Flaviviruses: Dengue

OVERVIEW: What every practitioner needs to know

Dengue is a mosquito-borne viral infection that usually causes a self-limited febrile illness, but can give rise to dengue hemorrhagic fever or dengue shock syndrome. There are currently no specific treatments, though a vaccine was recently licensed for use in limited countries. Dengue’s geographic range is ever-increasing, with an estimated global burden of 50 to 100 million infections per year and 2.5 billion people at risk for infection.

Are you sure your patient has dengue? What should you expect to find?

Clinical syndromes: The spectrum of illness seen with dengue includes a mild nonspecific febrile syndrome (often in younger children), classic dengue, dengue hemorrhagic fever (DHF), and dengue septic shock (DSS). Also known as “Seven Day Fever”, the course of dengue disease can be divided into three phases:

Febrile phase – Abrupt-onset fever and two of the following: headache, retro-orbital pain, arthralgia, myalgia, diffuse rash, and mild hemorrhagic manifestations. This may be accompanied by nausea, vomiting, and diarrhea, and dehydration when these latter symptoms are severe. Respiratory symptoms are reported rarely. This phase usually lasts 2 to 7 days, and then is followed by the critical phase.
Critical phase – Lasts 1 to 2 days. Patients with classic dengue fever and severe dengue disease (DHF, DSS) cannot be differentiated early in the course of illness.

As the fever subsides, warning signs such as abdominal pain, persistent vomiting, fluid accumulation (ascites, pleural effusion), lethargy or restlessness, mucosal bleeding, hepatomegaly, or hemoconcentration may occur.
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These signs and symptoms may quickly progress to shock due to hemorrhage or plasma leakage. Once a patient develops DSS or DHF, the case fatality rate is as high as 44%.

These patients exhibit symptoms of fluid accumulation in the pleural and abdominal space and hemodynamic instability. Upon adequate volume repletion, the patient enters the convalescent phase.
Convalescent (or reabsorption) phase – Plasma leakage stops, the reabsorption of fluids commences, and hemodynamic stability is restored. The patient regains appetite and a sense of well-being.

A diffuse, erythematous, at times mildly pruritic, maculopapular rash with small islands of normal skin may appear.

In patients with classic dengue as well as those with DHF or DSS, recovery tends to be complete but may be accompanied with fatigue and depression.
Physical findings:

Positive tourniquet sign (also known as the capillary fragility test).

▪ The appearance of 10 or more petechiae per square inch after inflating a blood pressure cuff between the systolic and diastolic blood pressure for 5 minutes.

Petechiae (usually on the lower extremities).

Rash (diffuse erythematous maculopapular rash with islands of normal skin).
Decreased skin turgor.
Ascites, diminished breath sounds due to pleural effusion, hepatomegaly.

How did the patient develop dengue? What was the primary source from which the infection spread?

Dengue is acquired by being bitten by an infected Aedes mosquito. Very rarely, dengue has been transmitted via organ transplantation or blood transfusion. Sexual, airborne, or droplet transmission does not occur.

Which individuals are of greater risk of developing dengue?

Risks associated with acquiring classic dengue fever are primarily living or traveling in an endemic region and being exposed to mosquito bites.

Dengue is now endemic in most subtropical and tropical regions.

Transmission in such regions is typically more pronounced in urban, crowded settings compared to rural settings.

Dengue is one of the most common causes of fever in the returning traveler.
Host factors associated with developing severe dengue (DHF, DSS) include age, sex, certain HLA-alleles, other genetic variations, and comorbidities.

Younger children (5 years old or less) are at greater risk of dying due to increased vascular permeability (in a Vietnamese cohort, the odds of dying was four-fold higher for children under 5 compared to children 11 to15 years).

Females are associated with slightly higher odds of severe disease and death due to dengue, possibly due to health-seeking behavior in gender differentials.

Certain HLA alleles appear to be protective (e.g. HLA DR alleles in Mexican and Vietnamese populations), whereas others are associated with greater susceptibility to disease (eg. HLA*0207 and dengue 1, HLA*B52 and dengue 2).

Polymorphisms in the vitamin D receptor and Fc-gamma receptor genes may be protective for severe dengue, whereas certain human platelet antigen allele polymorphisms are seen more frequently in patients with DSS.

While incompletely understood, comorbidities such as asthma, sickle cell disease, and diabetes mellitus appear to be associated with the development of severe disease.

