Dengue and severe dengue
J. E Cogan
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Dengue and severe dengue

2 March 2020

Key facts

  • Dengue is a mosquito-borne viral infection.
  • The virus responsible for causing dengue, is called dengue virus (DENV). There are four DENV serotypes, meaning that it is possible to be infected four times.
  • While many DENV infections produce only mild illness, DENV can cause an acute flu-like illness. Occasionally this develops into a potentially lethal complication, called severe dengue.
  • Severe dengue is a leading cause of serious illness and death in some Asian and Latin American countries. It requires management by medical professionals.
  • There is no specific treatment for dengue/severe dengue. Early detection of disease progression associated with severe dengue, and access to proper medical care lowers fatality rates of severe dengue to below 1%.
  • Dengue is found in tropical and sub-tropical climates worldwide, mostly in urban and semi-urban areas.
  • The global incidence of dengue has grown dramatically in recent decades. About half of the world's population is now at risk. There are an estimated 100-400 million infections each year.
  • Dengue prevention and control depends on effective vector control measures. Sustained community involvement can improve vector control efforts substantially.

Dengue is a mosquito-borne viral disease that has rapidly spread in all regions of WHO in recent years. Dengue virus is transmitted by female mosquitoes mainly of the species Aedes aegypti and, to a lesser extent, Ae. albopictus. These mosquitoes are also vectors of chikungunya, yellow fever and Zika viruses. Dengue is widespread throughout the tropics, with local variations in risk influenced by rainfall, temperature, relative humidity and unplanned rapid urbanization.

Dengue causes a wide spectrum of disease. This can range from subclinical disease (people may not know they are even infected) to severe flu-like symptoms in those infected. Although less common, some people develop severe dengue, which can be any number of complications associated with severe bleeding, organ impairment and/or plasma leakage. Severe dengue has a higher risk of death when not managed appropriately. Severe dengue was first recognized in the 1950s during dengue epidemics in the Philippines and Thailand. Today, severe dengue affects most Asian and Latin American countries and has become a leading cause of hospitalization and death among children and adults in these regions.

Dengue is caused by a virus of the Flaviviridae family and there are four distinct, but closely related, serotypes of the virus that cause dengue (DENV-1, DENV-2, DENV-3 and DENV-4). Recovery from infection is believed to provide lifelong immunity against that serotype. However, cross-immunity to the other serotypes after recovery is only partial, and temporary. Subsequent infections (secondary infection) by other serotypes increase the risk of developing severe dengue.

Dengue has distinct epidemiological patterns, associated with the four serotypes of the virus. These can co-circulate within a region, and indeed many countries are hyper-endemic for all four serotypes. Dengue has an alarming impact on both human health and the global and national economies. DENV is frequently transported from one place to another by infected travellers; when susceptible vectors are present in these new areas, there is the potential for local transmission to be established.

Global burden of dengue

The incidence of dengue has grown dramatically around the world in recent decades. A vast majority of cases are asymptomatic or mild and self-managed, and hence the actual numbers of dengue cases are under-reported. Many cases are also misdiagnosed as other febrile illnesses [1].

One modelling estimate indicates 390 million dengue virus infections per year (95% credible interval 284–528 million), of which 96 million (67–136 million) manifest clinically (with any severity of disease) [2]. Another study on the prevalence of dengue estimates that 3.9 billion people are at risk of infection with dengue viruses. Despite a risk of infection existing in 129 countries [3], 70% of the actual burden is in Asia [2].

The number of dengue cases reported to WHO increased over 15 fold over the last two decades, from 505,430 cases in 2000 to over 2,400,138 in 2010 and 3,312,040 in 2015. Deaths from  2000 to 2015 increased from 960 to more than 4032.

This alarming increase in case numbers is partly explained by a change in national practices to record and report dengue to the Ministries of Health, and to the WHO. But it also represents government recognition of the burden, and therefore the pertinence to report dengue disease burden. Therefore, although the full global burden of the disease is uncertain, this observed growth only brings us closer to a more accurate estimate of the full extent of the burden.

