2). Clinical characteristics were reported by age group for participants with confirmed or probable DENV, CHIKV, and ZIKV infections. A patient might have been enrolled in SEDSS more than one time over the course of the study. The denominator for this analysis was the number of unique patient visits. Arbovirus and acute respiratory virus infection data were aggregated into weekly infection counts and plotted by epidemiologic week and year over the surveillance period. The frequency of symptoms for dengue, chikungunya, and Zika cases, as well as the frequency of warning signs and indicators of severe dengue, were calculated. The proportion of AFI cases positive for arboviruses or acute respiratory viruses by municipality is presented using choropleth maps with 5% equal intervals. All analyses were done using R software (R Foundation for Statistical Computing; version 4.3.1).

The institutional review boards at CDC, Auxilio Mutuo, and Ponce Medical School Foundation approved the SEDSS study protocols 6,214 and 120308-VR, respectively. Written consent to participate was obtained from all adult participants and emancipated minors. For minors aged 14–20 years, written consent was obtained: for children aged 7–13 years, parental written consent and participant assent were obtained.

A total of 24,020 (27.2%) were recruited participants among 88,255 eligible patients from SLEH-Ponce (2012–2022), 2,893 (19.2%) among 15,071 from SLEH-Guayama (2013–2015), 9,240 (36.4%) recruited of 25,378 eligible from CEMI (2016–2022), 1,436 (23.6%) among 6,090 from UPR-Carolina (2013–2015), and 2,554 (10.6%) among 24,181 from Auxilio Mutuo Hospital (2021–2022) (Supplementary Table 2, https://stacks.cdc.gov/view/cdc/153721 ). The number of eligible patients was unavailable for Auxilio Mutuo Hospital (2018–2020); however, 2,733 participants were recruited during this period.

From May 2012 to December 2022, there were 43,608 unique visits from 35,855 total participants enrolled in SEDSS (Supplementary Figure 1, https://stacks.cdc.gov/view/cdc/153721 ), including 7,690 hospitalizations or transfers and 72 deaths ( Table 2 ). Participants in SEDSS resided in 76 of the 78 municipalities in Puerto Rico; most visits were from participants residing in municipalities near the sentinel surveillance sites (e.g., Ponce [19,612 visits], Juana Díaz [3,535], Peñuelas [3,449], San Juan metro area [2,460], Villalba [1,719], Carolina [1,694], and Guayama [1,578]). Visits from participants were reported by residents of 18 U.S. states including Florida (nine), Texas (seven), and New York (six).

Etiologic Agents

Laboratory testing identified positive results for arboviruses, including DENV (959 confirmed and 473 probable cases), ZIKV (1,449 confirmed and 469 probable cases), and CHIKV (1,804 confirmed and 489 probable cases) ( Figure 1 ). In addition, positive results were identified for the following respiratory viruses: IAV (3,756 cases), IBV (1,430 cases), SARS-CoV-2 (1,586 cases), HAdV (1,550 cases), RSV (1,489 cases), HPIV-1 (407 cases), HPIV-3 (993 cases), HMPV (862 cases), and HCoV (46 cases) ( Figure 2 ).

Geographic Distribution and Temporal Trends

Arboviruses.

The proportion of visits from participants testing positive for any arbovirus in municipalities with at least 100 participants tested was highest for those with residence in Guayama (539 of 1,543 [34.9%]), Salinas (144 of 594 [ 24.2%]), Patillas (64 of 308 [20.8%]), and Arroyo (62 of 303 [20.5%]) in southeast Puerto Rico and Loíza (33 of 146 [22.6%]) in northeast Puerto Rico ( Figure 3 ). Conversely, municipalities that had the lowest proportion of visits from participants testing positive for arboviruses included Toa Baja (two of 118 [1.7%]) and Toa Alta (three of 105 [2.9%]) in northern Puerto Rico. The proportion of participants with AFI who tested positive for DENV were relatively consistent across PRDH regions (Supplementary Figure 2, https://stacks.cdc.gov/view/cdc/153721 ). The highest proportion of visits from participants testing positive for CHIKV was from San Juan metro area (296 of 2,481 [11.9%]) and Ponce (1,952 of 23,804 [8.2%]); the highest proportion who tested positive for ZIKV was from Ponce (1,886 of 19,324 [9.6%]).

Circulation of DENV, CHIKV, and ZIKV had minimal overlap, with transmission of each virus occurring during distinct periods (Supplementary Figure 3, https://stacks.cdc.gov/view/cdc/153721 ). SEDSS was initiated during an ongoing dengue outbreak in May 2012, and circulation continued until approximately February 2014. The majority of the 948 serotyped dengue cases were DENV-1 (891 [94.0%]), followed by DENV-4 (50 [5.3%]) ( Figure 4 ) (Supplementary Figure 4, https://stacks.cdc.gov/view/cdc/153721 ). Six (0.6%) cases of DENV-2 and one (0.1%) case of DENV-3 were reported. CHIKV emerged on the island in January 2014 ( 25 ), and the first case was recorded in SEDSS in May 2014. Shortly after emergence, a large, time-limited outbreak of chikungunya occurred, which is reflected in the SEDSS data. During the peak of the chikungunya outbreak in September 2014, up to 195 cases per week were reported through SEDSS, representing 77.7% of all AFI cases in the system (Supplementary Figure 3, https://stacks.cdc.gov/view/cdc/153721 ). The outbreak eventually subsided in December 2014, with lingering low-level transmission occurring through November 2017. In December 2015, ZIKV emerged on the island, with the first case reported through SEDSS in January 2016. During the Zika outbreak peak, up to 101 cases per week were being reported through SEDSS before the outbreak ended in January 2017. In 2016, 1,612 of 6,301 (25.6%) of all ZIKV tests were positive (Supplementary Figure 5, https://stacks.cdc.gov/view/cdc/153721 ). ZIKV infections continued to be reported through SEDSS through 2018, albeit at low levels. During the Zika outbreak, 40 additional cases of probable flavivirus infections were reported, representing participants with cross-reactive IgM responses against ZIKV and DENV with no molecular evidence of infection. These cross-reactive IgM responses likely were associated with ZIKV because of the epidemiological context of a Zika outbreak and low DENV transmission during the same period. After the Zika outbreak subsided, low-to-no transmission of either ZIKV or DENV was observed until September 2019. Between September 2019 and December 2022, consistent low levels of weekly dengue cases (primarily DENV-1) were reported (Supplementary Figures 3 and 4, https://stacks.cdc.gov/view/cdc/153721 ), reaching a high of 23 cases observed in October 2020. Zero confirmed and nine probable ZIKV cases were reported from 2020 to 2022.

