Dengue Fever, A Global Crisis

Overview

The viral illness dengue, which is spread by mosquitoes, has recently spread quickly throughout all WHO areas. Female mosquitoes, primarily of the species Aedes aegypti and, to a lesser extent, Ae, carry the dengue virus. albopictus. These mosquitoes can transmit the Zika, yellow fever, and chikungunya viruses. The risk of dengue varies locally depending on local climate, socioeconomic, and environmental factors, which are both common in the tropics.

A wide range of illnesses is brought on by dengue. This can range from mild flu-like symptoms in those who are sick to severe disease (people may not even be aware they are infected). Even though it's less often, some people experience severe dengue, which can lead to a variety of issues including severe bleeding, organ damage, and/or plasma leakage. When severe dengue is not treated properly, a larger risk of death exists. During dengue epidemics in the Philippines and Thailand in the 1950s, severe dengue was first identified. Dengue fever has become a prominent cause of illness and death among children and adults in most Asian and Latin American nations today.

There are four different but closely related serotypes of the Flaviviridae family virus that causes dengue, which is the disease's primary cause. Immunity against that serotype is thought to last a lifetime following infection recovery. Cross-immunity to the other serotypes is only transitory and partial following recovery. The risk of acquiring severe dengue is increased by subsequent infections (secondary infection) by various serotypes. There are four different serotypes of the dengue virus, each of which has its specific epidemiological patterns. All four serotypes are hyperendemic in many countries, and they can co-circulate within a given area. Both human health and the world and national economies are adversely affected by dengue. Infected travelers frequently bring DENV from one location to another; if susceptible vectors are found in these new regions, there is a possibility for local transmission to be established.

Key facts

• The virus that causes dengue infects humans when infected mosquitoes bite them. Aedes aegypti mosquitoes and, to a lesser extent, Ae are the main carriers of the disease. albopictus.
• Dengue virus is the name of the virus that causes dengue. There are four DENV serotypes, and each infection can result in a total of four infections.
• In various Asian and Latin American nations, severe dengue is a primary cause of critical illness and fatalities. It needs to be managed by medical experts.
• Specific treatment is not available for dengue or severe dengue. Death rates from severe dengue are reduced to about 1% when disease progression is identified early and patients have access to quality medical care.
• Dengue is a tropical and subtropical disease that primarily affects urban and semi-urban settings.
• About half of the world's population is now at risk due to the sharp increase in dengue incidence worldwide. Although between 100 and 400 million infections are thought to occur annually, more than 80% are often minor and asymptomatic.
• Effective vector control methods are essential for preventing and controlling dengue. Long-term community involvement can significantly enhance vector control efforts.
• DENV can induce an acute flu-like disease, while many DENV infections only result in moderate sickness. This can occasionally progress into severe dengue, a potentially fatal consequence.

Global Effect

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. One modeling 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). 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, 70% of the actual burden is in Asia.

Over the past 20 years, there has been an over 8-fold increase in dengue cases reported to WHO, from 505,430 cases in 2000 to over 2.4 million in 2010, and 5.2 million in 2019. Between 2000 and 2015, the number of reported deaths increased from 960 to 4032, largely impacting younger age groups. The overall number of illnesses and reported deaths both appeared to be declining in the years 2020 and 2021. The data is not yet complete, and the COVID-19 pandemic may have made it more difficult for countries to disclose cases in some of them. A change in national policies to record and report dengue to the Ministries of Health and the WHO is one explanation for the overall alarming rise in cases of counts over the last 20 years. However, it also shows that the government is aware of the problem, making it necessary to record the burden of dengue disease.

Outbreak Information

Only nine nations had serious dengue epidemics before 1970. In the WHO regions of Africa, the Americas, the Eastern Mediterranean, South-East Asia, and the Western Pacific, the illness is currently endemic in more than 100 countries. The Americas, South-East Asia, and Western Pacific are the most severely impacted regions, with Asia accounting for over 70% of the worldwide disease load.

