Dengue and severe dengue

 

Overview

Dengue is a mosquito-borne viral disease that has rapidly spread to 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 climate parameters as well as social and environmental factors.

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

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 8 fold over the last two decades, from 505,430 cases in 2000, to over 2.4 million in 2010, and 5.2 million in 2019. Reported deaths between the year 2000 and 2015 increased from 960 to 4032, affecting mostly younger age group. The total number of cases seemingly decreased during years 2020 and 2021, as well as for reported deaths. However, the data is not yet complete and COVID-19 pandemic might have also hampered case reporting in several countries.

The overall alarming increase in case numbers over the last two decades 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.

Distribution and outbreaks

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 Americas, 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 annual basis in few European countries.

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.

In 2020, dengue affected several countries, with reports of increases in the numbers of cases in Bangladesh, Brazil, Cook Islands, Ecuador, India, Indonesia, Maldives, Mauritania, Mayotte (Fr), Nepal, Singapore, Sri Lanka, Sudan, Thailand, Timor-Leste and Yemen. Dengue continues to affect Brazil, India, Vietnam, the Philippines, Cook Islands, Colombia, Fiji, Kenya, Paraguay, Peru and, Reunion islands, in 2021. 

The COVID-19 pandemic is placing immense pressure on health care and management systems worldwide. WHO has emphasized the importance of sustaining efforts to prevent, detect and treat vector-borne diseases during this pandemic such as dengue and other arboviral diseases, as case numbers increase in several countries and place urban populations at highest risk for both diseases. The combined impact of the COVID-19 and dengue epidemics could have devastating consequences on the populations at risk.

Transmission

Transmission through mosquito bite

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].

Maternal 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].

Other transmission modes

Rare cases of transmission via blood products, organ donation and transfusions have been recorded. Similarly, transovarial transmission of the virus within mosquitoes have also been recorded. 

Vector Ecology

The Aedes aegypti mosquito is considered the primary vector of DENV. It could breed in natural containers such as tree holes and bromeliads, but nowadays it has well adapted to urban habitats and breeds mostly in man-made containers including buckets, mud pots, discarded containers and used tyres, storm water drains etc., thus making dengue an insidious disease in densely populated urban centers. 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 leading to clusters of infected individuals [20]. Once a female has laid her eggs, these eggs can remain viable for several months in dry condition, and will hatch when they are in contact with water.

Aedes albopictus, a secondary dengue vector and, 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). It favors breeding sites close to dense vegetation including plantations which is linked to increased risk of exposure for rural workers such as those in rubber and palm oil plantation, but it is also found to be established abundantly in urban areas. Ae. albopictus is highly adaptive. Its geographical spread is largely due to its tolerance of colder conditions, as an egg and adult [21, 22].  Similar to Ae. aegypti, Ae. albopictus is also a day biter and it 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)

While majority of dengue cases are asymptomatic or show mild symptoms, it can manifest as 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 minimize the risk of developing the more severe dengue[25] .

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 (2-7 days):

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. During the 24-48 hours of critical phase, a small portion of patients may manifest sudden deterioration of symptoms. 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:

1. severe abdominal painp
2. ersistent vomitingr
3. Rapid breathing
4. bleeding gums or nose 
5. fatigue
6. restlessness
7. liver enlargement
8. blood in vomit or stool. 

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. Close monitoring should also continue during the convalescent phase. 

Diagnostics

Several methods can be used for diagnosis of DENV infection. 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 methods mentioned below:

Virus isolation 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 and are considered the gold standard. However, they require specialised equipment and training for staff to perform these tests.

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, and 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 anti-dengue antibodies. IgM antibodies are detectable ~1 week after infection and  remain detectable for about 3 months. The presence of IgM is indicative of a recent DENV infection. IgG antibody levels take longer to develop and remains in the body for years. The presence of IgG is indicative of a past infection.

Treatment 

There is no specific treatment for dengue fever. Patients should rest, stay hydrated and seek medical advice. Depending on the clinical manifestations and other circumstances, patients may be sent home, be referred for in-hospital management, or require emergency treatment and urgent referral[25].

Supportive care such as 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 to less than 1% in majority of the countries.