Respiratory Viruses

The proportion of visits from participants testing positive for any acute respiratory virus in municipalities with at least 100 participants tested was highest for those with residence in Toa Alta (44 of 113;[38.9%]), Bayamón (135 of 363; [34.4%]), Guaynabo (102 of 323; [31.6%]), and Toa Baja (41 of 130; [31.5%]) in northern Puerto Rico, whereas Canóvanas (71 of 358; [19.8%]), Loíza (31 of 153; [20.3%]), and Río Grande (41 of 201; [20.4%]) in northeast Puerto Rico had the lowest proportions of visits from participants testing positive for respiratory viruses ( Figure 5 ). The proportions of visits from participants with AFIs who tested positive for HAdV, HMPV, IAV, IBV, RSV, and HPIV-3 were relatively consistent across PRDH regions (Supplementary Figure 2, https://stacks.cdc.gov/view/cdc/153721 ). Only participants from Ponce, San Juan metro area, and Bayamón tested positive for HPIV-1 (Supplementary Figure 2, https://stacks.cdc.gov/view/cdc/153721 ). Percentage positivity for SARS-CoV-2 ranged from 13.3% (825 of 6,211) in Ponce to 32.1% (35 of 109) in Fajardo.

Seasonality was observed for both IAV and IBV, with IAV circulation typically preceding IBV circulation each year (Supplementary Figure 6, https://stacks.cdc.gov/view/cdc/153721 ). Periods of sustained IAV transmission typically spanned late November to early March, whereas IBV transmission typically occurred from mid-April to mid-June. Two notable exceptions occurred during which sustained IAV transmission was observed from July through October 2013 and IBV transmission from October 2016 to January 2017. Strong seasonality also was observed for confirmed RSV infections. Each year, RSV outbreaks typically began between late October and early November, with seasonal peaks in late November and early December. Circulation of HAdV, HMPV, HPIV-1, and HPIV-3 occurred throughout the year. Each virus still exhibited seasonality, with more pronounced HAdV transmission in July, HPIV-1 in October, HPIV-3 in April and May, and HMPV in December and January. In March 2020, all acute respiratory viruses decreased after the emergence of SARS-CoV-2. From March 2020 to April 2021, approximately all identified respiratory viral infections were SARS-CoV-2 after which other respiratory viruses reemerged. The highest weekly number of SARS-CoV-2 infections occurred in January 2022, coinciding with the emergence of Omicron. In 2022, a total of 942 of 3,988 (23.6%) tests for SARS-CoV-2 were positive (Supplementary Figure 5, https://stacks.cdc.gov/view/cdc/153721 ).

Patient Characteristics, Signs, and Symptoms

Dengue patient characteristics, symptoms, and severity.

A total of 1,432 dengue infections were identified among 1,427 study participants, which includes five participants who had two dengue infections during the study period (2012–2022). Of these infections, 1,026 (71.6%) occurred in 2012 and 2013 (Figure 1) (Supplementary Table 2, https://stacks.cdc.gov/view/cdc/153721 ). The majority of participants with dengue (765 [53.4%]) visited SEDSS sites within 3 days of symptom onset ( Table 3 ). Most participants (764 [53.4%]) were male; among 668 female participants, 239 (35.8%) were women of childbearing age (15–44 years) and 11 were pregnant. A total of 587 (41.0%) participants with DENV infection were aged 10–19 years. Whereas 768 (53.6%) participants were ambulatory after the initial visit, 660 (46.1%) were admitted or transferred, and two participants died. The majority of common comorbidities were obesity (30.8%), hypertension (16.4%), chronic pulmonary disease (15.8%), and diabetes (9.6%). Before laboratory testing, 583 (40.7%) participants received a clinical diagnosis of dengue by a physician, 167 (11.7%) with a respiratory infection, and 560 (39.1%) with an unspecified infection. Among participants with DENV infection, 81 (5.7%) were coinfected with a respiratory virus, including 18 participants with HAdV and 28 with IAV or IBV.

Among the 1,432 participants with dengue reported through SEDSS, 263 (18.4%) received a diagnosis of dengue without warning signs, 788 (55.0%) received a diagnosis of dengue with warning signs and did not progress to severe dengue, and 381 (26.6%) received a diagnosis of severe dengue; two participants (0.1%) died. Among the 263 participants without warning signs, 788 with any warning sign, and 381 with severe dengue, 48 (18.3%), 293 (37.2%), and 319 (83.7%) were hospitalized or transferred, respectively. The distribution of dengue without warning signs, dengue with warning signs, and severe dengue was consistent across age groups with the exception that severe dengue was less prevalent among infants ( Figure 6 ). Among the 557 participants with warning signs or severe dengue who were not hospitalized, 98 (17.6%) received a correct initial physician diagnosis of dengue. Age distribution of 1) specific clinical indicators of severity and 2) dengue without warning signs, dengue with warning signs, and severe dengue are presented ( Table 4 ) (Figure 6). The most frequently reported general symptoms of dengue, in addition to fever, were headache (1,200 [83.8%]), myalgia (1,066 [74.4%]), and leukopenia (1,022 [71.4%]); however, all general symptoms, including fever, chills, nausea, rash, headache, retro-orbital pain, myalgia, arthralgia, and leukopenia, were reported in more than half of all participants with laboratory evidence of infection (Supplementary Figure 7, https://stacks.cdc.gov/view/cdc/153721 ). The most reported warning signs were abdominal pain (869 [60.7%]) and restlessness (699 [48.8%]). The most reported manifestation of severe dengue was severe plasma leakage (252 [17.6%]). Shock occurred in 32 (2.2%) participants. Severe organ impairment occurred in 57 (4.0%) participants, including 17 (1.2%) with liver impairment, seven (0.5%) with encephalopathy, seven (0.5%) with hepatitis, and one (0.1%) with aseptic meningitis. Seizures occurred in 26 (1.8%) participants (Table 4). Among the 11 pregnant women with laboratory evidence of DENV infection reported through SEDSS, seven (63.6%) had warning signs with no progression to severe dengue, and four (36.4%) had signs of severe dengue. Nine (81.2%) pregnant women were hospitalized.

Chikungunya Patient Characteristics and Symptoms

Among 2,293 confirmed or probable chikungunya cases reported to SEDSS, 1,884 (82.2%) were reported in 2014 (Figure 1) (Supplementary Table 2, https://stacks.cdc.gov/view/cdc/153721 ). Most participants (1,954 [85.2%]) visited SEDSS sites within 3 days of symptom onset (Table 3). A majority of participants were female (1,198 [52.2%]), and among the 450 women of childbearing age, 63 (14.0%) were pregnant. The plurality of cases with laboratory evidence of CHIKV infection were among participants aged ≥50 years (545 [23.8%]), followed by those aged 10–19 years (426 [18.6%]), those aged 1–4 years (309 [13.5%]), and those aged 20–29 years (281 [12.3%]). Most participants (1,923 [83.9%]) were discharged after the initial visit, whereas 337 (14.7%) were either admitted or transferred; three (0.1%) participants died. The most common comorbidities were hypertension (377 [16.4%]), asthma (354 [15.4%]), and diabetes (226 [9.9%]). Before laboratory testing, 345 (15.0%) participants received a clinical diagnosis of chikungunya by a physician after triage, 229 (10.0%) with a respiratory infection, and 1,297 (56.6%) with an unspecified infection. Among participants with CHIKV infection, 91 (4.0%) were coinfected with a respiratory virus, including 44 with IAV or IBV.