As the disease enters other regions, such as Europe, the number of cases is rising, and explosive outbreaks are also taking place. Since local transmission was first documented in France and Croatia in 2010 and imported cases were found in three other European nations, there is now a threat of a dengue outbreak. Over 2000 cases of dengue were reported in the Portuguese Madeira Islands in 2012, while imported cases were found in Portugal's mainland and ten other European nations. Few European countries now report autochthonous cases every year.

In 2019, there were more dengue cases than had ever been recorded globally. All areas were hit, and Afghanistan experienced its first case of dengue transmission. Over 25,000 of the 3.1 million cases recorded in the American region were considered serious. Despite this concerning number of infections, there were fewer dengue-related deaths than the year before. In Asia, Bangladesh (101,000 cases), Malaysia (131,000 cases), the Philippines (420,000 cases), and Vietnam (320,000 cases) also reported high numbers of cases.

There were reports of an increase in dengue cases in Bangladesh, Brazil, the Cook Islands, Ecuador, India, Indonesia, the Maldives, Mauritania, Mayotte (Fr), Nepal, Singapore, Sri Lanka, Sudan, Thailand, Timor-Leste, and Yemen in 2020. Brazil, India, Vietnam, the Philippines, the Cook Islands, Colombia, Fiji, Kenya, Paraguay, Peru, and the Reunion Islands are still experiencing dengue in 2021.

The COVID-19 epidemic is putting enormous strain on the world's health care and management systems. As cases rise in multiple countries and urban populations are most at risk for both diseases, WHO has stressed the necessity of continuing efforts to prevent, diagnose, and treat vector-borne illnesses like dengue and other arboviral infections during this pandemic. In the communities at risk, the combined effects of the COVID-19 and dengue epidemics could be disastrous.

Mosquito bites are the main cause of transmission

The virus spreads to people when infected female mosquitoes, primarily the Aedes aegypti mosquito, bite them. Although other Aedes genus species are capable of acting as vectors, Aedes aegypti is the primary contributor. The virus reproduces in the mosquito's midgut after it feeds on a host with DENV infection, then it spreads to secondary tissues like the salivary glands. The extrinsic incubation period refers to the amount of time between consuming the virus and transmitting it to a new host.

When the outside temperature is between 25 and 28 °C, the EIP takes approximately 8 to 12 days. The amplitude of daily temperature changes, the virus genotype, and the initial viral concentration are a few examples of variables that affect the extrinsic incubation period and can affect how long it takes a mosquito to transmit a virus. The mosquito can continue to spread viruses for the remainder of its life after becoming infected.

Mosquitoes can pick up the DENV virus from individuals who are infected with it. This can include persons who have symptoms of dengue infection, those who are pre-symptomatic but have not yet developed symptoms, as well as those who are completely well. Up to 2 days before or up to 2 days after a person stops having a fever, human-to-mosquito transmission can take place. High levels of the patient's viremia and fever are favorably correlated with the likelihood of mosquito infection; on the other hand, high levels of DENV-specific antibodies are negatively correlated with the risk of mosquito infection. Although viremia can persist for up to 12 days, most patients are only viremic for about 4–5 days.

Mosquito vectors have a major role in the main human-to-human transmission route for DENV. But there is evidence that maternal transmission could occur. While the likelihood of vertical transmission seems minimal, it may be related to the time of the dengue illness during pregnancy. Premature birth, low birth weight, and fetal distress are possible outcomes when a mother has a DENV infection while she is pregnant. Rare cases of transmission via blood products, organ donation, and transfusions have been recorded. Similarly, the transovarial transmission of the virus within mosquitoes has also been recorded.

The Aedes aegypti mosquito

It is regarded as the main DENV vector. Dengue was once able to breed in bromeliads and tree holes, but these days it has become well adapted to urban habitats and primarily breeds in man-made containers like buckets, mud pots, abandoned containers, used tires, storm water drains, etc. This makes dengue a sneaky disease in densely populated urban centers. Ae. aegypti feeds during the day; its peak biting times are in the early morning and just before sunset in the evening Female Ae. Aedes aegypti frequently feed repeatedly in the intervals between each egg-laying period, resulting in concentrations of infected people. Once a female has set her eggs, they can survive in a dry environment for several months before hatching when exposed to water.