Distribution and outbreaks of dengue

Before 1970, only 9 countries had experienced severe dengue epidemics. The disease is now endemic in more than 100 countries in the WHO regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. The America, South-East Asia and Western Pacific regions are the most seriously affected, with Asia representing ~70% of the global burden of disease.

Not only is the number of cases increasing as the disease spreads to new areas including Europe, but explosive outbreaks are occurring. The threat of a possible outbreak of dengue now exists in Europe; local transmission was reported for the first time in France and Croatia in 2010 and imported cases were detected in 3 other European countries. In 2012, an outbreak of dengue on the Madeira islands of Portugal resulted in over 2000 cases and imported cases were detected in mainland Portugal and 10 other countries in Europe. Autochthonous cases are now observed on an almost annual basis in many European countries. Among travellers returning from low- and middle-income countries, dengue is the second most diagnosed cause of fever after malaria.

The largest number of dengue cases ever reported globally was in 2019. All regions were affected, and dengue transmission was recorded in Afghanistan for the first time.

The American region alone reported 3.1 million cases, with more than 25,000 classified as severe. Despite this alarming number of cases, deaths associated with dengue were fewer than in the previous year. 

High number of cases were reported in Bangladesh (101,000), Malaysia (131,000) Philippines (420,000), Vietnam (320,000) in Asia.

The year 2016 was also characterized by large dengue outbreaks with the Region of the Americas reporting more than 2.38 million cases. During that year, Brazil alone contributed approximately 1.5 million cases, approximately three times higher than in 2014; 1032 dengue deaths were also reported in the region. In the same year, the Western Pacific Region reported more than 375,000 suspected cases of which the Philippines reported 176 411 and Malaysia 100 028 cases, representing a similar burden to the previous year for both countries. The Solomon Islands declared an outbreak with more than 7000 suspected. In the African Region, Burkina Faso reported a localized outbreak of dengue with 1061 probable cases.

In 2017, a significant reduction was reported in the number of dengue cases in the Americas - from 2 177 171 cases in 2016 to 584 263 cases in 2017. This represents a reduction of 73%. Panama, Peru and Aruba were the only countries that registered an increase in cases during 2017.

Similarly, a 53% reduction in severe dengue cases was also recorded during 2017. The post-Zika outbreak period (after 2016) saw a decline of cases of dengue and the exact factors leading to this fall are still unknown. WHO’s Western Pacific Region reported dengue outbreaks in several countries in the Pacific, as well as the circulation of DENV-1 and DENV-2 serotypes.

Transmission

Mosquito-to-human transmission

The virus is transmitted to humans through the bites of infected female mosquitoes, primarily the Aedes aegypti mosquito. Other species within the Aedes genus can also act as vectors, but their contribution is secondary to Aedes aegypti.

After feeding on an DENV-infected person, the virus replicates in the mosquito midgut, before it disseminates to secondary tissues, including the salivary glands. The time it takes from ingesting the virus to actual transmission to a new host is termed the extrinsic incubation period (EIP). The EIP takes about 8-12 days when the ambient temperature is between 25-28°C [4-6]. Variations in the extrinsic incubation period are not only influenced by ambient temperature; a number of factors such as the magnitude of daily temperature fluctuations[7, 8], virus genotype [9], and initial viral concentration [10] can also alter the time it takes for a mosquito to transmit virus. Once infectious, the mosquito is capable of transmitting virus for the rest of its life.

Human-to-mosquito transmission

Mosquitoes can become infected from people who are viremic with DENV. This can be someone who has a symptomatic dengue infection, someone who is yet to have a symptomatic infection (they are pre-symptomatic), but also people who show no signs of illness as well (they are asymptomatic) [11].

Human-to-mosquito transmission can occur up to 2 days before someone shows symptoms of the illness [5, 11], up to 2 days after the fever has resolved [12].

