Dengue Fever

Disease Overview

Summary

Dengue fever is a virus transmitted by the bite of a female Aedes mosquito (Aedes aegypti and Aedes albopictus) carrying dengue virus. The infection is caused by one of four dengue viruses (DENV 1-4).These mosquitos also spread Zika, chikungunya and other viruses. More than half of the world population is at risk of dengue. Dengue outbreaks are occurring in many countries of the world including Latin America, the Caribbean and Southeast Asia. Asia accounts for 75% of the dengue disease burden, followed by Latin America and Africa. Each year, about 58 million people get sick from a dengue infection and 13,500 die from it.

Dengue fever is an acute viral infection characterized by fever and flu-like symptoms. Presentation varies ranging from no symptoms to a mild fever to a life-threatening shock and/or hemorrhage syndrome. Approximately 75% of individuals infected do not show any symptoms. Those who do show symptoms most commonly present with a mild to moderate, nonspecific fever 3-10 days after the bite of the infected mosquito. Other common symptoms along with the fever include a skin rash, severe headache, pain behind the eyes, in the muscles and joints. For many affected individuals, the disease is self-limited, ending with full recovery after symptoms resolve in 5-7 days.

Up to 5% of all dengue affected individuals develop severe, life-threatening disease. Warning signs of progression to severe dengue include persistent vomiting, severe abdominal pain, rapid breathing, extreme fatigue, bleeding gums and a drop in blood pressure with position change.

There are no specific medications for dengue and affected individuals are advised to stay well hydrated and control their fever with acetaminophen and tepid sponge baths. There are no medications to prevent dengue and travelers in endemic areas (high risk areas) are advised to avoid mosquito bites by staying indoors, wearing long clothing that cover their arm and legs, using bed nets and insect repellants.

From 1975 to 2009, symptomatic dengue virus infections were classified according to the World Health Organization (WHO) guidelines as dengue fever, dengue hemorrhagic fever (DHF), and dengue shock syndrome (the most severe form of DHF). In 2009, the WHO issued a new guideline that classified cases as:

dengue without warning signs
dengue with warning signs
severe dengue

Introduction

Dengue infection is caused by one of four dengue viruses (DENV 1-4). Being infected from one dengue virus does not protect a person from the others. A primary dengue infection is when an individual is infected with the virus for the first time; a secondary infection is when the same individual is infected a second time with a different dengue virus. If the secondary dengue infection is more than 2 years after the primary infection, there is a higher risk of developing severe symptoms.

Individuals with suspected dengue should seek help from a healthcare provider for early recognition of warning signs and prompt initiation of aggressive therapy when necessary.

Severe dengue (previously known as dengue hemorrhagic fever) was first recognized in the 1950s during dengue epidemics in the Philippines and Thailand. Today it affects over a hundred countries and has become one of the leading causes of hospitalization among individuals in these regions.

Next section >

< Previous section
Next section >

Synonyms

dengue
dengue virus
breakbone fever
dandy fever

< Previous section
Next section >

< Previous section
Next section >

Signs & Symptoms

Dengue has a wide clinical spectrum with some individuals showing no symptoms, while others show mild symptoms to severe symptoms. The incubation period is a period between being infected with the virus to appearance of the first symptoms and for dengue it lasts 3-10 days. Approximately 25% experience a self-limited febrile illness, accompanied by mild-to-moderate haematological and biochemical abnormalities. Clinically relevant complications develop in a small proportion of these patients, including a systemic vascular leak syndrome, coagulation abnormalities that can be associated with bleeding, and organ involvement, typically hepatic or neurological. However, although these severe complications are infrequent the spectrum of clinical manifestations is broad. The most important risk factor for severe dengue is a prior dengue infection. The risk of developing severe dengue is greatest after a secondary infection with a different infecting type of dengue virus.

The three classifications recommended by WHO are (1) dengue without warning signs, (2) dengue with warning signs and (3) severe dengue

Dengue without warning signs: if an individual resides in or has traveled to an endemic area and has fever with any of the following:
- Headache, eye pain
- Nausea, vomiting
- Muscle and joint pain
- Maculopapular rash (flat or raised skin rash) over the face, chest, abdomen and arms/legs
- Aches and pains (eye pain, typically behind the eyes, muscle joint or bone pain)

For many affected individuals, the disease is self-limited, ending with full recovery after symptoms resolves in 5-7 days.