Aedes albopictus, a secondary dengue vector, has expanded to over 25 nations in Europe and over 32 states in the United States, primarily as a result of global traffic in old tires and other products. Although it is reported to be extensively established in metropolitan areas, it prefers breeding locations close to dense vegetation, particularly plantations, which are connected to greater exposure risk for rural workers, notably those in rubber and palm oil plantations. Ae. The albopictus is very adaptable. Its ability to survive in colder climates as an egg and an adult is a major factor in its wide geographic distribution.

Signs and Symptoms

Dengue can emerge as a serious, flu-like sickness that affects newborns, young children, and adults but seldom results in death, even though the majority of patients are asymptomatic or exhibit minor symptoms. After an incubation period of 4–10 days following the bite by an infected mosquito, symptoms typically last for 2–7 days. Dengue is divided into two main categories by the World Health Organization: mild dengue and severe dengue. The sub-categorization of dengue with or without warning signals is intended to assist medical professionals in prioritizing patients for hospital admission, assuring close surveillance, and reducing the risk of contracting the more severe dengue.

Key facts

• Dengue is a viral infection transmitted to humans through the bite of infected mosquitoes. The primary vectors that transmit the disease are Aedes aegypti mosquitoes and, to a lesser extent, Ae. albopictus.
• The virus responsible for causing dengue is called the dengue virus (DENV). There are four DENV serotypes and it is possible to be infected four times.
• 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 with about half of the world's population now at risk. Although an estimated 100-400 million infections occur each year, over 80% are generally mild and asymptomatic.
• Dengue prevention and control depend on effective vector control measures. Sustained community involvement can improve vector control efforts substantially.
• 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.

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 diseases. 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 travelers; 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 modeling 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 years 2000 and 2015 increased from 960 to 4032, affecting mostly the younger age group. The total number of cases seemingly decreased during the years 2020 and 2021, as well as for reported deaths. However, the data is not yet complete and the COVID-19 pandemic might have also hampered case reporting in several countries.

The overall alarming increase in case of 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 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 a 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.

A high number of cases were reported in Bangladesh (101,000), Malaysia (131,000) Philippines (420,000), and 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, the Cook Islands, Colombia, Fiji, Kenya, Paraguay, Peru, and, the 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 the 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 a 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 a 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; several 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 the virus. Once infectious, the mosquito is capable of transmitting the virus for the rest of its life.

Human-to-mosquito transmission

Mosquitoes can become infected by 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]}, and up to 2 days after the fever has resolved ^[12].

The 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, the risk of vertical transmission is seemingly linked to the timing of the dengue infection during pregnancy ^[14-17]. When a mother does have a DENV infection when she is pregnant, babies may suffer from pre-term birth, low birth weight, and fetal distress ^[18].

Other transmission modes

Rare cases of transmission via blood products, organ donation, and transfusions have been recorded. Similarly, the transovarial transmission of the virus within mosquitoes has 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 tires, 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. Egypt frequently feeds 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 conditions 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 tires (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 to 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 outbreaks, where Aedes aegypti is either not present, or present in low numbers ^{[23, 24]}

Disease characteristics (signs and symptoms)

While the 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, ensure close observation, and 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 the 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:

• severe abdominal pain
• persistent vomiting
• rapid breathing
• bleeding gums or nose
• fatigue
• restlessness
• liver enlargement
• 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

DENV infection can be diagnosed using a variety of techniques. Different diagnostic techniques may be applied more or less appropriate depending on the time the patient presents. Both of the following testing techniques should be used on patient samples obtained during the first week of illness:

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 specialized 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 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. Patients should rest, stay hydrated and seek medical advice. Depending on the clinical manifestations and other circumstances, patients may be sent home, referred for in-hospital management, or require emergency treatment and urgent referral.

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 a 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 the majority of the countries.