Beware: there are other diseases that can mimic dengue:

Zika
Malaria
Chikungunya
Leptospirosis
Venezuelan equine encephalitis
Typhoid fever
West Nile fever
Mayaro
Oropouche
Rickettsioses
Childhood viral illnesses (parvovirus, measles, rubella, human herpes virus-6)
Influenza
Acute HIV
Epstein-Barr infection
Cytomegalovirus infection
Rift Valley Fever

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Thrombocytopenia – most symptomatic cases of dengue are associated with low platelets. More severe disease manifestations are characterized by platelets <50,000/mL and bleeding risk.
Leucopenia.
Hemoglobin – mild cases may present with normal hemoglobin, but elevated hemoglobin is often a harbinger of more severe disease as hemoconcentration occurs secondary to capillary leakage. Low hemoglobin in severe dengue can be a sign of hemorrhage.
In classic and severe dengue, elevated transaminases (>1000) can be seen with liver involvement.

Results that confirm the diagnosis

Up to 5 days of symptom onset:

Reverse-transcription polymerase chain reaction (RT-PCR) – this test allows for the serotyping of the strain and is highly sensitive and specific; viral isolation – most diagnostic laboratories do not routinely perform dengue virus isolation;

NS1 antigen test (by ELISA or lateral flow rapid test) – not currently available in the US. For primary infections, NS1 Ag test sensitivity is high (>90%), but in secondary infections, sensitivity can be low (60-80%).
Greater than 4 days after symptom onset:

IgM ELISA with IgG ELISA on acute and convalescent sera.

▪ In cases of primary dengue, dengue IgM will be elevated, whereas IgG will lag behind by 1 or 2 weeks.

▪ If the patient has previously had dengue infection, IgM may be low, but IgG is very elevated within days of symptom onset.

▪ In areas where other flavivirus infections occur (e.g. due to West Nile virus, yellow fever virus, Saint Louis Encephalitis virus, Japanese encephalitis) or yellow fever or Japanese encephalitis vaccination has taken place, care must be taken when interpreting ELISA results, as crossreactions with other members of the flavivirus group are common (more so with IgG than IgM ELISA).

▪ Plaque reduction neutralization tests (PRNTs) are more specific, and can determine dengue serotype (whereas ELISAs typically cannot). However, most laboratories do not routinely perform PRNTs.
If only a single serum sample can be obtained 5 days after symptom onset, IgM ELISA is the preferred test (such as the DENV Detect IgM Capture ELISA test).

Again, in secondary infections IgM may be low and give rise to false negatives.

A positive result should be interpreted as probable evidence of dengue infection in the preceding 3 months.
Lateral flow rapid tests measuring NS1 antigen, dengue IgM and IgG are available. These are useful in situations where laboratory infrastructure is poor to nonexistent. However, the sensitivity of these tests tends to be low.

What imaging studies will be helpful in making or excluding the diagnosis of dengue?

Abdominal and thorax ultrasound can be helpful adjuncts to diagnose dengue hemorrhagic fever or dengue septic shock. The detection of pleural effusions and/or ascites is highly suggestive of severe dengue.
Computed tomography and magnetic resonance imaging of the brain can help differentiate focal disease from dengue encephalitis. However, these imaging studies cannot effectively differentiate different infectious causes of encephalitis.
Ultrasound $, head CT scan $$, brain MRI scan $$$$.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

An infectious diseases consultant is recommended to aid in the diagnosis and management of the patient. Critical care services should be sought if the patient exhibits significant hypotension or hemorrhage.

If you decide the patient has dengue, what therapies should you initiate immediately?

Key principles of therapy:

No dengue-specific therapy is available. Most cases are self-limited and require only oral fluid administration and acetaminophen. NSAIDS and other drugs with anti-platelet and anticoagulant effects should be avoided.

For severe disease (with manifestations of plasma leakage or hemorrhage), fluid management is the mainstay of therapy. WHO 2009 guidelines are as follows:

For compensated shock: isotonic crystalloid intravenous fluids (IVF) at 5-10 mg/kg over 1 hour. If the patient improves, gradually reduce the IVF rate. If the patient remains unstable, check a hematocrit after the first bolus.

If the hematocrit is still high or increases (>50%), repeat a second bolus of IVF over 1 hour. If there is improvement, gradually reduce the IVF rate.

However, if the hematocrit has decreased, this may indicate bleeding and the need to transfuse red blood cells immediately.

For hypotensive shock: check a hematocrit and start IVF with colloid or crystalloid at 20mg/kg as a bolus over 15 minutes.

If the patient improves, reduce the IVF rate to 10mg/kg over 1 hour, then reduce gradually.

If the patient remains unstable, review the hematocrit before the first IVF bolus.

▪ If the hematocrit was low, this may indicate bleeding and the need to transfuse red blood cells.