In addition to fever, (2,271 [99.0%]) and chills (1,668 [72.7%]), the most reported symptoms among the 2,293 participants with laboratory evidence of CHIKV infection were myalgia (1,726 [76.5%]), arthralgia (1,726 [75.3%]), and headache (1,664 [72.6%]) ( Table 5 ) (Supplementary Figure 7, https://stacks.cdc.gov/view/cdc/153721 ). The proportion of participants reporting headache, myalgia, and arthralgia consistently increased with age (p≤0.027); however, young children might be less likely to self-report certain of these symptoms.

Zika Patient Characteristics and Symptoms

Among 1,918 confirmed or probable Zika cases, 1,612 (84.0%) were reported to SEDSS in 2016 (Figure 1) (Supplementary Table 2, https://stacks.cdc.gov/view/cdc/153721 ). Most participants (1,467 [76.5%]) visited SEDSS sites within 3 days of symptom onset (Table 3). A larger proportion of participants with Zika were female (57.7%) versus participants with dengue (46.6%) (p<0.001), and approximately half of visits by women with ZIKV infection who enrolled in SEDSS (544 [49.1%]) were of childbearing age; 77 (14.2%) were pregnant. The plurality of participants with laboratory evidence of ZIKV infection were aged ≥50 years (456 [23.8%]), followed by those aged 20–29 years (370 [19.3%]), 10–19 years (337 [17.6%]), and 30–39 years (261 [13.6%]). Most participants (1,770 [92.3%]) were discharged after the initial visit, whereas 117 (6.1%) were either admitted or transferred; one participant died. The most common comorbidities were hypertension (374 [19.5%]), asthma (341 [17.8%]), and diabetes (224 [11.7%]). Before laboratory testing, 82 (4.3%) participants received a clinical diagnosis of Zika, 131 (6.8%) with a respiratory infection, and 1,231 (64.2%) with an unspecified infection. A total of 152 (7.9%) participants with ZIKV infection were coinfected with respiratory viruses, 82 of whom had IAV or IBV.

In addition to fever and chills, the most reported common symptoms among the 1,918 participants with laboratory evidence of ZIKV infection were headache (1,493 [77.8%]), arthralgia (1,451 [75.7%]), and myalgia (1,405 [73.3%]). A total of 1,411 (73.6%) participants reported respiratory illness (e.g., nasal discharge, sore throat, and cough), and 1,089 (56.8%) reported gastrointestinal symptoms. The proportion of participants reporting symptoms such as myalgia, arthralgia, and headache consistently increased with age (p≤0.002) ( Table 6 ).

Respiratory Virus Patient Characteristics

Most confirmed respiratory virus cases were attributed to IAV (3,756), followed by SARS-CoV-2 (1,586), HAdV (1,550), RSV (1,489), IBV (1,430), HPIV-3 (993), HMPV (862), and HPIV-1 (407) ( Table 7 ) (Figure 2) (Supplementary Table 3, https://stacks.cdc.gov/view/cdc/153721 ). A total of 1,842 participants with AFIs were tested for any of the HCoVs and 46 (2.5%) were infected, the majority of these cases were reported in 2012 and 2013 (41 [89.1%]) (Supplementary Figure 5, https://stacks.cdc.gov/view/cdc/153721 ). Among 11,922 participants testing positive for any of the respiratory viruses examined herein, 5,919 (49.7%) received a diagnosis of any respiratory virus before laboratory testing, whereas the remaining participants had AFI diagnosed that was attributed to other causes. The age distribution varied by virus identified. A plurality of cases with confirmed IAV or IBV infections were among participants aged 10–19 years (1,036 [20.0%]) followed by those aged 5–9 years (960 [18.5%]). Conversely, detection of RSV, HAdV, HPIV-1, HPIV-3, and HMPV was most frequent among those aged 1–4 years (758 [50.9%], 729 [47.0%], 222 [54.5%], 483 [48.6%], and 333 [38.6%]), respectively). RSV was the most frequent virus among infants aged <1 year (289 [19.4%]), whereas SARS-CoV-2 was most frequent among adults aged ≥50 years (36.4%). Most participants were discharged after triage; however, 367 (24.6%) of all participants with confirmed RSV infection were admitted or transferred. Nineteen participants with acute respiratory virus infections died; 12 were positive for SARS-CoV-2. The most common comorbidity across all participants with respiratory virus infections was asthma.

Initially designed for enhanced dengue surveillance, SEDSS has evolved into a valuable and nimble AFI surveillance system, providing insights into the early epidemiology of various emerging pathogens, including CHIKV, ZIKV, and SARS-CoV-2, while also monitoring trends in influenza and other respiratory viruses during the surveillance period. The system’s flexibility allowed for the rapid setup of studies to understand new viruses and support the development of public health guidelines, exemplified by the successful implementation of a study to evaluate the duration of ZIKV RNA in body fluids ( 26 ) as well as the evaluation of rapid, point-of-care testing for SARS-CoV-2 detection and an IgM assay to distinguish between DENV and ZIKV infections ( 27 , 28 ). Other studies leveraged SEDSS to examine epidemiologic, clinical, and spatiotemporal patterns of Zika, chikungunya, leptospirosis, and COVID-19 in Puerto Rico ( 29 – 32 ).

In contrast to the limitations of passive surveillance (e.g., underreporting and delayed case identification), SEDSS facilitated real-time detection and collection of detailed information about participants affected by arboviruses and respiratory viruses. This adaptability highlights the value of SEDSS as a surveillance tool for novel infectious threats, addressing the limitations associated with relying solely on passive surveillance. The expansion of SEDSS’s scope allowed for the documentation of temporal variations in both endemic arboviruses and respiratory viruses, providing a more comprehensive understanding of disease dynamics. Furthermore, this analysis assessed disease severity, including the proportion of participants with warning signs and those requiring hospitalization, aiding in clinical care evaluation. These data are useful in evaluating the health care system’s response to these diseases, offering insights that can guide future interventions, research gaps, and clinical care guidelines.

Among the three arboviruses, the chikungunya epidemic in 2014 recorded the highest number of participants with confirmed disease reported through SEDSS (2,293 cases). This observation aligns with observations from other regions in the Western Hemisphere that similarly experienced intense periods of CHIKV transmission among immunologically naïve populations in 2014 ( 33 ). Chikungunya typically has a higher symptomatic attack rate than Zika, resulting in a larger number of reported cases compared with other arboviruses, which might contribute to observed differences in case numbers between chikungunya and Zika ( 34 , 35 ). ZIKV was the second most reported arbovirus in SEDSS, with 1,918 cases reported. The first Zika case reported through SEDSS in January 2016 followed the first cases reported islandwide in December 2015. ZIKV transmission slowed after the first quarter of 2017, with the last confirmed case reported in April 2018 and low numbers of probable cases reported through 2019. The presence of persistent ZIKV IgM antibodies in these cases might not necessarily indicate recent infection because ZIKV IgM antibodies can persist for an extended period after the acute phase of infection, complicating the interpretation of serologic results ( 36 ). Cross-reactivity with DENV antibodies further challenges precise diagnosis. Since 2019, patients among all locally acquired Zika cases in U.S. territories had Zika diagnosed by antibody testing (probable cases), which cannot distinguish recent from past infections. Although the total number of dengue cases reported through SEDSS was lower, the most recent dengue outbreak persisted for >2 years. The lower transmission intensity of dengue compared with chikungunya and Zika likely reflects a certain degree of population immunity from previous DENV infections during the outbreak periods. No confirmed dengue cases were reported through SEDSS in 2017 and 2018, the years immediately following the Zika epidemic. This observation comports with a stochastic compartmental model trained on surveillance data from Colombia and Brazil (accounting for combinations of enhancement or cross-protection) that supports cross-protection against dengue for 2.2–3.5 years after a Zika outbreak ( 37 ) and precedes dengue resurgence. Insights from studies in Thailand and Nicaragua suggest that contrary to a 2-year waning period, cross-reactive binding antibodies linked to protection or enhancement reach a stable setpoint approximately 8 months after primary infection and persist for many years afterward ( 38 , 39 ). Although cross-protection provides a partial explanation, other factors (e.g., public health interventions such as mosquito control programs, educational campaigns, and vector surveillance) could have been intensified in response to the Zika outbreak, potentially contributing to the decrease in DENV transmission.

