By Julie L. Hanson, MD, and Philip R. Fischer, MD

Dr. Hanson is a resident in pediatrics at the Mayo Clinic in Rochester, MN. Dr. Fischer is professor of pediatric and adolescent medicine, Mayo Clinic, Rochester, MN.

Dr. Hanson and Dr. Fischer report no financial relationships relevant to this field of study.

SYNOPSIS: Dengue is increasingly recognized in the southern United States. When recently surveyed, however, clinicians in Texas seemed incompletely prepared to understand and manage patients with dengue.

SOURCE: Adam JK, Abeyta R, Smith B, et al. Clinician survey to determine knowledge of dengue and clinical management practices, Texas, 2014. Am J Trop Med Hyg 2017;96:708-714.

The vast majority of dengue cases in the United States have been imported from endemic regions by U.S. travelers. However, in recent years there has been increasing evidence of autochthonous dengue transmission in Texas, Florida, and Hawaii. The southern border of Texas is at particular risk of recurrent dengue outbreaks given the close proximity to Mexican states with relatively frequent dengue epidemics. Given this continual threat of dengue outbreaks at the Texas-Mexico border, Adam and eight coauthors from the Centers for Disease Control and Prevention (CDC) and Texas Department of State Health Services developed strategies to reduce morbidity and mortality associated with local dengue infections. As part of this effort, they developed a clinician survey to further understand local Texas clinicians’ knowledge of dengue presentation and clinical management.

The clinician survey was sent to 2,375 physicians, physician extenders, and physician assistants in south Texas and the Houston metropolitan area. Two hundred seventeen clinicians (9%) fully completed the survey and were practicing within the catchment area. The clinician group was stratified further by specialty, practice site (i.e., inpatient, outpatient, or acute care), years of practice, and number of dengue cases diagnosed in their career. The survey questions focused on three knowledge areas, including dengue prevention and anticipatory guidance, clinical presentation and course, and clinical management. All clinician sub-divisions and categories of experience with dengue displayed a deficiency in knowledge of dengue.

Approximately half (56%) of participants were able to identify all clinical signs of dengue and could identify indicators of early shock. However, < 1% recognized all warning signs for severe dengue. Fifty-five percent of clinicians recognized that intravenous crystalloids should be the primary initial fluid replacement in patients with elevated hematocrit, but only 7% correctly identified all three indications for crystalloid use. A minority of clinicians (19%) correctly identified situations in which patients with suspected dengue should return for reevaluation after discharge. This survey highlights the need for improved dengue education in the United States and, in particular, in regions at risk for continued dengue outbreaks.

COMMENTARY

As the continued geographic spread of dengue virus threatens the southern United States, it is helpful to review the basics of dengue virus presentation, management, and prevention. Returning to dengue disease basics will assist in closing knowledge gaps as displayed by the clinician survey conducted in Texas.

Epidemiology

Aedes aegypti and Aedes albopictus, the mosquitoes that serve as vectors for the four dengue virus types (DENV-1 to -4), have been able to reach subtropical and temperate regions, including North America. Dengue is thought to have been present in the United States since the end of the 18th century, with frequent dengue epidemics occurring up until the mid-1900s. After 1945, there was a relatively quiescent period of dengue cases in the United States until 1980 when an autochthonous case of DENV-1 was identified in south Texas. Since 1980, surveillance studies have reported several additional cases of dengue in southern Texas associated with epidemics in northern Mexico, including outbreaks in 1999, 2005, and 2013. During the most recent outbreak in 2013, 53 cases of dengue virus were identified, with 49% of these patients acquiring the infection locally.1 In addition to cases in southern Texas, an epidemic occurred on the island of Maui, Hawaii, in 2001, and the first autochthonous case of dengue in 75 years was identified in Florida in 2009.2 Dengue also has been reported in several U.S. territories, with the largest number of cases reported in the U.S. Virgin Islands and Puerto Rico. While autochthonous dengue infections have been limited thus far to these three states and two U.S. territories, both dengue vector species are distributed widely throughout the southern parts of the United States, indicating that a larger portion of the continental United States may be at risk for dengue infection in the future.

Clinical Presentation

Infection by dengue viruses can lead to a wide variety of clinical presentations ranging from a mild, influenza-like illness to hypovolemic shock and death. This spectrum of dengue infection has been subdivided into three primary syndromes, including classic dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Classic dengue fever, or “break bone fever,” is characterized by onset of a high fever, headache, rash, myalgias, and arthralgias three to 10 days after sustaining a bite from an infected mosquito. As the fever begins to subside three to seven days after symptom onset, the patient may have complete resolution of symptoms, or go on to develop dengue hemorrhagic fever. DHF is defined by four characteristics: recent history of fever, any hemorrhagic manifestation, thrombocytopenia, and evidence of increased vascular permeability. The most common hemorrhagic manifestations are petechiae, a positive tourniquet test, and gingival bleeding. Increased vascular permeability can lead to an elevated hematocrit, presence of pleural effusion or ascites, or hypoalbuminemia. Cases of dengue shock syndrome meet the four criteria for DHF, but also show signs of circulatory failure, such as a rapid, weak pulse, narrow pulse pressure, or hypotension. The risk of progression to DHF or DSS is increased in secondary infections when the individual has been infected previously by a different virus serotype. The fatality rate of patients with DSS can be 10% or higher without proper recognition and management, but mortality can be decreased to < 1% with appropriate intervention.3

Diagnosis

Efficient and accurate diagnosis of dengue is important for prompt clinical care, disease surveillance, and outbreak control. In endemic regions, clinical diagnosis of dengue usually is sufficient, but laboratory testing can be useful when the diagnosis is uncertain or in regions where dengue is sporadic. Dengue can be diagnosed by isolation of the virus, molecular methods, or serologic studies. Virus isolation is the traditional diagnostic method for detecting dengue virus infection; however, it has been replaced by RT-PCR tests and the NS1 antigen ELISA. RT-PCR testing allows for viral identification from the onset of the illness and is fast, sensitive, and specific. Unfortunately, PCR-based testing requires specialized equipment and staff that may not be feasible in a resource-poor region.