▪ If the hematocrit was high, change to IV colloids at 10-20mg/kg and infuse over 30 minutes to one hour.

▪ If still unstable, check hematocrit after second bolus. If the hematocrit decreases, transfuse red blood cells. If the hematocrit remains high or increases (>50%), add a third bolus of colloid over 1 hour, then reduce the rate and change to crystalloid.

1. Anti-infective agents

No anti-infective agents are available for dengue.

If I am not sure what pathogen is causing the infection what anti-infective should I order?

While awaiting specific diagnosis, malaria and typhoid fever therapy should be considered in the returning traveler with fever. In those with fever and gastrointestinal symptoms, treatment for invasive enteric organisms (e.g. salmonella, shigella, campylobacter) may be considered. During periods of influenza activity, neuraminidase inhibitors may be considered.

2. Next list other key therapeutic modalities.

What other therapies are helpful for reducing complications?

None

Controversial or evolving therapies:

Despite some in vitro efficacy against dengue, therapies such as IVIG, chloroquine, alpha interferon-2a, and ribavirin have not yielded significant differences in outcomes such as viremia and platelet count in animal studies.

Anti-TNF-alpha antibody was tested in mice with dengue 2 virus infection, and mortality in the placebo vs treatment group was 100% vs 40%, respectively.

Corticosteroids appear to be no different than placebo in reducing severity of disease.

Platelets are often administered prophylactically for thrombocytopenia to prevent the development of hemorrhage, but multiple small studies have demonstrated that prophylactic platelets are not associated with different outcomes. The WHO 2009 guidelines recommend against the use of platelets for thrombocytopenia in an otherwise hemodynamically stable patient. It is unclear whether platelet transfusion in patients with active bleeding results in improved outcomes. In patients with DSS, platelets are consumed within hours to 1 day.

What complications could arise as a consequence of dengue?

Gastrointestinal bleeding or hematuria
Shock
Dehydration
Fluid overload
Acute hepatic failure
Bacterial infection
Encephalitis
Respiratory failure
Multiorgan failure

What should you tell the family about the patient's prognosis?

Usually patients recover without any sequelae, but a small number of patients who develop severe dengue may have complications associated with hemorrhage and shock (e.g. multiorgan failure, anemia).
Mortality due to dengue ranges from 1% to 5% without adequate treatment; with prompt and appropriate treatment, mortality is less than 1%.

How do you contract dengue and how frequent is this disease?

Dengue virus is transmitted to humans by Aedes mosquitoes (usually Ae. aegypti).

With the exception of sylvatic strains, dengue virus serotypes 1 through 4 do not require nonhuman reservoir hosts for the maintenance of transmission.
All four serotypes now circulate in most tropical and many subtropical regions.
Ae. aegypti and Ae. albopictus have a predilection for breeding in urban settings in artificial containers. These mosquitoes bite during the day, rendering the use of mosquito nets at night ineffective for dengue prevention.
The transmission cycle starts with an adult female Aedes feeding on a dengue infected person. The virus then develops within the mosquito in approximately seven days (shorter in warm weather, longer in cooler weather). Once the mosquito has become infective, it transmits the virus when biting a subsequent human.
The adult mosquito lays eggs (in sites such as water collection tanks, discarded tires, tree holes), from which infected larvae may emerge (via vertical transmission).

Severe dengue (dengue hemorrhagic fever and dengue septic shock) is believed to occur when a person who has been previously infected with dengue develops a subsequent dengue infection due to a different serotype.

This process is termed antibody-dependent enhancement, and is caused by the presence of dengue antibodies at non-neutralizing titers giving rise to enhanced viral replication in peripheral blood leukocytes.
Outbreaks of severe dengue are also associated with the virus serotype and genotype. For example, Sri Lanka had reported the presence of all four serotypes circulating between 1980 and 1989, but the first cases of dengue hemorrhagic fever occurred only once a new dengue 3 strain was introduced.

Incidence, seasonal variation. Incidence and seasonality vary from country to country. Incidence is highest in tropical urban areas in the Americas and Asia. In Puerto Rico, for example, the incidence of dengue has varied between 3000 and 9000 cases per year during non-outbreak years, and was as high as 24,700 cases during one outbreak year (1994). Epidemiological studies in Africa have been scarce, but serological data suggests that dengue is circulating in coastal and tropical urban areas in much of Africa as well.