Most participants affected by any of the three arboviruses were aged 5–50 years, but disproportionately more participants aged ≥50 years had Zika or chikungunya compared with the age distribution of the overall SEDSS population. Relatively few cases among infants aged <1 year were reported through SEDSS with any of the three arboviruses, but more cases among infants were reported with laboratory evidence of chikungunya infection (4.7% of the overall population) compared with dengue and Zika (2.0% and 1.7% of the overall population, respectively). This observation might reflect the possible higher morbidity including cutaneous alterations and arthralgia or arthritis associated with chikungunya infection in infancy ( 40 , 41 ) compared with the low relative morbidity associated with primary dengue or Zika infections ( 42 ). Twenty-seven percent of participants with dengue progressed to severe dengue. However, only 10.1% of children aged 1–4 years had severe dengue, which could reflect lower likelihood of experiencing antibody-dependent enhancement because of infection from other serotypes during previous outbreaks ( 43 , 44 ).

Fewer pregnant women were reported through SEDSS with evidence of dengue infection (4.6%) compared with Zika (14.2%) or chikungunya (14.0%). The higher proportion of pregnant women reported through SEDSS with evidence of confirmed or probable ZIKV infection could be because of increased health care-seeking behavior by pregnant women during the Zika epidemic ( 45 ).

The highest proportion of participants testing positive for any arbovirus was observed among residents in southeast Puerto Rico, particularly in Guayama. Urbanization and population density are associated with Aedes aegypti abundance, driven by favorable breeding conditions, higher larval development rates, and adult survival times, especially in rapidly urbanizing areas with unplanned settlements ( 46 , 47 ). Previous research has confirmed high mosquito populations in southern Puerto Rico ( 48 , 49 ). Abandoned and inhabited houses in lower socioeconomic neighborhoods in southern Puerto Rico contribute to Ae. aegypti pupal productivity, emphasizing the need for targeted vector control strategies in these neighborhoods ( 49 ).

These findings highlight challenges and gaps in arboviral disease management with a focus on dengue. First, many participants with confirmed dengue, Zika, and chikungunya were initially misdiagnosed with other diseases (e.g., respiratory illnesses) by ED physicians. Obtaining an accurate diagnosis based on clinical presentation alone is challenging, as demonstrated by systemic reviews of the accuracy of clinical definitions of dengue ( 50 , 51 ). Certain symptoms (e.g., headache) increased with age for dengue and Zika cases, and these findings were consistent with another SEDSS study that focused on children; however young children might be less likely to vocalize these symptoms ( 12 ). Another study using SEDSS data also reported overlapping symptoms between dengue and chikungunya, but patients receiving a diagnosis of chikungunya were more likely to report arthritis, skin rash, and irritability, and less likely to have signs of poor circulation, diarrhea, headache, and cough ( 52 ). Age-related symptom variations and frequent coinfections with respiratory viruses (e.g., IAV, IBV, and HAdV) highlight the complexity of arboviral infections and the necessity for precise diagnostic approaches that consider multiple pathogens for timely and accurate diagnoses ( 8 , 12 ).

Second, 37% of all participants with a dengue diagnosis who had warning signs and 84% of those with severe dengue diagnosed were hospitalized. The most recent guidelines recommend hospitalization for suspected patients with dengue and having warning signs or severe dengue ( 53 ). Among participants with warning signs or severe dengue who were not hospitalized, 17.6% received a correct initial dengue diagnosis. Taken together, these findings highlight the need for ongoing training for physicians on dengue clinical management guidelines and the need for more rapid detection of dengue. Moreover, these findings also underscore the potential strain on the health care system when a substantial proportion of patients necessitate hospitalization. SEDSS plays a pivotal role in enabling precise disease diagnosis and addressing the challenge of misclassification ( 29 , 54 ); however, results are still not prompt enough to guide clinical decision making at the bedside. Implementation of rapid diagnostic testing for dengue, currently unavailable in the United States or its territories, could expedite the identification of patients requiring hospitalization and address gaps in clinical care.

SEDSS continues to be used to monitor endemic arboviruses in Puerto Rico and acts as a sentinel for emerging pathogens which initially might be missed by clinical diagnosis. Approximately 545 recognized arboviruses exist worldwide, although estimates suggest this figure might represent less than 1% of all arboviruses because most are zoonotic infections among hosts other than humans ( 55 – 57 ). Among the recognized arboviruses, approximately 150 have been documented to cause human disease ( 55 ). This observation highlights the importance of robust surveillance systems like SEDSS, which are essential for timely identification and monitoring of emerging infectious threats that might otherwise go undetected.

Distinct seasonality in the circulation of respiratory viruses was observed, consistent with findings documented in the literature on virus-virus interactions and their effect on disease dynamics ( 58 – 60 ). A related study using SEDSS found distinct seasonal patterns in Puerto Rico, with respiratory viruses peaking in fall and winter, while arboviruses (e.g., dengue) peaked in summer and early fall, emphasizing the importance of recognizing these seasonal trends for accurate diagnosis and public health interventions in pediatric patients with AFI ( 10 ). Viral interference, a phenomenon highlighted in previous research, plays a role in shaping the observed patterns ( 61 , 62 ). At the population level, viral interference might be induced when an outbreak caused by one virus hastens or delays an epidemic caused by another virus ( 58 , 60 ). These results indicate that the seasonality of IAV typically precedes that of IBV each year, consistent with documented interactions between influenza types and subtypes that might involve cross-immunity mechanisms ( 63 , 64 ). Another study using SEDSS data analyzed influenza trends in Puerto Rico during 2012–2018, illustrated that influenza seasonality in the region differed from that in the continental United States, with irregular and asynchronous epidemics initially but increased synchrony in recent years ( 54 ). The study suggests that factors beyond climate, such as travel and viral introductions, might contribute to the observed changes in influenza dynamics in Puerto Rico.