Dengue with warning signs of severe dengue: at day 3-7 after symptom onset, a small portion of symptoms do not resolve and progress to any of the following:
- Severe abdominal pain
- Persistent vomiting
- Extreme fatigue or restlessness
- Spontaneous bleeding in the mucosa (ex: gums)
- Vomiting blood
- Rapid breathing

When these warning signs are seen, the affected individual should be rushed to the emergency room or to the closest health care provider.

Severe dengue:
- Severe bleeding
- Severe organ impairment (organ failure, impaired consciousness)
- Severe plasma leakage from the blood vessels leading to a drop in blood pressure and/or fluid accumulating outside the blood vessels

< Previous section
Next section >

< Previous section
Next section >

Causes

Transmission
Dengue fever is a virus transmitted by the bite of a female Aedes mosquito (Aedes aegypti and Aedes albopictus) carrying dengue virus. The infection is caused by one of four dengue viruses (DENV 1-4). These mosquitos also spread Zika, chikungunya and other viruses.

Once an individual is bit by an infected mosquito, the mosquito transmits the virus to that individual. The individual then becomes a carrier of the virus and the virus multiplies inside them. The virus circulates inside the blood of the infected person for 2-7 days during which time they become a source of the virus for uninfected mosquitos and can transmit the infection to another individual via Aedes mosquitos.

When an individual recovers from the infection by one dengue virus, they become immune against that particular type of virus but can be infected by any of the other dengue virus types.

< Previous section
Next section >

< Previous section
Next section >

Affected populations

There is a high risk of contracting dengue throughout the tropics and subtropics and it is the leading cause of fever among travelers returning from Latin America, the Caribbean and Southeast Asia. Sporadic outbreaks with local transmission have also been seen in Florida, Hawaii and Texas along the border with Mexico. The geographic distribution of dengue is similar to that of malaria; however the risk for dengue is higher in urban and residential areas versus malaria which is found in rural areas.

< Previous section
Next section >

< Previous section
Next section >

Disorders with Similar Symptoms

Chikungunya
Chikungunya virus and dengue cause similar symptoms and are also transmitted by the same mosquito vector. Chikungunya is a viral infection transmitted by the bite of an infected mosquito. The most common symptoms are fever and joint pain, however other symptoms include headache, muscle pain, joint swelling and a rash. Symptoms typically being 3-7 days after being bitten by the infected mosquito. Most affected individuals feel better within a week, however in some people the joint pain may last for months or years. It primarily occurs in tropical areas of the world. (For more information on this disorder, choose “Chikungunya” as your search term in the Rare Disease Database.)

Zika Virus
Zika virus and dengue have similar symptoms and are transmitted by the same mosquito vector. Zika is primarily transmitted by the bite of an infected mosquito, but it is also transmitted from a pregnant woman to her fetus, through sexual contact, blood transfusion and organ transplant. Zika infection during pregnancy is a cause of congenital abnormalities in the developing fetus and newborn including microcephaly (smaller head circumference than normal). It can also result in pregnancy complications such as fetal loss, stillbirth and preterm birth. Many infected individuals will not have symptoms or will only have mild symptoms including a fever, rash, headache joint pain, red eyes (conjunctivitis) and muscle pain lasting for several days to a week.

Malaria
Malaria is a communicable parasitic disorder spread through the bite of the Anopheles mosquito. Major symptoms may vary depending on which species of parasite causes the infection and the stage of development of the parasite. Chills and fever commonly occur, although not every case follows the same pattern. Although the disorder was once thought to be under control throughout the world, malaria is a widespread infection especially in the tropics where certain types of mosquitos are becoming resistant to pesticides. The annual number of cases reported in the United States has increased in recent years. (For more information on this disorder, choose “Malaria” as your search term in the Rare Disease Database.)

Other viruses
Other viruses that can cause a hemorrhagic fever include Ebola virus, Yellow fever virus, Crimean Congo hemorrhagic fever, Marburg virus etc. Viral hemorrhagic fevers are a group of illness that cause severe multisystem syndrome (multiple organ systems are affected) and also cause internal bleeding (hemorrhage). Blood tests may be used to identify the virus.

< Previous section
Next section >

< Previous section
Next section >

Diagnosis

Dengue can be suspected in an individual showing the symptoms listed above and if they reside in or have traveled within the past 2 weeks to an endemic area. Early clinical presentation of dengue is similar to other viral infections such as Zika and Chikungunya; therefore laboratory tests are useful in such cases.

During the incubation period after the mosquito bites, the infected individual presents with no symptoms, however during this period the virus replicates, and an antibody response is developed.

