Dengue (DENV)

On 25 Jun 2024, CDC issued a Health Advisory for risk of dengue virus (DENV) infections in the United States, due to record high levels of Dengue globally, particularly in the Americas. CDC Health Advisory 25 Jun 2024- Dengue Virus Infections

Overview

Dengue (colloquially known as “break-bone fever”) is a viral illness transmitted primarily by mosquito bites. Like chikungunya and Zika, the most common mosquito vectors are Aedes aegypti and Aedes albopictus. Both mosquito species prefer urban environments and are considered “day-biters,” although they are most active in the early mornings and evenings. Outbreaks are common in much of the world, to include countries in Africa, the Americas, Southeast Asia, the Caribbean, and the Pacific Islands. U.S. territories (American Samoa, Puerto Rico and the U.S. Virgin Islands) and freely associated states (Federated States of Micronesia, Republic of Marshall Islands and the Republic of Palau) experience regular outbreaks of dengue. Imported cases and small outbreaks have occurred in areas of the United States with hot, humid climates, including the Southeastern U.S. and Hawaii.

Only about a quarter of individuals infected with dengue become ill, and most symptomatic cases get better without specific treatment in 1-2 weeks. The most common symptoms are high fever, severe head/eye pain, body aches, nausea and a rash. However, about 5% of cases result in severe disease that can require hospitalization and intensive care. Severe dengue can be fatal.

There are 4 serologically distinct dengue viruses (DENV), conveniently called DENV-1, DENV-2, DENV-3 and DENV-4. Infection with one type of dengue gives permanent immunity only to that specific type, meaning that a person can get dengue again from one of the other serotypes. Importantly, subsequent infections with other serotypes are more likely to result in severe dengue than the first.

Prevention is mainly mosquito-bite avoidance, which is best accomplished by careful use of the DoD Insect Repellent System and Insect Repellent Treatment of Military Uniforms. Vector control activities may also be employed to reduce vector exposure. While there is an FDA-approved dengue vaccine available (Denvaxia), it is only recommended for children aged 9-16 years who have already had laboratory-confirmed dengue. Because DoD personnel are 1) adults and 2) have in most cases not previously had dengue, it is NOT currently recommended for U.S. Forces.

Regional outbreaks of dengue have potential to disrupt military operations due to intense transmission and potentially severe cases. In the event of operational cases, early consultation with the supporting Navy Environmental and Preventive Medicine Unit (NEPMU) and the unit’s operation medical command is critical to ensure that prevention activities are optimized.

Clinical Features:

Dengue has an incubation period of 5-7 days, with approximately 75% of infections being asymptomatic.

Phases of Illness: Dengue Fever is characterized by 3 distinct phases: Febrile, Critical and Convalescent. Progression to severe dengue typically occurs in the late febrile to critical phases, and clinical alertness for progression is essential for reducing mortality.

Febrile Phase (2-7 days): Dengue Fever is characterized by the abrupt onset of fever, severe headache, retro-orbital eye pain, muscle/joint/bone pain, and maculopapular or petechial rash. Minor hemorrhagic signs may also present, including petechia, ecchymosis, purpura, epistaxis, bleeding gums, hematuria or a positive tourniquet test. CBC is characterized by prominent leukopenia; thrombocytopenia is also common.

Critical Phase (24-48 hrs): While most patients clinically improve upon defervescence, plasma leakage (where plasma escapes the small vessels and becomes extravascular) may rapidly evolve to irreversible shock.

Warning Signs: Vomiting, abdominal pain, liver enlargement, fluid accumulation (ascites, edema), difficulty breathing (pleural effusion), major hemorrhagic signs (hematemesis, melena, significant mucosal bleeding), lethargy/restlessness, postural hypotension, decreased pulse pressure (due to a rising diastolic BP), rising hematocrit.

Convalescent Phase: Plasma leakage resolves and hemodynamic status stabilizes. Diuresis and desquamation of rash are common.

WHO Classification of dengue is notable in that previously described warning signs do not automatically indicate severe dengue. Definitions are clinical and as follows:

Dengue: a combination of ≥2 clinical findings in a febrile person who traveled to or lives in a dengue-endemic area. Clinical findings include nausea, vomiting, rash, aches and pains, a positive tourniquet test, leukopenia, and the following warning signs: abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy, restlessness, and liver enlargement.

Severe Dengue: dengue with any of the following symptoms: severe plasma leakage leading to shock or fluid accumulation with respiratory distress; severe bleeding; or severe organ impairment such as elevated transaminases ≥1,000 IU/L, impaired consciousness, or heart impairment.

Treatment: There is no specific treatment for Dengue. Since aspirin and NSAIDs (e.g. Motrin) can worsen the hemorrhagic picture of dengue, acetaminophen (Tylenol) should be used preferentially for fever and pain control until diagnostic testing rules out dengue.

Diagnostic Testing

Dengue virus infection should be strongly considered in patients with acute onset of febrile illness in travelers or deployers either in or recently returned from areas with known or suspected virus transmission. If the patient has been in areas where malaria is also present, malaria testing should also be performed. Molecular testing (either RT-PCR or Antigen testing for NS1) is recommended during the febrile phase of illness. IgM may also be useful, particularly after the first few days of illness. IgG is a less useful test, particularly during the febrile phase of illness, because it rises later in the course of illness. Also, a positive IgG result is non-specific and may indicate prior dengue infection or be due to cross-reactivity with other flavivirus antibodies (e.g. West Nile Virus, Yellow Fever vaccine, or Japanese Encephalitis vaccine). Convalescent serum collection and testing is necessary if IgG is used.

