OVERVIEW: What every practitioner needs to know

Are you sure your patient has dengue? What are the typical findings for this disease?

Dengue virus infection in humans causes a wide variety of manifestations, ranging from inapparent infection to nonspecific febrile illness to severe and fatal disease. Symptomatic disease primarily affects patients 4-5 years of age and upward, although infants younger than 1 year may also experience clinical disease. After an incubation period of 4-7 days, symptoms typically follow three phases: an initial febrile phase, a critical phase during which complications may occur, and a spontaneous recovery phase.

Febrile Phase

The febrile phase begins with sudden onset of high fever, often accompanied by headache, malaise, vomiting, facial flushing, severe myalgia, and bone pain. Younger children experience the high fever but are generally less symptomatic than older children or adults. Some children experience gastrointestinal symptoms (diarrhea) or upper respiratory symptoms, and occasionally an evanescent macular rash may be noted. Mild hemorrhagic manifestations, such as skin petechiae or easy bruising, are often present, and some children experience epistaxis and/or gum bleeding. The liver may be palpable but is rarely significantly enlarged at this stage, and jaundice is unusual.

Critical Phase

The febrile phase lasts 3-7 days, and most patients recover without complications at this time. However, in a small proportion of patients signs of a systemic vascular leak syndrome become apparent as the fever settles. Other severe complications may also occur, but are not common in children.

Systemic vascular leak syndrome is the most serious of the complications that occur during the critical phase. It is evidenced by increasing hemoconcentration, hypoproteinemia, pleural effusions, and ascites. If severe, the loss of plasma from the systemic circulation leads to the potentially life-threatening dengue shock syndrome (DSS). During the period of leakage, compensatory mechanisms (e.g., adrenal, renal) are upregulated in an attempt to maintain adequate circulation to critical organs; the diastolic pressure rises, the pulse pressure narrows, and the patient becomes cool and peripheral shutdown occurs.

When the pulse pressure narrows to less than 20 mm Hg, the patient is said to have DSS and urgent resuscitation is required; at this stage the systolic pressure may remain normal or even be elevated, and the patient may appear deceptively well. However, once hypotension develops, the systolic pressure tends to fall rapidly and irreversible shock and death may follow despite aggressive resuscitation. During the transition from febrile phase to critical phase, clinical warning signs that the patient may be experiencing significant vascular leakage include persistent vomiting, increasingly severe abdominal pain, and tender hepatomegaly.

Hemorrhagic manifestations tend to be more common during the critical phase than during the febrile period but are still usually limited to mild skin or mucosal bleeding. Clinically significant bleeding is unusual in children, except in patients with profound or prolonged shock in whom the terminal event is often major gastrointestinal bleeding. However adolescents and young adults are more likely to experience severe bleeding problems; in these age groups major gastrointestinal bleeding or menorrhagia/abnormal vaginal bleeding are sometimes seen in patients without cardiovascular compromise and with little evidence of vascular leakage.

Infrequently, other severe manifestations occur, usually in older patients during the second week of illness and often in the absence of severe plasma leakage. These include acute liver failure, myocarditis, encephalopathy/encephalitis, and visual loss resulting from retinal hemorrhage and/or maculopathy.

Recovery Phase

The altered permeability is short-lived, reverting spontaneously to normal after approximately 24-48 hours. Fluid is rapidly reabsorbed, often with an obvious diuresis as the patient improves.

A second rash, varying in form from scarlatiniform to maculopapular, may appear after day 6 to 7 of illness, typically on the extremities, although sometimes involving the trunk and face. The rash may be accompanied by intense pruritus and often resolves with desquamation over 1-2 weeks.

Some patients experience depression and profound tiredness for several weeks afterward, but both these neuropsychiatric manifestations and the convalescent rash are more common in adolescents and adults than in younger children.

What other disease/condition shares some of these symptoms?

In the initial stages, the differential diagnosis includes other arboviral infections (e.g., Chikungunya, Japanese encephalitis virus infection) as well as measles, rubella, enterovirus infections, adenovirus infections, and influenza. Other diseases that should be considered, depending on epidemiologic local disease characteristics, and travel history, include typhoid, malaria, leptospirosis, hepatitis A, rickettsial diseases, and bacterial sepsis.