In addition, the strong seasonality observed for RSV reflects patterns observed in various regions, with increasing RSV epidemics over the years, particularly among children ( 65 ). The findings from this report revealed a high proportion of acute respiratory viral cases among children aged <5 years, including RSV, HPIV-3, HPIV-1, HAdV, and HMPV. Children, particularly those aged <5 years, have increased susceptibility to viral infections compared with adults, possibly because of higher contact frequencies with peers in school and child care settings, naïve immune systems, limited previous exposure, and a greater likelihood of medical care-seeking by parents ( 60 , 66 ).

From March 2020 to April 2021, nearly all respiratory viral infections identified were SARS-CoV-2, demonstrating its high transmissibility compared with other respiratory pathogens ( 67 , 68 ). The COVID-19 pandemic considerably altered RSV seasonality, with atypical transmission patterns observed in mid-2021 and during September–November 2022 ( 69 ). These trends in Puerto Rico align with those in the continental United States ( 69 ). Findings from this report align with recent research on the impact of the emergence of SARS-CoV-2, which led to a substantial reduction in the circulation of other acute respiratory viruses ( 70 ). Previous analyses conducted using data from SEDSS during the 2019–2020 respiratory virus season revealed a considerable reduction in the test positivity of IAV, IBV, RSV, HAdV, and other respiratory viruses following the implementation of COVID-19 stay-at-home orders ( 71 ). The reductions in test positivity persisted even after the initial impact of COVID-19 mitigation measures, indicating a sustained effect on the transmission of respiratory infections. This reduction is attributed to a combination of changes in human interactions, nonpharmaceutical interventions, reduced testing of seasonal respiratory viruses, and potential viral interferences ( 70 ).

The results presented in this study should be interpreted in the context of external factors that could influence disease dynamics. Puerto Rico has been increasingly vulnerable to climate change, characterized by more frequent and severe hurricanes. Extreme weather events, such as hurricanes, can disrupt health care infrastructure and disease surveillance efforts. The erosion of infrastructure during severe storms might have heightened the occurrence of certain diseases and led to population movements, potentially affecting population immunity. Severe storms might increase the number of mosquitoes by filling containers with rainwater, increasing the edge surface of groundwater habitats, and generating additional container aquatic habitats in destroyed or abandoned properties. This increase in aquatic habitats was observed after Hurricanes Irma and Maria in Caguas, where adult female Ae. aegypti doubled in numbers after the hurricanes, possibly because of an increase in the number of containers holding water, even in years with similar rainfall ( 72 ). The impact of these climatic disruptions, natural disasters, and population dynamics on disease patterns in Puerto Rico needs further investigation. In addition, climate change can alter the distribution and behavior of disease vectors, potentially affecting the geographic range of arboviral diseases ( 73 ).

The findings in this report are subject to at least six limitations. First, SEDSS was established at certain sentinel sites based on historically high dengue incidence. Therefore, these results might not be reflective of all of Puerto Rico. The results included in this report were derived principally from sentinel sites in southern Puerto Rico as well as the San Juan metro area; the geographic distribution of participant residences are skewed toward these regions. Second, the symptoms in the SEDSS clinic intake and follow-up forms were based on participant self-report and, in certain instances, were not sufficient to differentiate between dengue warning signs and signs of severe dengue. For example, SEDSS intake forms could capture self-reported mucosal bleeding (e.g., nose and gum bleeding, gastrointestinal bleeding, and excessive vaginal bleeding), but these self-reports could not clinically distinguish severe bleeding from the gastrointestinal tract (e.g., hematemesis and melena) or vagina (e.g., menorrhagia) as defined by the requirement for medical intervention, including intravenous fluid resuscitation or blood transfusion ( 74 ). Inpatient data, where available, were merged with the SEDSS data and enabled further dengue severity differentiation. Third, differentiating between dengue and Zika presented challenges after Zika emerged because probable dengue diagnosis relied on IgM tests for DENV with negative results for ZIKV and vice versa for probable Zika diagnosis because of cross-reactivity between dengue and Zika IgM antibodies in serologic tests. Fourth, SEDSS is a convenience sample, and recruited cases represent a fraction of total eligible patients (Supplementary Table 1, https://stacks.cdc.gov/view/cdc/153721 ). Fifth, the subjective nature of some self-reported symptoms (e.g., restlessness and abdominal pain) might have contributed to over-reporting of dengue warning signs, while health care provider-only warning signs (e.g., abdominal tenderness, liver enlargement, or substantial changes in hematocrit or platelet counts over two measurements) could have been missed. Subsequent iterations of intake and follow-up forms will address this issue in current and future years. Finally, SEDSS, while offering real-time and detailed information, presents challenges because of its labor-intensive nature and higher costs compared with passive surveillance methods, posing resource and infrastructure demands that might be challenging for implementation in various countries.

In addition to contributing to research and public health efforts, SEDSS also provides a valuable system for piloting health care provider diagnostic support tools. The data in this report guide evidence-based strategies for preventing and controlling arboviral diseases and emerging pathogens with global relevance beyond Puerto Rico. Puerto Rico’s experience with febrile illness surveillance provides a model for similar applications in other areas where Ae. aegypti is prevalent. This is particularly relevant considering the potential of changes in climate and weather, which could lead to rising global temperatures and expand the geographic range of disease vectors ( 75 ). Leveraging the lessons from SEDSS, an opportunity to enhance health care system resilience by improving diagnostic capabilities, increasing surge capacity, and ensuring the stockpiling of essential medical supplies exists. SEDSS has the potential to integrate into global surveillance networks, strengthening international collaboration for early detection and response to emerging infectious diseases. Expansion of SEDSS to additional sentinel sites can supplement and enhance information provided through existing passive reporting mechanisms and improve the geographic representation of this active surveillance system.

SEDSS is uniquely positioned to provide a source population for future real-world effectiveness studies of novel vaccines for arboviral diseases. These vaccines might include vaccines like the live-attenuated, single-dose VLA1553 for chikungunya ( 76 ) and dengue antivirals (e.g., JNJ-1802) ( 77 ). Data analytics, modeling, and machine learning could be applied to SEDSS data to help identify disease trends, predict outbreaks, and optimize resource allocation for public health responses. SEDSS data might provide a quantitative measure of effectiveness for vector control strategies (e.g., novel insecticides and genetically modified mosquitoes) derived from observed case counts before and after intervention implementation. Prioritizing capacity building and training for local health care providers, researchers, and public health personnel is essential to enhance expertise in disease surveillance and management, ultimately improving responses to future outbreaks both in Puerto Rico and elsewhere.

SEDSS enables in-depth patient tracking and follow-up to identify common and emerging arboviral and respiratory viruses causing AFI. SEDSS also facilitates understanding the temporal patterns of these viruses, potential interactions between them, and the populations most at risk for illness. In addition, SEDSS proved adaptable in detecting and collecting detailed information on participants affected by emerging arboviruses in Puerto Rico (e.g., CHIKV and ZIKV) and numerous respiratory viruses, including SARS-CoV-2. SEDSS serves as a versatile model for effective disease surveillance, offering valuable insights applicable beyond the context of Puerto Rico in the dynamic field of infectious disease monitoring.

Nicole P. Lindsey, J. Erin Staples, National Center for Emerging and Zoonotic Infectious Diseases, CDC.