Mode of spread. Dengue virus is transmitted primarily by Aedes aegypti mosquitoes. Other Aedes species may participate in transmission during epidemics (i.e. Aedes albopictus) or in sylvatic dengue. Once an infected mosquito bites a person, viremia becomes apparent in the following days. During this period of viremia (usually lasting 3 to 7 days), the infected person may transmit the virus to uninfected Aedes mosquitoes. The vector usually has a short flight range, and infections may cluster by households. Human movement, however, has contributed to the spread of dengue to unprecedented numbers of countries.

Epidemiology

Dengue virus was first isolated and characterized in 1943. From then, the average number of cases reported to the WHO has risen from under 1000 in the 1950s to 2.3 million in 2010. This no doubt is an underestimate of the true burden of disease, which is estimated at 50 to 100 million infections worldwide per year. At present, 40% of the world’s population is deemed at risk for infection. Furthermore, the number of countries reporting autochthonous dengue cases has increased from nine in 1970 to more than 100. All four serotypes now circulate in most endemic regions.

Disease transmission has also expanded from urban to rural areas. In all, 50 to 100 million dengue infections are estimated to occur yearly, with 500,000 hospital admissions for severe disease. In addition to human movement contributing to the spread of disease, unplanned urbanization, population growth, and the decline of vector control programs have been important factors. All people living and traveling in endemic regions are at risk for acquiring infection. Disease severity, however, is associated with host and viral factors.

Zoonotic transmissions. Sylvatic dengue transmission is maintained by canopy-dwelling Aedes and lower primates in Southeast Asia and Africa. Little crossover occurs, however, between these forest transmission cycles and urban/human dengue.

What pathogens are responsible for this disease?

Dengue virus (serotypes 1, 2, 3, 4) is exclusively responsible for dengue fever. Dengue is a single-stranded positive sense virus in the genus Flavivirus, family Flaviviridae. In addition to different serotypes, different genotypes circulate as well and are associated with varying degrees of disease severity. Dengue serotype 5 was recently discovered in Malaysia, but transmission appears to be limited at present.

How do these pathogens cause dengue?

The dengue virus gains entry via the bite of an infected Aedes mosquito and initially infects immature Langerhans cells.

Infected cells disseminate through the lymphatic system, where myeloid dendritic cells, blood-derived monocytes, and splenic and hepatic macrophages are subsequently infected.
Bone marrow stromal cells also appear to be susceptible to infection, as are endothelial cells and hepatocytes.
The incubation period from infected mosquito bit to the development of symptoms is 3 to 5 days.
Thrombocytopenia, seen in the majority of patients with dengue, results from the suppression of hematopoiesis as well as the consumption of platelets.
In most patients, the virus is cleared and controlled within 1 week.

The humoral immune response is crucial in this process. Antibodies are specific for a single dengue serotype, but do provide crossreactive neutralization to other dengue serotypes in the initial months following infection.

Thereafter, these crossreactive antibodies fall below the levels required for protection, and have been implicated in the development of severe dengue as hypothesized by the antibody-dependent enhancement (ADE) theory.

According to this theory, non-neutralizing antibody actually enhances viral uptake by Fc-receptor bearing cells (especially macrophages), thereby increasing the viral load.

▪ This gives rise to the release of proinflammatory cytokines (such as interferon-gamma, tumor necrosis factor-alpha, interleukin-6 and interleukin-10) and lead to increased vascular endothelial permeability.

▪ Post-mortem studies have suggested that this may be especially pronounced in pulmonary and gastrointestinal vasculature and may explain the selective plasma leakage into the pleural and peritoneal spaces seen in severe dengue.

▪ Interestingly, increased vascular permeability is not associated with endothelial damage but rather with the loss of integrity of endothelial junctions. This may explain why recovery in DSS and DHF is so rapid after sufficient volume repletion.

▪ Due to a lack of good animal models for DSS and DHF, however, the pathogenesis of severe dengue remains incompletely understood.

What other clinical manifestations may help me to diagnose and manage dengue?

Unusual presentations include meningoencephalitis, encephalitis, mono- and polyneuropathy, Guillain-Barre syndrome, myelitis, fulminant hepatic failure, cholecystitis, pancreatitis, parotitis, hemolytic uremic syndrome, renal failure, myocarditis, pericarditis, conduction abnormalities, ARDS, pulmonary hemorrhage, myositis, rhabdomyolysis, and splenic rupture.

What other additional laboratory findings may be ordered?

Detection of NS1 antigen, IgM and IgG from oral swabs, and dengue RNA in urine are being evaluated and may prove useful, especially in children and infants.

How can dengue fever be prevented?