Subsequently, the occurrence of shock due to vascular leakage around the fourth or fifth day of fever in a child from an endemic area is virtually pathognomonic for DSS.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory confirmation relies either on direct detection of viral components or on indirect serologic methods. During the febrile phase, viral isolation or detection of viral RNA by reverse transcriptase polymerase chain reaction is the most reliable method available. Alternatively enzyme-linked immunoassay (ELISA) or lateral flow rapid tests that detect soluble nonstructural protein 1 (NS1), a glycoprotein expressed by infected cells, can be performed during this period and may remain positive for up to 2 weeks. Such NS1 tests are very specific, but sensitivities range between 60% and 80% and vary according to the infecting serotype and immune status of the patient.

Serologic diagnosis requires seroconversion of dengue virus (DENV)-reactive IgM and/or IgG on paired samples, usually using ELISA methodology, although lateral flow rapid tests are also available. Since IgM may be detectable between 3 and 4 days after fever onset, but then often remains positive for several months, seroconversion is required to make a definitive diagnosis. However in a patient with a clinical syndrome consistent with dengue, detection of DENV-reactive IgM is usually accepted as presumptive evidence of infection.

Serologic diagnosis is further complicated by the existence of flavivirus cross-reactivity, making it necessary to perform tests for other locally prevalent flaviviruses in parallel with the dengue serologic tests to make a definitive diagnosis.

Would imaging studies be helpful? If so, which ones?

In general, imaging studies are not helpful for diagnosis, except to exclude other disorders (e.g., pneumonia). However both plain chest radiography and ultrasonography of the chest and abdomen may be useful to detect and quantify vascular leakage during the critical and early recovery phases. Pleural effusions, ascites, and gallbladder wall thickening are recognized features associated with vascular leakage, but assessment is subjective and the upper limit of normal is not well defined for some parameters, especially thickness of the gallbladder wall.

Confirming the diagnosis

Differentiation of dengue from other common febrile illnesses on clinical grounds and/or using standard hematologic or biochemical laboratory parameters is difficult, particularly early in the evolution of the disease before complications develop. Several clinical decision algorithms have been published but none has been established to be useful, and further work is needed before any can be recommended for practical use.

If you are able to confirm that the patient has dengue, what treatment should be initiated?

Currently no effective antimicrobial agents are available for dengue, and no other drugs have been shown to be beneficial during acute infections. Treatment remains supportive, with particular emphasis on careful fluid management. Supportive therapy and counseling should be instituted as soon as the diagnosis is suspected without waiting for laboratory confirmation, especially in endemic areas where resource limitations frequently preclude diagnostic testing.

During the febrile phase, oral rehydration should be encouraged and fever controlled with standard measures. Both aspirin and nonsteroidal antiinflammatory drugs are contraindicated, as many patients have significant thrombocytopenia and a coagulopathy even without clinical bleeding manifestations. Baseline blood tests (complete blood count [CBC], liver function tests, and a sample for diagnostic virologic/serologic tests) should be obtained at the first visit.

Patients who have no complications and are able to tolerate oral fluids may remain at home but should be reviewed daily, and caregivers should be instructed to return immediately if the child develops any bleeding problems or any symptoms suggestive of increasing leakage (persistent vomiting or worsening abdominal pain).

Patients who experience any of these warning signs or in whom a daily CBC count shows a progressive rise in the hematocrit or a precipitous fall in the platelet count should be admitted for observation. Judicious use of isotonic crystalloid therapy may be necessary for children unable to tolerate oral fluids or if there is a rapid rise in the hematocrit. During the critical period for leakage, it is recommended that such patients be managed in a setting where vital signs can be checked frequently and there is immediate access to repeated hematocrit measurements.

If the patient progresses to DSS, prompt restoration of circulating plasma volume with intravenous fluid therapy is essential, followed by ongoing fluid therapy to support the circulation at a level just sufficient to maintain critical organ perfusion until permeability reverts to normal. Isotonic crystalloids should be used in the first instance, with isotonic colloid solutions reserved for patients presenting with profound shock or those who fail to respond to initial crystalloid therapy.

The volume of parenteral fluid therapy should be kept to the minimum required to maintain cardiovascular stability and acceptable urine output, but it is not necessary to bring the hematocrit down to normal levels if the patient is otherwise stable.

As soon as the recovery phase begins, usually 36-48 hours after the onset of shock, intravenous fluids should be stopped, and the hematocrit will drop rapidly as the leaked fluid is reabsorbed into the circulation. Conventionally, volumes of 10-20 mL/kg/hr are given for the first 2-3 hours, depending on clinical severity, reducing gradually down to maintenance fluid levels over 8-12 hours. Further episodes of cardiovascular decompensation may occur within the ongoing leakage period, requiring additional boluses of colloid that must be titrated carefully against the clinical response.