Corresponding author: Zachary J. Madewell, PhD, Division of Vector-Borne Diseases, CDC, Telephone: 787-706-2399; Email: [email protected] .

1 Division of Vector-Borne Diseases, CDC, San Juan, Puerto Rico; 2 Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico; 3 Auxilio Mutuo Hospital, San Juan, Puerto Rico

Conflicts of Interest

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

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Abbreviations: DENV = dengue virus; CHIKV = chikungunya virus; ZIKV = Zika virus. * Sources: 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 Jun 14;68:1-10. CDC. Arboviral diseases, neuroinvasive and non-neuroinvasive 2015 case definition [Internet]. Atlanta, GA: US Department of Health and Human Services, CDC; 2021. https://ndc.services.cdc.gov/case-definitions/arboviral-diseases-neuroinvasive-and-non-neuroinvasive-2015

* Sex was not recorded for seven visits. † Among persons with available body mass index, n = 15,191 males, n = 17,501 females, and N = 32,698 total persons.

FIGURE 1 . Confirmed or probable dengue, chikungunya, and Zika virus cases, by year — Sentinel Enhanced Dengue Surveillance System, Puerto Rico, May 2012–December 2022*

* Cases were deemed to be laboratory-confirmed if a serum or urine specimen was polymerase chain reaction– or immunoglobulin M–positive for a particular arbovirus.

FIGURE 2 . Acute respiratory virus cases, by year — Sentinel Enhanced Dengue Surveillance System, Puerto Rico, May 2012–December 2022*

* Respiratory viruses were identified and confirmed by reverse transcription–polymerase chain reaction testing of nasopharyngeal swabs.

FIGURE 3 . Number and proportion of acute febrile illness cases with participants testing positive for any arbovirus, by municipality — Sentinel Enhanced Dengue Surveillance System, Puerto Rico, 2012–2022* ,†

Abbreviation: SEDSS = Sentinel Enhanced Dengue Surveillance System.

* Arboviruses included dengue, chikungunya, and Zika viruses; the number of tests for any arbovirus in each municipality is shown.

† The proportion of acute febrile illness cases testing positive for arboviruses is divided into intervals of equal size (5%).

FIGURE 4 . Confirmed dengue cases, by serotype and year — Sentinel Enhanced Dengue Surveillance System, Puerto Rico, May 2012 – December 2022*

* Dengue cases were assigned a serotype if a participant’s serum specimen was polymerase chain reaction–positive for a specific dengue virus serotype.

FIGURE 5 . Number and proportion of acute febrile illness cases with participants testing positive for any acute respiratory virus, by municipality — Sentinel Enhanced Dengue Surveillance System, Puerto Rico, 2012–2022* ,†

* Respiratory viruses included influenza A and B, respiratory syncytial virus, human adenovirus, human metapneumovirus, human parainfluenza viruses 1 and 3, human coronavirus, and SARS-CoV-2; the number of tests for any arbovirus in each municipality is shown.

† The proportion of acute febrile illness cases testing positive for respiratory viruses is divided into intervals of equal size (5%).

Abbreviations: DENV = dengue virus; IgM = immunoglobulin M; ZIKV = Zika virus. * Confirmed infection for the three arboviruses was by positive reverse transcription-polymerase chain reaction results. Before Zika, probable dengue included positive IgM tests. After Zika emerged, probable dengue included IgM positivity for DENV along with negative IgM results for ZIKV because of notable cross-reactivity between dengue IgM and Zika IgM antibodies in serologic tests. Probable Zika included IgM positivity for ZIKV along with negative IgM results for DENV. Excludes unspecified flavivirus infections. † Respiratory infections include pneumonia, upper respiratory tract infections, bronchitis, bronchiolitis, respiratory syncytial virus, and COVID-19. § Infections not otherwise specified include urinary tract infections, gastroenteritis, pharyngitis, fever unspecified, viral syndrome, tonsillitis, otitis media, sinusitis, impetigo, cellulitis, infected wound, lymphadenopathy cervical, herpangina, febrile seizure, meningitis, sepsis, bacteremia, encephalitis, pancreatitis, myositis, conjunctivitis, myocarditis, Guillain-Barré syndrome, mononucleosis, and pyelonephritis. ¶ Among persons with available body mass index: dengue (n = 581), Zika (n = 1,893), and chikungunya (n = 962). ** Denominators for these analyses include visits from women of childbearing age defined as any female aged 15–44 years. †† Respiratory virus coinfections included adenovirus, human parainfluenza virus (types 1 and 3), influenza virus (types A and B), respiratory syncytial virus (types A and B), human metapneumovirus, human coronavirus (HcoV-229E, HcoV-HKU1, HcoV-NL63, and HcoV-OC43), and SARS-CoV-2.

FIGURE 6 . Number and proportion of dengue cases, by participant age group without warning signs, with warning signs without progressing to severe dengue, and severe dengue — Sentinel Enhanced Dengue Surveillance System, Puerto Rico, 2012–2022

Abbreviation: bpm = beats per minute. * Fever defined as either fever during the visit or in past 7 days † Tachypnea is an age-specific variable defined by respiratory rate (breaths per minute). Persons aged 0–3 months: >60 breaths per minute; persons aged 4–6 months: >45 breaths per minute; persons aged 7–12 months: >40 breaths per minute; persons aged 13 months–3 years: >30 breaths per minute; persons aged 4–6 years: >25 breaths per minute; persons aged 7–12 years: >22 breaths per minute; and persons aged >13 years: >18 breaths per minute. § Clinical fluid accumulation included pleural effusion, ascites, peritoneal fluid, pericardial effusion, free fluid, and swollen hands. ¶ Mucosal bleeding defined as bleeding from gums or nose, vaginal bleeding, or hematuria. ** Restlessness defined as nervousness, agitation, irritability, or disorientation. †† Severe plasma leakage defined as respiratory distress and plasma leakage. Respiratory compromise defined as tachypnea, respiratory distress, accessory muscles use, supplemental oxygen, or intubation. Plasma leakage defined as pleural effusion, pericardial effusion, ascites, free fluid in abdomen, hematocrit change >20% during illness, hematocrit value >20% above baseline for age and sex at any time, or albumin low for age. §§ Hemoconcentration defined as hematocrit change ≥20% during illness or hematocrit value ≥20% above baseline for age and sex at any time. Baseline values (females and males): 0–7 days: <61.2; 8–29 days: <52.8; 30–59 days: <42; 60 days – <3 years: <43.2; 3 – <6 years: <44; 6 – <9 years: <45.6; 9 – <12 years: <46.8; Males: 12 – <15 years: <50.4; 15 – <50 years: <54; 50 – <60 years: <52.8; ≥60 years: <51.6; Females: 12 – <15 years: <48; 15 – <50 years: 46.8; >50 years: <48. ¶¶ Low albumin defined based on age-specific criteria. If albumin level falls below the specified cut-off values (g/dL) by age: 0–15 days: <3.0; 15 days–1 year: <2.2; >1–15 years: <3.6; 16–18 years: <3.9; ≥19 years: <3.2. *** Shock is defined as 1) shock listed in medical assessment at any time; 2) use of vasopressors, inotropes, or vasodilators, or albumin; 3) pulse pressure <20 mmHg or hypotension or drop in systolic blood pressure >40 mmHg and any two of the following: elevated heart rate, capillary refill >2 seconds, mottled skin, thready, weak pulse, pale or cold skin, blue skin or lips, cyanotic limbs, or cold limbs. Source: Paz-Bailey G, Sánchez-González L, Torres-Velasquez B, et al. Predominance of severe plasma leakage in pediatric patients with severe dengue in Puerto Rico. J Infect Dis 2022;226:1949–58. ††† For persons aged ≥10 years, hypotension is defined as systolic blood pressure of <90 mmHg or mean arterial pressure <70 mmHg. Hypotension in children aged <10 years defined as systolic blood pressure of <70 + (age in years x 2) mmHg. §§§ Tachycardia is an age-specific variable that might be an indicator of hypovolemia and dengue severity when combined with indicators of plasma leakage. A participant was defined as tachycardic at the following age-specific variables, according to Nelson’s Essentials of Pediatrics (2002): <1 day: >154 bpm; 1–2 days: >159 bpm; 3–6 days: >166 bpm; 1–3 weeks: >182 bpm; 1–2 months: >179 bpm; 3–5 months: >186 bpm; 6–11 months: >169 bpm; 1–2 years: >151 bpm; 3–4 years: >137 bpm; 5–7 years: >133 bpm; 8–11 years: >130 bpm; 12–15 years: >119 years; >16 years: >100 bpm.