Sanofi Pasteur released the first licensed dengue vaccine, Dengvaxia, in December 2015. It is currently licensed for use in the Phillipines, Mexico, and Brazil in people between 9 and 45 years of age. In clinical trials, average vaccine efficacy for the four dengue serotypes was 59%, and 79% against severe dengue.
Approximately five other vaccine candidates are currently in clinical trials.
The disease can be prevented by avoiding mosquito bites. The Aedes mosquitoes responsible for transmission bite during the day. Bites are best avoided by wearing DEET mosquito repellent or permethrin-impregnated clothing when outdoors. Aedes mosquitoes also bite indoors; having screened windows or air-conditioning can reduce mosquito abundance indoors.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

Anders, KL, Nguyet, NM, Chau, NVV. “Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam”. Am J Trop Med Hyg. vol. 84. 2011. pp. 127-134. (Host factors such as age and sex are associated with dengue severity and death in hospitalized children in Vietnam.)

Gubler, DJ. “Dengue and dengue hemorrhagic fever”. Clin Microbiol Rev. vol. 11. 1998. pp. 480-96. (Overview of dengue epidemiology, natural history, transmission, and clinical manifestation in the context of increasing worldwide incidence.)

Kanakaratne, N, Wahala, WM, Messer, WB. “Severe dengue epidemics in Sri Lanka, 2003-2006”. Emerging Infectious Disease. vol. 15. 2009. pp. 192-9. (Example of dengue genotype or clade being implicated in dengue hemorrhagic fever outbreaks.)

Clinical presentation

Araujo, F, Nogueira, R, de Sousa Araujo, M. “Dengue in patients with central nervous system manifestations, Brazil”. Emerg Infect Dis. vol. 18. 2012. pp. 677-9. (Even though this article describes a patient population in a specific geographic region, it is a helpful overview of possible CNS manifestations of dengue)

Barniol, J, Gaczkowski, R, Barbato, EV. “Usefulness and applicability of the revised dengue case classification by disease: multi-centre study in 18 countries”. BMC Infect Dis. vol. 11. 2011. pp. 106(An evaluation of the new WHO dengue case classification; 13.7% of dengue cases could not be classified by expert reviewers using the prior WHO case classifications, but only 1.6% could not be classified with the updated 2009 classification system.)

Gulati, S, Maheshwari, A. “Atypical manifestations of dengue”. Trop Med Int Health. vol. 12. 2007. pp. 1287-95. (A review of the many nonclassical dengue presentations.)

“Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control”. 2009. (Most up-to-date WHO guidelines summarizing diagnostic and treatment modalities. Although there is no complete consensus for clinical warning signs to triage patients for hospitalization, these guidelines are an improvement on the prior iteration. The previous WHO guidelines for defining dengue/DHF/DSS cases were not sensitive enough and missed many cases.)

Treatment

Ham, DTH, Ngoc, TV, Tien, NTH. “Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized placebo-controlled trial”. Clin Infect Dis. vol. 55. 2012. pp. 1216-24. (A small study evaluating low- and high-dose prednisolone 3-day therapy and dengue outcomes; underpowered for efficacy, nonetheless, no difference was seen in the low- or high-dose steroid or placebo arms.)

Isarangkura, P, Tuchinda, S. “The behavior of transfused platelets in dengue hemorrhagic fever”. Southeast Asian J Trop Med Public Health. vol. 24. 1993. pp. 222-4. (A rare article that examines the duration of transfused platelets in vivo in DHF, thereby providing a compelling argument against the use of prophylactic transfusion.)

Lye, DC, Lee, VJ, Leo, YS. “Lack of efficacy of prophylactic platelet transfusion for severe thrombocytopenia in adults with acute uncomplicated dengue infection”. Clin Infect Dis. vol. 48. 2009. pp. 1262-65. (188 of 256 patients with platelets <20,000/microliter were given platelet transfusion. No difference in bleeding or platelet recovery was seen in the two groups.)

Pathogenesis

Martina, BEE, Koraka, P, Osterhaus, ADME. “Dengue virus pathogenesis: an integrated review”. Clin Microbiol Reviews. vol. 22. 2009. pp. 564-81. (Review of pathogenesis that incorporates viral and host factors.)

Whitehorn, J, Simmons, CP. “The pathogenesis of dengue”. Vaccine. vol. 29. 2011. pp. 7221-8. (An up-to-date discussion of recent developments in dengue pathogenesis with reference to vaccine development.)

Diagnosis

“Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control”. 2009. (Provides a good overview of diagnostic modalities and their application.)

Poloni, T, Oliveira, AS, Alfonso, HL. “Detection of dengue virus in saliva and urine by real time RT-PCR”. Virology J. vol. 7. 2010. pp. 22(An example of novel diagnostic methods in dengue.)

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