Risk of mosquito infection is positively associated with high viremia and high fever in the patient; conversely, high levels of DENV-specific antibodies are associated with a decreased risk of mosquito infection (Nguyen et al 2013 PNAS). Most people are viremic for about 4-5 days, but viremia can last as long as 12 days [13].

Other modes of transmission

The primary mode of transmission of DENV between humans involves mosquito vectors. There is evidence however, of the possibility of maternal transmission (from a pregnant mother to her baby). While vertical transmission rates appear low, with the risk of vertical transmission seemingly linked to the timing of the dengue infection during the pregnancy [14-17]. When a mother does have a DENV infection when she is pregnant, babies may suffer from pre-term birth, low birthweight, and fetal distress [18].

Vector Ecology

The Aedes aegypti mosquito is considered the primary vector of DENV. It lives in urban habitats and breeds mostly in man-made containers. Ae. aegypti is a day-time feeder; its peak biting periods are early in the morning and in the evening before sunset [19]  Female Ae. aegypti frequently feed multiple times between each egg-laying period [20]. Once a female has laid her eggs, these eggs can remain viable for several months, and will hatch when they in contact with water.

Aedes albopictus, a secondary dengue vector in Asia, has spread to more than 32 states in the USA, and more than 25 countries in the European Region, largely due to the international trade in used tyres (a breeding habitat) and other goods (e.g. lucky bamboo). Ae. albopictus is highly adaptive. Its geographical spread is largely due to its tolerance of colder conditions, as an egg and adult [21, 22]Aedes albopictus has been implicated as the primary vector of DENV in a limited number of outbreak, where Aedes aegypti is either not present, or present in low numbers [23, 24]

Disease characteristics (signs and symptoms)

Dengue is a severe, flu-like illness that affects infants, young children and adults, but seldom causes death. Symptoms usually last for 2–7 days, after an incubation period of 4–10 days after the bite from an infected mosquito [25]. The World Health Organization classifies dengue into 2 major categories: dengue (with / without warning signs) and severe dengue. The sub-classification of dengue with or without warning signs is designed to help health practitioners triage patients for hospital admission, ensuring close observation, and to minimise the risk of developing the more severe dengue (see below).

Dengue

Dengue should be suspected when a high fever (40°C/104°F) is accompanied by 2 of the following symptoms during the febrile phase:

  • severe headache
  • pain behind the eyes
  • muscle and joint pains
  • nausea
  • vomiting
  • swollen glands
  • rash. 

Severe dengue

A patient enters what is called the critical phase normally about 3-7 days after illness onset. It is at this time, when the fever is dropping (below 38°C/100°F) in the patient, that warning signs associated with severe dengue can manifest. Severe dengue is a potentially fatal complication, due to plasma leaking, fluid accumulation, respiratory distress, severe bleeding, or organ impairment.

Warning signs that doctors should look for include:

  • severe abdominal pain
  • persistent vomiting
  • rapid breathing
  • bleeding gums
  • fatigue
  • restlessness
  • blood in vomit. 

If patients manifest these symptoms during the critical phase, close observation for the next 24–48 hours is essential so that proper medical care can be provided, to avoid complications and risk of death.

Diagnostics

Several methods can be used for diagnosis of DENV infection. These include virological tests (that directly detect elements of the virus) and serological tests, which detect human-derived immune components that are produced in response to the virus). Depending on the time of patient presentation, the application of different diagnostic methods may be more or less appropriate. Patient samples collected during the first week of illness should be tested by both serological and virological methods (RT-PCR).

Virological methods

The virus may be isolated from the blood during the first few days of infection. Various reverse transcriptase–polymerase chain reaction (RT–PCR) methods are available. In general, RT–PCR assays are sensitive, but they require specialised equipment and technical training for staff implementing the test, therefore they are not always available in all medical facilities. RT–PCR products from clinical samples may also be used for genotyping of the virus, allowing comparisons with virus samples from various geographical sources.