Clinical Testing and Work-Up
A blood test can be done to detect particles of the genetic material of the virus or it can indirectly detect the increase in antibody to fight off the virus. Depending on the duration of the illness and when the patient presents for the evaluation, the health care professional will decide which test is more appropriate.

Molecular testing: during the first week of the illness, the diagnosis may be established by directly detecting particles of the virus in the blood. Some of the tests used to detect the virus are RT-PCR and real time RT-PCR, NS1 Ag rapid tests, NAAT, NS1 Ag ELISA and immunohistochemistry.
Antibody testing: the antibody IgM can be detected as early as four days after the onset of illness. On average, IgM is detected in 50% of cases by day 3-4 after the onset of the illness, peaks at day 10-14 and disappears after about 3 months. In primary infection dengue IgG can be detected at day 9-10 and is thought to persist for life. Some of the tests to detect increased antibody levels are ELISA, antibody rapid tests, Neutralization test, IgG ELISA and HIA.

Performing a molecular and IgM antibody test can detect more cases than performing just one test during the first week after symptom onset.

If an individual has symptoms of dengue and resides in or has traveled to an endemic area, they should seek help from a healthcare professional. During the initial evaluation, the healthcare provider will review the individual’s past medical history, recent travel history and vaccination record to determine the likelihood that the illness is due to dengue.

If the infected individual presents to the healthcare provider within the first week of symptom onset, performing both a molecular test and an IgM antibody is preferred rather than one test.

If the infected individual presents more than seven days after symptom onset, antibody testing is preferred.

Dengue virus testing is not recommended for individuals who do not show symptoms after the incubation period.

< Previous section
Next section >

< Previous section
Next section >

Standard Therapies

Treatment
There is no treatment for the virus that causes dengue, but the symptoms can be managed and treated. Management is largely supportive and maintaining adequate fluid volume in the blood vessels by keeping the patient hydrated. Infected individuals with mild symptoms in the absence of warning signs may be told by their doctor to stay home. In these cases, the individual should rest and drink plenty of fluids and watch for signs of dehydration (decreased urination, dry mouth or lips, cold hands or feet). Acetaminophen (Tylenol) can also be taken to relieve fever and aches. It is not recommended to take aspirin or NSAIDS (such as ibuprofen – Advil, Motrin) or Naproxen (Aleve) as they can increase the risk of bleeding. These individuals should also be aware of the warning signs of severe dengue infection and present to the hospital if warning signs are present or symptoms get worse.

If the infected individual’s symptoms are more severe and presents with warning signs of severe infection, the doctor may decide to admit them to the hospital. Treatments in the hospital may include getting fluids through IV. Some individuals are at higher risk of developing severe dengue such as pregnant women, infants, elderly and individuals with asthma, obesity, diabetes, kidney failure or certain blood diseases.

Prevention
The best way to prevent dengue is to stay away from mosquitos that carry it. This can be done by

Staying indoors during the day in an airconditioned building when these mosquitos are most active
Wearing shoes, long-sleeved shirts, long pants and hats when going outdoors
Wearing bug spray or cream that contains DEET or picaridin.
Using bug repellants on clothes and gear
Using a bed net during sleep
Draining standing water near your house such as wading pools and buckets as mosquitos breed in standing water

Vaccination
CYD-TDV (Dengvaxia) is a vaccine that was approved in Europe in 2018 and by the US Food and Drug Administration (FDA) in 2019 for use in dengue endemic territories and only in children ages 9-16 years of age with evidence of a previous dengue infection. It is approved in other countries for people aged 9-45 years of age. It is not yet approved for travelers visiting dengue endemic areas and is not commercially available in the United States or Europe. The main approach to avoid dengue in travelers is to avoid mosquitos carrying the dengue virus.

The World Health Organization (WHO), European Union and the Unites States regulatory agencies recommend the use of this vaccine only for individuals with laboratory evidence of previous dengue infection as a secondary infection can be more severe. Dengue vaccines are not 100% effective, however, and immunized individuals may present with a milder infection. The vaccine does not provide protection to people who have not had a dengue infection and should not be administered to seronegative persons.

< Previous section
Next section >

< Previous section
Next section >

Clinical Trials and Studies

A tetravalent dengue vaccine candidate is currently being studied in a clinical trial in Asia and Latin America by Takeda to determine the efficacy of 2 doses of this vaccine in preventing symptomatic dengue fever of any severity due to any of the four dengue virus serotypes in 4-16-year-olds. Another promising vaccine candidate developed by the National Institute of Allergy and Infectious Diseases is being studied in Brazil in people 2-50 years of age. This vaccine is only one dose.