* Fever defined as either fever during the visit or in the past 7 days.

* Respiratory syncytial virus includes subtypes A and B. † Human coronavirus includes types 229E, OC43, NL63, and HKU1. § Respiratory infections include pneumonia, upper respiratory tract infections, bronchitis, bronchiolitis, respiratory syncytial virus, and COVID-19. ¶ Infections not otherwise specified include urinary tract infections, gastroenteritis, pharyngitis, fever unspecified, viral syndrome, tonsillitis, otitis media, sinusitis, impetigo, cellulitis, infected wound, lymphadenopathy cervical, herpangina, febrile seizure, meningitis, sepsis, bacteremia, encephalitis, pancreatitis, myositis, conjunctivitis, myocarditis, Guillain-Barré syndrome, mononucleosis, and pyelonephritis. ** Among persons with available body mass index. Influenza A (n = 2,917), influenza B (n = 1,430), respiratory syncytial virus (n = 1,167), adenovirus (n = 1,037), human parainfluenza virus 1 (n = 282), human parainfluenza virus 3 (n = 780), human metapneumovirus (n = 651), human coronavirus (n = 17), and SARS-CoV-2 (n = 1,437). †† Denominators for these analyses include visits from women of childbearing age defined as any female aged 15–44 years.

Suggested citation for this article: Madewell ZJ, Hernandez-Romieu AC, Wong JM, et al. Sentinel Enhanced Dengue Surveillance System — Puerto Rico, 2012–2022. MMWR Surveill Summ 2024;73(No. SS-3):1–29. DOI: http://dx.doi.org/10.15585/mmwr.ss7303a1 .

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Maxillary Osteomyelitis Post-Dengue: A Rare Clinical Phenomenon

  • CASE REPORT
  • Published: 27 May 2024

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presentation in dengue

  • Shallu Bansal   ORCID: orcid.org/0000-0002-3316-9174 1 ,
  • Abhishek Singh Tanwar 1 ,
  • Namrata Chitaliya 1 &
  • Meenal Verma 2  

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Maxillary osteomyelitis following dengue infection, unaccompanied by additional comorbidities, is a rare but significant clinical entity. We present the first documented case of such a condition in a 22-year-old male who, following recovery from dengue, presented with loose teeth, difficulty chewing, and pus discharge from the upper front jaw area. A comprehensive diagnostic approach, including detailed medical and dental history, clinical examination, radiographic assessment, and incisional biopsy, confirmed the diagnosis of maxillary osteomyelitis. Surgical intervention comprising sequestrectomy and debridement was done under general anaesthesia with histopathological reconfirmation of osteomyelitis. Subsequent provision of a prosthesis facilitated functional and aesthetic restoration for the patient. A 2-year follow-up revealed no recurrence of disease, underscoring the efficacy of the management approach. This case highlights the importance of recognizing uncommon presentations of osteomyelitis post-dengue, enabling timely intervention and favourable outcomes. Such cases serve as valuable learning experiences, emphasizing the necessity of vigilance in diagnosing and managing rare clinical conditions to optimize patient care.

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Department of Oral and Maxillofacial Surgery, Geetanjali Dental and Research Institute, Udaipur, Rajasthan, India

Shallu Bansal, Abhishek Singh Tanwar & Namrata Chitaliya

Department of Oral Pathology and Microbiology, Geetanjali Dental and Research Institute, Udaipur, Rajasthan, India

Meenal Verma

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Bansal, S., Tanwar, A.S., Chitaliya, N. et al. Maxillary Osteomyelitis Post-Dengue: A Rare Clinical Phenomenon. J. Maxillofac. Oral Surg. (2024). https://doi.org/10.1007/s12663-024-02199-0

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Received : 21 February 2024

Accepted : 30 April 2024

Published : 27 May 2024

DOI : https://doi.org/10.1007/s12663-024-02199-0

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presentation in dengue

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https://www.barrons.com/news/spanish/dengue-causa-al-menos-35-muertes-en-centroamerica-en-2024-9f86879b

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Dengue Causa Al Menos 35 Muertes En Centroamérica En 2024

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Un trabajador del Ministerio de Salud de Guatemala fumiga contra el mosquito Aedes aegypti aulas de una escuela de la capital, el 24 de mayo de 2024

Al menos 35 personas han muerto en Centroamérica en lo que va de año a causa del dengue, por lo que varios países de la región declararon el estado de emergencia, informaron este viernes autoridades de Salud locales.

Guatemala es el país de Centroamérica más afectado con 12 muertos y de 18.256 casos registrados desde principio de año, lo que quintuplica el número reportado en el mismo periodo de 2023 (3.189 casos). Más de la mitad de enfermos son menores de 15 años.

En Honduras, las autoridades registran 16.400 casos y 11 muertos en 2024, lo que llevó al Gobierno a declarar el estado de "alerta máxima". Mientras que en Panamá, el Ministerio de Salud informó este viernes de 4.479 casos y 12 fallecidos.

El virus del dengue

Las autoridades de Costa Rica, El Salvador y Nicaragua no reportan muertes hasta ahora, pero los casos se cuentan por miles.

Ante la ola de casos, las autoridades realizan fumigaciones masivas en varias poblaciones de esos países para erradicar el mosquito "Aedes aegypti", transmisor de la enfermedad.

En Guatemala, el pasado 30 de abril, el Gobierno del presidente Bernardo Arévalo declaró la emergencia sanitaria nacional ante el aumento de casos de dengue.

Según la Organización Panamericana de la Salud (OPS), América Latina y el Caribe vivirán probablemente su "peor temporada de dengue" este año, favorecida por la combinación del fenómeno El Niño y el cambio climático.