The virus may also be detected by testing for a virus-produced protein, called NS1. There are commercially-produced rapid diagnostic tests available for this, because it takes only ~20 mins to determine the result, and the test does not require specialized laboratory techniques or equipment.

Serological methods

Serological methods, such as enzyme-linked immunosorbent assays (ELISA), may confirm the presence of a recent or past infection, with the detection of IgM and IgG anti-dengue antibodies. IgM antibodies are detectable ~1 week after infection and are highest at 2 to 4 weeks after the onset of illness. They remain detectable for about 3 months. The presence of IgM is indicative of a recent DENV infection. IgG antibody levels take longer to develop than IgM, but IgG remain in the body for years. The presence of IgG is indicative of a past infection.

Treatment

There is no specific treatment for dengue fever.

Fever reducers and pain killers can be taken to control the symptoms of muscle aches and pains, and fever.

  • The best options to treat these symptoms are acetaminophen or paracetamol.
  • NSAIDs (non-steroidal anti-inflammatory drugs), such as ibuprofen and aspirin should be avoided. These anti-inflammatory drugs act by thinning the blood, and in a disease with risk of hemorrhage, blood thinners may exacerbate the prognosis.

For severe dengue, medical care by physicians and nurses experienced with the effects and progression of the disease can save lives – decreasing mortality rates from more than 20% to less than 1%. Maintenance of the patient's body fluid volume is critical to severe dengue care. Patients with dengue should seek medical advice upon the appearance of warning signs.

Vaccination against dengue

The first dengue vaccine, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur was licensed in December 2015 and has now been approved by regulatory authorities in ~20 countries. In November 2017, the results of an additional analysis to retrospectively determine serostatus at the time of vaccination were released. The analysis showed that the subset of trial participants who were inferred to be seronegative at time of first vaccination had a higher risk of more severe dengue and hospitalizations from dengue compared to unvaccinated participants. As such, use of the vaccine is targetted for persons living in endemic areas, ranging from 9-45 years of age, who have had at least 1 documented dengue virus infection previously.

If you know you have dengue, avoid getting further mosquito bites during the first week of illness. Virus may be circulating in the blood during this time, and therefore you may transmit the virus to new uninfected mosquitoes, who may in turn infect other people.

WHO position on the CYD-TDV vaccine

As described in the WHO position paper on the Dengvaxia vaccine (September 2018) the live attenuated dengue vaccine CYD-TDV has been shown in clinical trials to be efficacious and safe in persons who have had a previous dengue virus infection (seropositive individuals). However, it carries an increased risk of severe dengue in those who experience their first natural dengue infection after vaccination (those who were seronegative at the time of vaccination). For countries considering vaccination as part of their dengue control programme, pre-vaccination screening is the recommended strategy. With this strategy, only persons with evidence of a past dengue infection would be vaccinated (based on an antibody test, or on a documented laboratory confirmed dengue infection in the past). Decisions about implementing a pre-vaccination screening strategy will require careful assessment at the country level, including consideration of the sensitivity and specificity of available tests and of local priorities, dengue epidemiology, country-specific dengue hospitalization rates, and affordability of both CYD-TDV and screening tests.

Vaccination should be considered as part of an integrated dengue prevention and control strategy. There is an ongoing need to adhere to other disease preventive measures such as well-executed and sustained vector control. Individuals, whether vaccinated or not, should seek prompt medical care if dengue-like symptoms occur.

Prevention and control

If you know you have dengue, avoid getting further mosquito bites during the first week of illness. Virus may be circulating in the blood during this time, and therefore you may transmit the virus to new uninfected mosquitoes, who may in turn infect other people.