Severe bleeding is rare in children and almost always is associated with prolonged or profound shock. Transfusion is indicated for life-threatening bleeding that compromises cardiovascular function but should be undertaken with extreme care because of the potential for fluid overload.

Internal bleeding should be considered in children who fail to improve after appropriate fluid resuscitation, particularly if the hematocrit is falling and the abdomen is distended and tender.

A small-volume transfusion (5-10 mL/kg) may be given and the response noted, with further small transfusions if there is a good clinical response or significant bleeding is confirmed. In addition, platelet concentrates, fresh frozen plasma, cryoprecipitate and the like may be needed depending on the coagulation profile. However there is no evidence that platelet concentrates are beneficial, even for profound thrombocytopenia, unless there is clinically significant bleeding requiring transfusion of blood.

Management of rare complications such as encephalopathy, myocarditis, and fulminant hepatitis, should follow standard guidelines for these problems.

What are the adverse effects associated with each treatment option?

Fluid overload with respiratory compromise is a well-recognized complication and a significant contributor to mortality. All fluid therapy must be given with great care; clinical assessments should be performed at least hourly, with hematocrit measurements every 2-4 hours, and fluid prescriptions should be written for short periods only, initially every 1-2 hours until the patient stabilizes.

Inevitably some patients with profound shock do require large volumes of fluid and will experience significant pleural effusions and ascites; respiratory support should be provided early with oxygen and nasal continuous positive airway pressure, progressing if necessary to full invasive ventilation. Diuretics are contraindicated until a stable circulation has been established.

What are the possible outcomes of dengue?

Most children make a fullrecovery from dengue, and long-term consequences are unusual. AlthoughDSS is the most frequent complication seen in children, it remains uncommon. Among hospitalized patients, between 5% and 10% experience DSS, and in experienced centers, the mortality is less than 1%.

Poor prognostic factors include early presentation (day 3-4 of fever), younger age, profound shock with unrecordable pulse and blood pressure at presentation, and repeated episodes of decompensation within the first 24 hours after onset of shock. The rare patients who experience complications such as hepatic failure, encephalopathy, and visual disorders may be left with long-term sequelae.

What causes this disease and how frequent is it?

Dengue is a systemic viral infection, caused by any one of four dengue viral serotypes (DENV-1 to DENV-4) that constitute one subgroup of the genus Flavivirus, family Flaviviridae.

Dengue is transmitted by Aedes mosquitoes and is the most important mosquito-borne viral infection affecting humans. Although Aedes aegypti is the primary vector Aedes albopictus is becoming increasingly important in the ecology of transmission. Aedes are highly urban-adapted mosquitoes and the dispersal of these efficient vectors across much of the tropics and subtropics over the last 50 years has been a major factor in the emergence of dengue as a public health problem of global significance.

Over half the world's population is thought to live in areas at risk for transmission, and recent estimates suggest around 400 million infections occur annually, of which almost 100 million are clinically apparent. Dengue is now hyperendemic in most Asian cities, has become established as a significant problem in the Pacific region and in the Americas, and reports of small numbers of cases of autochthonous transmission have recently begun to emerge from warmer European countries. Disease transmission has also been recognized in Africa, although the extent of the problem remains unclear.

Rapid urbanization with increasing population density and an abundance of vector breeding sites in close proximity to the human population has undoubtedly contributed to the current dengue pandemic.

Various genetic markers have been examined and a number of factors identified, such as different HLA alleles, variations in vitamin D receptor and Fc gamma receptor II genes, that confer either susceptibility or resistance to severe dengue disease. However these genetic association studies have generally been small, and the findings have not been replicated in second populations. More recently, however, a genome-wide association study of more than 2000 DSS cases and controls identified susceptibility loci at MICB (major histocompatibility complex class I polypeptide-related sequence B), and PLCE1 (phospholipase C, epsilon 1. Subsequent studies in other populations have confirmed that these genotypes are not only associated with DSS, but also associated with less severe clinical phenotypes of dengue.

Women have a lower threshold for vascular leakage than do men and a preponderance of women has been found among DSS cases and among fatal cases. Ethnicity has also been highlighted as another possible risk factor; thus black individuals appear to be protected from severe disease when compared with white individuals during dengue epidemics in Cuba.

How do these pathogens/genes/exposures cause the disease?