From CDC Yellow Book, 2024

The Biofire Global Fever Panel tests (RT-PCR) for all 4 Dengue serotypes.

Additionally, Dengue RT-PCR and ELISA IgM testing for DoD personnel may be performed within the DoD at the Naval Infectious Diseases Diagnostic Laboratory (NIDDL): NIDDL Dengue Testing Instructions

Operational Public Health

Because most dengue cases are asymptomatic, a single known case in an operational environment is a red flag. This likely indicates more widespread exposure with current undiagnosed cases and more symptomatic cases expected soon. Operational leaders should be advised of the increased threat, and strict adherence to proper uniform wear and repellent use as described in DoD Insect Repellent System and Insect Repellent Treatment of Military Uniforms is essential to limit future cases. Mosquito management measures should be implemented, to include larval breeding site reduction (i.e., removal of standing water) and pesticide application if possible and appropriate.

Public Health Case Management:

Ensure appropriate clinical testing is being conducted (see Diagnostic Testing).
Dengue patients should be housed in a screened area away from other patients during their infective period (typically 7 days, which may coincide with fever and viremia) to break the mosquito-human transmission cycle. While dengue is not spread person-to-person, mosquitos become infected by feeding on a dengue patient and then transmitting the virus by feeding on another person.
Enhanced surveillance for febrile illness should be initiated, and a line list should be prepared and populated with confirmed and suspected cases.
Cases should be reported through DRSi (see Reporting)

Risk Communication: Consider working with Public Affairs to implement a dengue public awareness campaign.

Contact local Preventive Medicine (if available) for support. The cognizant Navy Environmental and Preventive Medicine Unit (NEPMU) can advise on and/or assist with case investigation activities, laboratory testing, and vector control measures.

Web Resources

Center for Disease Control and Prevention (CDC): CDC Dengue Main Page
Center for Disease Control and Prevention (CDC) “Yellow Book”, 2024: CDC Yellow Book-Dengue
World Health Organization: WHO Dengue Page
Pan American Health Organization: PAHO Dengue Resources

Policy and Guidance

Mosquito Bite Avoidance-Vector Control

Apply 25-30% DEET or 20% picaridin based repellents on exposed skin and treat clothing with a permethrin-containing product.
Wear long-sleeved light-colored shirts and pants whenever outdoors or in places where mosquitoes may be present.
Reduce the number of breeding mosquitoes by removing water from any containers around buildings.
Limit vegetation around buildings to prevent overgrowth and potential mosquito harborages.

Reporting

Dengue is a nationally notifiable disease. BUMEDINST 6220.12C and NMCPHC-TM-PM 6220.12 require that all cases of Dengue be reported to Preventive Medicine authorities. Notify your Public Health Emergency Officer, cognizant Navy Environmental and Preventive Medicine Unit (NEPMU), and state or local health department so that measures can be taken to mitigate the risk of local transmission. NEPMU staff can advise on and/or assist with case investigation activities, laboratory testing, and vector control measures. NMCFHPC Medical Surveillance and Reporting Resources

Case Classification per Armed Forces Medical Reportable Events Guide

Probable:
A case that meets the clinical description as described above with:

• Dengue positive IgM antibody from CSF or serum where alternate flavivirus exposure has not been ruled out

Confirmed:
A case that meets the clinical description as described above with any of the following:

• Dengue nucleic acid (RNA) detected (example: PCR, sequencing, NAAT) from any clinical specimen or
• Dengue positive antigen by DFA or IFA from tissue or
• Histopathologic identification of dengue antigen by IHC from tissue
• Dengue NS1 positive antigen from serum or plasma or
• Dengue identified by culture from a serum, plasma, or CSF or
• Dengue positive IgM antibody from serum or CSF in a person who has had no documented exposure to other flaviviruses (example: Yellow Fever virus, Japanese encephalitis virus, West Nile virus) or recent receipt of a flavivirus vaccine or
• Seroconversion from a negative IgM in an acute sera collected < 5 days after illness onset followed by a positive IgM in convalescent sera collected > 5 days after illness onset or
• Seroconversion from a negative IgG followed by a positive IgG in samples separated by at least 2 weeks or
• At least a four-fold increase of antibody titer between paired acute and convalescent sera separated by at least 2 weeks followed by a confirmatory neutralization test (example: PRNT, ELISA) that has a greater than four-fold higher end point titer as compared to the other flaviviruses tested with it.

Critical Reporting Elements: Serotype (if known). Travel and/or deployment history during the incubation period, circumstances of exposure if known (e.g. duty, occupation, environmental factors).

Epidemiology and Publications

AFHSD MSMR Feb 2021 Vo1 28 No. 2 Surveillance for Vector Borne Diseases among AD, 2016-2020
AFHSD MSMR 2018 Vol 25 No. 2 Surveillance for Vector Borne Diseases among AD, 2010-2016
Hesse EM, Martinez LJ, Jarman RG, Lyons AG, Eckels KH, De La Barrera RA, Thomas SJ. Dengue Virus Exposures Among Deployed U.S. Military Personnel Am J Trop Med Hyg. 2017 May;96(5):1222-1226. doi: 10.4269/ajtmh.16-0663. Epub 2017 Feb 13. PMID: 28193746; PMCID: PMC5417220.
Hayes CG, O’Rourke TF, Fogelman V, et al. Dengue Fever in US Military Personnel in the 1984 Philippines Outbreak NAMRU-2, Southeast Asian J Trop Med Pub Health Vol. 20 No. 1 March 1989
Melanson VR, Ryu M, Gagnon M, et al. Combating Dengue: A US Military Perspective Virology & Retrovirology Journal. 2019; 2(2):123
Center for Disease Control and Prevention (CDC): Geography and US Cases

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