The proximity of mosquito vector breeding sites to human habitation is a significant risk factor for dengue as well as for other diseases that Aedes mosquito transmit. At present, the main method to control or prevent the transmission of dengue virus is to combat the mosquito vectors. This is achieved through:

  • Prevention of mosquito breeding:
    • Preventing mosquitoes from accessing egg-laying habitats by environmental management and modification;
    • Disposing of solid waste properly and removing artificial man-made habitats that can hold water;
    • Covering, emptying and cleaning of domestic water storage containers on a weekly basis;
    • Applying appropriate insecticides to water storage outdoor containers;
  • Personal protection from mosquito bites:
    • Using of personal household protection measures, such as window screens, repellents, insecticide treated materials, coils and vaporizers. These measures must be observed during the day both inside and outside of the home (e.g.: at work/school) because the primary mosquito vectors bites throughout the day;
    • Wearing clothing that minimises skin exposure to mosquitoes is advised;
  • Community engagement:
    • Educating the community on the risks of mosquito-borne diseases;
    • Engaging with the community to improve participation and mobilization for sustained vector control;
  • Reactive vector control:
    • Emergency vector control measures such as applying insecticides as space spraying during outbreaks may be used by health authorities;
  • Active mosquito and virus surveillance:
    • Active monitoring and surveillance of vector abundance and species composition should be carried out to determine effectiveness of control interventions;
    • Prospectively monitor prevalence of virus in the mosquito population, with active screening of sentinel mosquito collections;

In addition, there is ongoing research amongst many groups of international collaborators in search of novel tools and innovative strategies that will contribute in global efforts to interrupt transmission of dengue, as well as other mosquito-borne diseases. The integration of vector management approaches is encouraged by WHO to achieve sustainable, effective locally adapted vector control interventions.

WHO response

WHO responds to dengue in the following ways:

  • supports countries in the confirmation of outbreaks through its collaborating network of laboratories;
  • provides technical support and guidance to countries for the effective management of dengue outbreaks;
  • supports countries to improve their reporting systems and capture the true burden of the disease;
  • provides training on clinical management, diagnosis and vector control at the country and regional level with some of its collaborating centres;
  • formulates evidence-based strategies and policies;
  • support countries in the development of dengue prevention and control strategies and adopting the Global Vector Control Response (2017-2030)
  • reviews the development of new tools, including insecticide products and application technologies;
  • gathers official records of dengue and severe dengue from over 100 Member States; and
  • publishes guidelines and handbooks for surveillance, case management, diagnosis, dengue prevention and control for Member States.

Cited references

 [1] Waggoner, J.J., et al., Viremia and Clinical Presentation in Nicaraguan Patients Infected Wi1. Waggoner, J.J., et al., Viremia and Clinical Presentation in Nicaraguan Patients Infected With Zika Virus, Chikungunya Virus, and Dengue Virus. Clinical Infectious Diseases, 2016. 63(12): p. 1584-1590. 

 [2] Bhatt, S., et al., The global distribution and burden of dengue. Nature, 2013. 496(7446): p. 504–507.

 [3] Brady, O.J., et al., Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLOS Neglected Tropical Diseases, 2012. 6(8): p. e1760.

 [4] Tjaden, N.B., et al., Extrinsic Incubation Period of Dengue: Knowledge, Backlog, and Applications of Temperature Dependence. Plos Neglected Tropical Diseases, 2013. 7(6): p. 5.

[5] Siler, J.F., M.W. Hall, and A.P. Hitchens, Dengue: Its history, epidemiology, mechanism of transmission, etiology, clinical manifestations, immunity and prevention. 1926, Manila: Bureau of Science.

[6] Watts, D.M., et al., Effect of Temperature on the vector efficiency of Aedes aegypti for Dengue 2 virus. American Journal of Tropical Medicine and Hygiene, 1987. 36(1): p. 143-152.

[7] Carrington, L.B., et al., Fluctuations at low mean temperatures accelerate dengue virus transmission by Aedes aegypti. PLOS Neglected Tropical Diseases, 2013. 7(4): p. e2190.