The pathogenetic mechanisms underlying the severe complications associated with dengue infection remain poorly understood, and no suitable animal model exists to investigate either the systemic vascular leak syndrome or the associated coagulopathy. These clinical features indicate involvement of the vascular endothelium in the disease process, but the virus does not appear to infect endothelial cells in vivo, and only minor nonspecific changes have been demonstrated in histopathologic studies of the microvasculature.

Infection with any one of the four dengue viral serotypes elicits lifelong immunity to that particular serotype but does not provide long-term cross-protective immunity to the remaining serotypes. Primary infections are infrequently associated with severe disease, whereas subsequent infections with a different serotype are epidemiologically linked to more severe disease.

Antibody-dependent enhancement is thought to underlie this phenomenon. Heterotypic non-neutralizing antibodies from the previous exposure bind to the new infecting virus, facilitating uptake and productive infection in cells of the macrophage-monocyte lineage, thereby resulting in an increase in viral load in the early phase of the infection. Viral antigens presented by infected cells are thought to trigger an immunopathogenic cascade that alters microvascular permeability and thromboregulation in some as yet undefined way.

Theoretically, these effects are likely to be mediated through changes to the endothelial surface glycocalyx, a fiber-matrix layer anchored in the plasma membrane of all endothelial cells that is now considered to be the primary barrier controlling intrinsic permeability. Both the virus itself and dengue NS1 are known to interact with important elements of this layer, although specific effects have yet to be elucidated during dengue disease in vivo.

Are additional laboratory studies available; even some that are not widely available?

A daily CBC should be performed. The total white blood cell count, lymphocyte count, and platelet count typically show a progressive decline to the lowest levels around day 6 of illness. Platelet nadirs of less than 30,000/mm3 are common, especially in those with more severe vascular leakage. However the platelet count rebounds rapidly during the second week of illness, so no intervention is required unless significant bleeding occurs.

Liver transaminase levels are frequently elevated, usually to a mild/moderate degree (50-500 IU/L). Aspartate aminotransferase levels are typically elevated more than alanine aminotransferase levels, likely reflecting muscle as well as liver involvement. Rarely, severe liver dysfunction occurs with marked elevation of enzyme levels and sometimes jaundice. The abnormalities usually improve gradually during the second to third week of illness without specific intervention, but acute liver failure is sometimes seen in young adults and may be fatal.

Plasma protein levels, especially plasma albumin, fall during the critical period. However the effect of hemoconcentration may mask these changes until intravenous fluid therapy is commenced, at which time the plasma albumin may fall to very low levels, especially in cases of DSS.

A prolonged activated partial thromboplastin time with a reduced fibrinogen level, but with little in the way of procoagulant activation (i.e., with minimal increase in prothrombin time and negative D-dimers), are the typical coagulation abnormalities seen. These abnormalities follow the expected evolution of the clinical illness, deteriorating toward the end of the first week and then improving spontaneously, and the severity of the derangements correlates with the severity of vascular leakage observed. No intervention is necessary unless significant bleeding occurs.

How can dengue be prevented?

Major efforts are being directed toward development of safe and effective vaccines for dengue. Several candidate vaccines are undergoing clinical trials, but large-scale deployment is unlikely for some years to come. In the meanwhile, prevention continues to rely on eradication of mosquitoes and their breeding sites using a variety of biologic and chemical control strategies. Novel techniques involving introduction of genetically modified or Wolbachia infected mosquitoes are also being explored. Avoidance of mosquito bites using repellants and protective clothing are the most effective measures for travelers to endemic areas.

What is the evidence?

"World Health Organization. Dengue: Guidelines for diagnosis, treatment, prevention, and control". World Health Organization. 2009.

Simmons, CP, Farrar, J, Nguyen, VC, Wills, B. "Dengue". N Engl J Med. vol. 366. 2012. pp. 1423-32.

Bhatt, S, Gething, PW, Brady, OJ. "The global distribution and burden of dengue". Nature. vol. 496. 2013. pp. 504-7.

Ongoing controversies regarding etiology, diagnosis, treatment

There are some concerns regarding eventual deployment of dengue vaccines in dengue-endemic areas because of the theoretical possibility that waning vaccine-elicited immunity over time may predispose recipients to more severe disease if they acquire a natural infection subsequently. Second or subsequent natural infections are clearly associated with more severe disease outcomes and long-term follow-up of vaccinees will be essential to make sure that a similar phenomenon does not occur with induced immunity.

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