El dengue es una enfermedad endémica de zonas tropicales que provoca fiebres altas, dolores de cabeza, náuseas, vómitos, dolor muscular y, en los casos más graves, hemorragias que pueden causar la muerte.

La Organización Mundial de la Salud (OMS) advirtió en abril de 2023 que el dengue y otras enfermedades transmitidas por mosquitos se propagan mucho más y más lejos de sus zonas habituales por efecto del cambio climático.

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IMAGES

  1. Dengue Ppt(1)

    presentation in dengue

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    presentation in dengue

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    presentation in dengue

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    presentation in dengue

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    presentation in dengue

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    presentation in dengue

VIDEO

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COMMENTS

  1. Dengue virus infection: Clinical manifestations and diagnosis

    Dengue virus infection. Picture 2. 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.

  2. Dengue fever

    Dengue (DENG-gey) fever is a mosquito-borne illness that occurs in tropical and subtropical areas of the world. Mild dengue fever causes a high fever and flu-like symptoms. The severe form of dengue fever, also called dengue hemorrhagic fever, can cause serious bleeding, a sudden drop in blood pressure (shock) and death.

  3. Clinical Features of Dengue

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  4. Dengue and severe dengue

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  5. Dengue Clinical Presentation: History, Physical Examination

    Patients with dengue will have a history of living in, or recent travel to, a region where the disease is endemic. The incubation period is 3-14 days (average, 4-7 days); symptoms that begin more than 2 weeks after a person departs from an endemic area probably are not due to dengue. Many patients experience a prodrome of chills, erythematous ...

  6. Dengue Fever: Causes, Symptoms & Treatment

    Severe dengue is a life-threatening worsening of dengue symptoms. Warning signs of severe dengue are usually seen 24 to 48 hours after your fever goes away. Severe dengue is a medical emergency that can be fatal. If you have dengue or live in an area where dengue is common, go to the nearest ER immediately if you experience any of these symptoms:

  7. Dengue- Global situation

    Dengue cases have increased in the Americas over the past four decades, from 1.5 million cases from 1980 to 1989 to 17.5 million in 2010-2019. Before 2023, the highest historical dengue caseload was in 2019, with over 3.18 million cases, 28 208 severe cases, and 1823 deaths (CFR 0.06).

  8. Dengue Fever

    Dengue is a mosquito-transmitted virus and is the leading cause of arthropod-borne viral disease worldwide, posing a significant global health concern. This disease is also known by various monikers, such as breakbone or 7-day fever, and is characterized by intense muscle spasms, joint pain, and high fever, reflecting both the severity and the duration of symptoms. Although most dengue fever ...

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    Dengue is a dynamic disease ―Presentation can change quickly Monitoring and identification of warning signs and severe criteria are key to classification and management of dengue patients Plasma leakage and progression to severe dengue, usually occurs in the critical phase Shock (not bleeding) is the most common severe dengue

  10. Dengue

    As of 30 April 2024, over 7.6 million dengue cases have been reported to WHO in 2024, including 3.4 million confirmed cases, over 16 000 severe cases, and over 3000 deaths. While a substantial increase in dengue cases has been reported globally in the last five years, this increase has been particularly pronounced in the Region of the Americas, where the number of cases has already exceeded ...

  11. Dengue Hemorrhagic Fever/Dengue Shock Syndrome

    Dengue hemorrhagic fever is a variant presentation of dengue infection that occurs primarily in children < 10 years living in areas where dengue is endemic. Dengue hemorrhagic fever, which has also been called Philippine, Thai, or Southeast Asian hemorrhagic fever, frequently requires prior infection with the dengue virus.

  12. Clinical Presentation and Platelet Profile of Dengue Fever: A

    Abstract. Background: Dengue fever (DF) is a mosquito-borne viral illness carried worldwide by Aedes aegypti and Aedes albopictus mosquitoes. The aim of the present study was to observe the different clinical presentations of dengue fever and the platelet profile analysis in DF patients. Methods: This retrospective study was performed on 130 ...

  13. PDF Dengue Case Management

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  14. PDF DENGUE: EFFECTIVE ACTION FOR TREATMENT AND PREVENTION Pathophysiology

    Dengue infection begins with Aedes mosquito that carries dengue viruses bites human being and introduces dengue viruses throug\൨ skin into the subcutaneous tissues. Dendritic cells and monocytes/macrophages are the 2 major cells response to dengue viruses對 by stimulating both T and B cells. Cytokines are released by T-cells reactions and ...

  15. PDF Dengue: the disease and epidemiology

    Salje et al. Dengue diversity across spatial and temporal scales. Science 2017 Yoon et al. Fine scale spatiotemporal clustering of dengue virus transmission in rural Thai villages. PLoS Negl Trop Dis 2012 Spatial heterogeneity dependent on socioeconomic factors, population density, ecological factors: Kamphaeng Phet, Thailand, school

  16. Knowledge, attitude and practice on dengue prevention and dengue

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  17. FREQUENTLY ASKED QUESTIONS ON DENGUE

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  19. PDF Summary of Key Points WHO Position Paper on Dengue Vaccine, September 2018

    Introduction. This position paper replaces the WHO position paper on dengue vaccines published in 2016. In November 2017, results of a retrospective analysis of data from clinical trials, using a new serological assay, became available. The assay enabled classification of trial participants according to their dengue serostatus prior to receipt ...

  20. Viral characteristics and clinical presentation in dengue co

    This is the first ever study from the state of Odisha exploring the viral characteristics and clinical presentations in dengue co-infection. Among all the cases investigated, 33.6% were dengue positive. A study from Puerto Rico found that 18.6% of the total fever cases are because of dengue. The mean age of dengue cases was 31.52 years and the ...

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  22. DENGUE FEVER.pptx

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  23. Diabetes mellitus as a risk factor for severe dengue fever and West

    We refer to DHF/DSS as "severe clinical presentation of dengue". (2) Applying the WHO 2009 classification criteria for dengue, a severe dengue case is defined as a suspected dengue patient with one or more of the following diseases: (i) severe plasma leakage that leads to shock (dengue shock) and/or fluid accumulation with respiratory ...

  24. Sentinel Enhanced Dengue Surveillance System

    Introduction. Dengue is an acute febrile viral illness transmitted by Aedes spp. mosquitoes and caused by four closely related dengue virus serotypes (DENV 1-4). DENV causes an estimated 390 million infections (1) and 40,500 deaths worldwide each year (2).In contrast to data suggesting that the prevalence of most communicable diseases is declining worldwide, dengue incidence and disease ...

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  26. Dengue fever ppt

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  27. Maxillary Osteomyelitis Post-Dengue: A Rare Clinical Phenomenon

    Maxillary osteomyelitis following dengue infection, unaccompanied by additional comorbidities, is a rare but significant clinical entity. We present the first documented case of such a condition in a 22-year-old male who, following recovery from dengue, presented with loose teeth, difficulty chewing, and pus discharge from the upper front jaw area. A comprehensive diagnostic approach ...

  28. Dengue Causa Al Menos 35 Muertes En Centroamérica En 2024

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