[8] Lambrechts, L., et al., Impact of daily temperature fluctuations on dengue virus transmission by Aedes aegypti. Proceedings of the National Academy of Sciences of the United States of America, 2011. 108(18): p. 7460-7465.

[9] Anderson, J.R. and R. Rico-Hesse, Aedes aegypti vectorial capacity is determined by the infecting genotype of dengue virus. American Journal of Tropical Medicine and Hygiene, 2006. 75(5): p. 886-892.

[10] Ye, Y.X.H., et al., Wolbachia Reduces the Transmission Potential of Dengue-Infected Aedes aegypti. PLOS Neglected Tropical Diseases, 2015. 9(6): p. e0003894.

[11] Duong, V., et al., Asymptomatic humans transmit dengue virus to mosquitoes. Proceedings of the National Academy of Sciences of the USA, 2015. 112(47): p. 14688–14693.

[12] Nguyen, N.M., et al., Host and viral features of human dengue cases shape the population of infected and infectious Aedes aegypti mosquitoes. Proceedings of the National Academy of Sciences of the United States of America, 2013. 110(22): p. 9072-9077.

[13] Gubler, D.J., et al., Viraemia in patients with naturally acquired dengue infection. Bulletin of the World Health Organisation, 1981. 59: p. 623-630.

[14] Basurko, C., et al., Estimating the Risk of Vertical Transmission of Dengue: A Prospective Study. American Journal of Tropical Medicine and Hygiene, 2018. 98(6): p. 1826-1832.

[15] Mazarin, N., J.M. Rosenthal, and J. Devenge, Mother infant dengue transmission during the 2009-2010 dengue epidemic: Observation of four cases. Archives De Pediatrie, 20141.  Waggoner, J.J., et al., Viremia and Clinical Presentation in Nicaraguan Patients Infected With Zika Virus, Chikungunya Virus, and Dengue Virus. Clinical Infectious Diseases, 2016. 63(12): p. 1584-1590.

[16] Sinhabahu, V.P., R. Sathananthan, and G.N. Malavige, Perinatal transmission of dengue: a case report. BMC Research Notes, 2014. 7(795).

[17] Basurko, C., et al., Maternal and foetal consequences of dengue fever during pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology, 2009. 147(1): p. 29-32.

[18] Pouliot, S.H., et al., Maternal Dengue and Pregnancy Outcomes A Systematic Review. Obstetrical & Gynecological Survey, 2010. 65(2): p. 107-118.

[19] Trpis, M., et al., DIEL PERIODICITY IN LANDING OF AEDES-AEGYPTI ON MAN. Bulletin of the World Health Organization, 1973. 48(5): p. 623-629.

[20] Scott, T.W., et al., Longitudinal studies of Aedes aegypti (Diptera: Culicidae) in Thailand and Puerto Rico: Blood feeding frequency. Journal of Medical Entomology, 2000. 37(1): p. 89-101.

[21] Medlock, J.M., et al., Analysis of the potential for survival and seasonal activity of Aedes albopictus (Diptera: Culicidae) in the United Kingdom. Journal of Vector Ecology, 2006. 31(2): p. 292-304.

[22] Romi, R., F. Severini, and L. Toma, Cold acclimation and overwintering of female Aedes albopictus in Roma. Journal of the American Mosquito Control Association, 2006. 22(1): p. 149-151.

[23] Paupy, C., et al., Comparative role of Aedes albopictus and Aedes aegypti in the emergence of dengue and chikungunya in Central Africa. Vector-Borne and Zoonotic Diseases, 2010. 10(3): p. 259-266.

[24] Metselaar, D., et al., AN OUTBREAK OF TYPE-2 DENGUE FEVER IN THE SEYCHELLES, PROBABLY TRANSMITTED BY AEDES-ALBOPICTUS (SKUSE). Bulletin of the World Health Organization, 1980. 58(6): p. 937-943.

[25] World Health, O., Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control. Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control. 2009, Geneva: World Health Organization. 1-147.