In contrast, the NS1 ELISA has emerged as a simple, low-cost diagnostic tool to detect dengue virus in the early stage of infection. The qualitative NS1 ELISA has become the standard for dengue diagnosis worldwide, and quantitative NS1 ELISA continues to be researched as initial studies suggest a direct correlation between NS1 levels and the risk of progression to severe disease. Serological studies also are important tools in diagnosing dengue infection, especially outside of the acute phase. IgM antibodies typically are detectable three to five days after illness onset and peak several weeks after recovery. IgG is usually not present in the acute phase in a primary infection, but may appear as early as three days after illness onset in a secondary infection. The ratio of IgM and IgG in the acute phase of disease may provide an indication as to whether it is a primary or secondary infection. IgM and IgG serologies are susceptible to cross-reactivity with other flaviviruses, which can provide a diagnostic challenge in areas of the world where more than one flavivirus is circulating. Overall, no single assay can be used to definitively diagnose dengue at all stages of infection. Therefore, a combination of NS1 testing and IgM/IgG serologies is recommended to maximize disease detection. Several diagnostic kits, including rapid point-of-care devices, use this combination with nearly 100% detection sensitivity from disease onset through recovery.4

Treatment

While there are a wide variety of clinical manifestations of dengue, treatment is relatively simple and generally effective in reducing the morbidity and mortality associated with infection. Patients in the early febrile phase generally can be managed safely as outpatients with adequate follow-up and anticipatory guidance. Warning signs of severe disease that should prompt return for care include abdominal pain, persistent vomiting, signs of bleeding, and change in mental status. Acetaminophen is safe for symptomatic management of the febrile patient, but nonsteroidal anti-inflammatory drugs should be avoided given the increased risk of bleeding complications. If the patient begins to show warning signs suggestive of more significant disease, or if there are co-existing risk factors, the patient should be hospitalized for further management. Initial treatment focuses on fluid resuscitation with the use of isotonic crystalloids, as well as monitoring of hematocrit and signs of plasma leakage. Patients who present with signs of shock, severe hemorrhage, or severe organ impairment should be hospitalized in a facility with access to intensive care services and blood products. Isotonic crystalloid infusion is still the most effective intervention for patients with severe dengue; however, blood products and more intensive hemodynamic and electrolyte monitoring may be required.5

Prevention and Control

Dengue prevention and control methods have been focused largely on vector management as well as the development of dengue-specific vaccines. Vector control efforts include the reduction of mosquito breeding sites, application of insecticides to high-yield targets (e.g., bed nets, window curtains, school uniforms), use of bacteria or fungi to decrease mosquito survivability, and genetic modification of wild mosquito populations to reduce transmission. Vector control is particularly challenging given the varying efficacies and costs of mosquito control measures, but efforts such as the World Health Organization’s (WHO) Integrated Vector Management strategy seek cost-effective, efficacious, and ecologically appropriate solutions to vector control.6

A considerable amount of research has been devoted to the development of a dengue vaccine. The live attenuated tetravalent vaccine, CYD-TDV, has been registered in several countries. CYD-TDV is indicated for individuals 9-60 years of age who are living in an area with endemic dengue. Mathematical models have been carried out that demonstrate the possible effect of the CYD-TDV vaccine over time. The greatest effect of vaccination is in settings with high transmission intensity (seroprevalence > 70% at 9 years) where the reduction in symptomatic and hospitalized dengue ranged from 10-30% over a 30-year period. In contrast, the models predicted an increase in dengue hospitalization rates in very low transmission intensity settings (seroprevalence 10% at 9 years). This finding suggests that the vaccine may act like an asymptomatic infection in a previously seronegative individual, setting up the individual for a secondary-like infection if he or she is exposed to the dengue virus. Therefore, the WHO takes a stance that the vaccine should be considered for regions with seroprevalence > 70%, but it is not recommended for regions with seroprevalence < 50%.7 The CYD-TDV vaccine, as well as other vaccines in development, will continue to be researched to provide an efficacious and safe method for dengue prevention.

REFERENCES

  1. Thomas DL, Santiago GA, Abeyta R, et al. Reemergence of dengue in southern Texas, 2013. Emerg Infect Dis 2016;22:1002-1007.
  2. Añez G, Rios M. Dengue in the United States of America: A worsening scenario? Biomed Res Int 2013;2013:678645.
  3. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Dengue and dengue hemorrhagic fever. 2009.
  4. Muller DA, Depelsenaire AC, Young PR. Clinical and laboratory diagnosis of dengue virus infection. J Infect Dis 2017;215(Suppl 2):S89-S95.
  5. Hermann LL, Gupta SB, Manoff SB, et al. Advances in the understanding, management, and prevention of dengue. J Clin Virol 2015;64:153-159.
  6. World Health Organization. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. World Health Organization; 2009.
  7. [No authors listed]. Dengue vaccine: WHO position paper — July 2016. Wkly Epidemiol Rec 2016;91:349-364.