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

< Previous section
Next section >

< Previous section
Next section >

References

BOOKS
Handbook for clinical management of dengue. Geneva, Switzerland: World Health Organization; 2012. https://apps.who.int/iris/bitstream/handle/10665/76887/9789241504713_eng.pdf?sequence=1&isAllowed=y

Dengue Guidelines for Diagnosis Treatment Prevention and Control: New Edition. Geneva, Switzerland: World Health Organization; 2009. https://apps.who.int/iris/bitstream/handle/10665/44188/9789241547871_eng.pdf?sequence=1.

JOURNAL ARTICLES
Messina JP Brady OJ, Golding N, et al. The current and future global distribution and population at risk of dengue, Nat Microbiol. 2019;4:1508–1515. https://doi.org/10.1038/s41564-019-0476-8.

Wilder-Smith A, Ooi EE, Horstick O, Wills B. Dengue. Lancet. 2019 Jan 26;393(10169):350-363. doi: 10.1016/S0140-6736(18)32560-1.

Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. Antibody399 dependent enhancement of severe dengue disease in humans. Science (New York, NY). 2017;358(6365):929-32.

Stanaway JD, Shepard DS, Undurraga EA, et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect Dis. 2016: Jun;16(6):712-723.
doi: 10.1016/S1473-3099(16)00026-8. Epub 2016 Feb 10.

Bhatt, PW Gething, OJ Brady, et al. The global distribution and burden of dengue.Nature 2013;496:504-507.

Nujum ZT, Thomas A, Vijayakumar K, et al. Comparative performance of the probable case definitions of dengue by WHO (2009) and the WHO-SEAR expert group (2011). Pathog Glob Health. 2014;108(2):103-110. doi:10.1179/2047773214Y.0000000131. Published March 2014.

Anders KL, Hay SI. Lessons from malaria control to help meet the rising challenge of dengue. Lancet Infect Dis. 2012;12(12):977-984. doi:10.1016/S1473-3099(12)70246-3.

INTERNET
Dengue. Center for Disease Control and Prevention. Updated July 14, 2020. https://www.cdc.gov/dengue/index.html. Accessed Feb 9, 2021.

Dengue – Testing Guidance. Center for Disease Control and Prevention. Updated January 24, 2020 https://www.cdc.gov/dengue/healthcare-providers/testing/testing-guidance.html.. Accessed Feb 9, 2021.

Thomas SJ, Rothman AL, Srikiatkhachorn A and Kalayanarooj S. Dengue virus infection: prevention and treatment. UpToDate. Updated: Oct 27, 2020. https://www.uptodate.com/contents/dengue-virus-infection-prevention-and-treatment. Accessed Feb 9, 2021.

Zika Virus. Center for Disease Control and Prevention. Updated November 20, 2019. https://www.cdc.gov/zika/index.html. Accessed Feb 9, 2021.

Dengue Vaccine. Center for Disease Control and Prevention. Updated September 23, 2019. https://www.cdc.gov/dengue/prevention/dengue-vaccine.html. Accessed Feb 9, 2021.

Chikungunya Virus. Center for Disease Control and Prevention. Updated September 19, 2019. https://www.cdc.gov/chikungunya/index.html. Accessed Feb 9, 2021.

Thomas SJ, Rothman AL, Srikiatkhachorn A and Kalayanarooj S. Dengue virus infection: clinical manifestations and diagnosis. UpToDate Updated: Nov 25, 2019. https://www.uptodate.com/contents/dengue-virus-infection-clinical-manifestations-and-diagnosis#:~:text=Infection%20may%20be%20asymptomatic%20or,%2C%20disease%2C%20and%20disease%20severity. Accessed Feb 9, 2021.

Zika Virus. World Health Organization. Updated July 20, 2018. https://www.who.int/news-room/fact-sheets/detail/zika-virus. Accessed Feb 9, 2021.

Viral Hemorrhagic Fevers (VHFs). Center for Disease Control and Prevention. Updated January 29, 2014. https://www.cdc.gov/vhf/index.html. Accessed Feb 9, 2021.

Promoting dengue vector surveillance and control. World Health Organization. https://www.who.int/denguecontrol/disease/en/. Accessed Feb 9, 2021.

< Previous section
Next section >

Programs & Resources

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/