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Dengue virus infection

Category: Illness or disabilities

Type

Involuntary

Introduction and description

Dengue is a mosquito-transmitted virus [Dengue virus - DENV] and the leading cause of arthropod-borne viral disease in the world. 

 Infection with dengue virus causes either a relatively mild disease, known as classic dengue fever (DF), or a more severe form, dengue hemorrhagic fever (DHF), a fulminating illness that is characterized by hemorrhagic manifestations and plasma leakage and that can progress to dengue shock syndrome (DSS) and death.  Dengue is also known as breakbone fever due to the severity of muscle spasms and joint pain, dandy fever, or seven-day fever because of the usual duration of symptoms.

Epidemiology

DENV affects more than two thirds of the world's population.  The infection is now endemic in more than 100 countries, primarily affecting 2.5 billion inhabitants in the tropical and subtropical regions.  It is also the main cause after malaria of tropical fever among travellers affecting at least 120 million travellers to these regions every year.

According to the CDC, as many as 400 million people are infected with DENV yearly.  The World Health Organization (WHO) estimates that there are approximately 500,000 people with dengue haemorrhagic fever (DHF) requiring hospitalization, a large proportion being children. Dengue causes 20,000 to 25,000 deaths annually, primarily in children. 

Epidemics occur annually in the Americas, Asia, Africa, and Australia and it now ranks as the most important mosquito-borne viral disease in the world.  It is also the fastest spreading mosquito-borne viral disease in the world.

Nearly all dengue cases reported in the 48 continental states were acquired elsewhere by travellers or immigrants. Most dengue cases in U.S. citizens occur in those inhabitants of Puerto Rico, the U.S. Virgin Islands, Samoa and Guam, which are endemic for the virus. Dengue and DHF have been a particular challenge in Puerto Rico, where outbreaks have been reported since 1915 and large island-wide epidemics have been documented since the late 1960s..

There appears to be a genetic susceptibility to dengue virus

Dengue viruses – an overview - Anne Tuiskunen Bäck, PhD1,2,3,* and Åke Lundkvist, Professor

Indirect evidence of the host's genetic importance has been derived from Cuban dengue epidemics where a reduced risk for DHF/DSS was observed in those with an African ancestry compared to those with European ancestry. The Cuban observations coincide with the low susceptibility to DHF reported in African and Black Caribbean populations. It is interesting that despite the circulation of DENV in 19 African countries, there are only sporadic reports of DHF cases

 

Serotypes

Dengue fever (DF) is caused by any of four closely related viruses, or serotypes: dengue 1-4.  Infection by one serotype results in lifelong immunity to that serotype but not to others.  Sequential infections put people at greater risk for dengue hemorraghic fever (DHF) and dengue shock syndrome (DSS).  The dengue viral serotype causing disease outbreaks has varied with time, as has the occurrence of severe dengue fever. 

Dengue viruses – an overview - Anne Tuiskunen Bäck, PhD1,2,3,* and Åke Lundkvist, Professor

The number of reported dengue cases has increased dramatically since the 1980s due to several complex reasons. The primary driving forces include rapid, unplanned urbanization combined with substandard living conditions, lack of vector control and surveillance, poor public health programs, international travel, and virus and vector evolution. The contribution of climatic change is controversial, and it is not known to what extent this enhances the spread of mosquitoes, and indirectly the DENVs ………………
Rapid, unplanned growth of urban centers in South-East Asian and South American countries combined with inadequate water supply and sewerage systems have dramatic consequences on the transmission of DENV……………
Many parts of the world have become hyperendemic, implying that all four serotypes of DENV co-circulate in the same country, with the consequence that secondary infections are common scenarios….. In Cuba, 17.5% of the total DHF dengue cases were caused by third or fourth infections ..

Transmission routes

 Aedes mosquitoes

The primary vectors of the disease are female mosquitoes of the species Aedes aegypti and Aedes albopictus. Although A. aegypti is associated with most infections, A. albopictus’ range is expanding and may be associated with increasing numbers. These species of mosquitoes tend to live indoors and are active during the day.

The female mosquitoes lay their eggs in artificial water containers such as tires, cans, and jars. Due to water requirements for breeding, mosquito densities peak during wet season, with the direct consequence of rising numbers of dengue cases. The Ae. aegypti mosquito is well adapted to an urban environment and is a highly competitive vector due to its anthropophilic nature. It thrives in close proximity to humans and is an intermittent feeder implying a high frequency of multiple host contacts during a single gonotrophic cycle. Thus, the female mosquito can infect multiple persons in order to complete a single blood meal.

Although Aedes are common in the southern U. S., dengue is endemic in northern Mexico, and the U.S. population has no immunity, the lack of dengue transmission in the continental U.S. is primarily because contact between people and the vectors is too infrequent to sustain transmission.

Other routes

In rare cases dengue can be transmitted in organ transplants or blood transfusions from infected donors, and there is evidence of transmission from an infected pregnant mother to her fetus. Transmission via breast milk has been reported.  But in the vast majority of infections, a mosquito bite is responsible.

Symptoms

Incubation period

Symptoms of infection usually begin 4 – 7 days after the mosquito bite and typically last 3 – 10 days. In order for transmission to occur the mosquito must feed on a person during a 5- day period when large amounts of virus are in the blood; this period usually begins a little before the person become symptomatic. Some people never have significant symptoms but can still infect mosquitoes. After entering the mosquito in the blood meal, the virus will require an additional 8-12 days incubation before it can then be transmitted to another human. The mosquito remains infected for the remainder of its life, which might be days or a few weeks.

Severity classification of infection

Dengue appears to be a disease that is more severe when caught as an adult. Primary infections are supposed to cause mild disease in children, compared to secondary infections that tend to lead to severe dengue.  Infections are classified as:

  • Asymptomatic in up to 75% of infected humans.
  • Severe illness - A spectrum of disease, from self-limiting dengue fever to haemorrhage and shock, may be seen. A fraction of infections (0.5% - 5%) progress to severe dengue.  As stated the severe illness is known as dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)
  • Death - Without proper treatment, fatality rates may exceed 20%. These occur primarily in children.

Progress of disease

The three phases of dengue include febrile, critical, and recovery. 

The febrile phase -  a sudden high-grade fever of approximately 40 C occurs that usually lasts two to seven days. During the febrile phase, dehydration may cause neurological disturbances and febrile seizures in young children.  Associated symptoms include facial flushing, skin erythema, myalgias, arthralgias, headache, sore throat, conjunctival injection, anorexia, nausea, and vomiting. For skin erythema, a general blanchable macular rash occurs in the first one to two days of fever and the last day of fever. Or, within 24 hours, a secondary maculopapular rash can develop.

The Critical phase - Defervescence characterizes the critical phase with a temperature of approximately 37.5 C to 38 C or less on days three through seven. It is associated with increased capillary permeability. This phase usually lasts one to two days. 
There may be abdominal pain, persistent vomiting, clinical fluid accumulation such as ascites or pleural effusion, mucosal bleeding, lethargy, liver enlargement greater than 2 cm, increase in hematocrit, and thrombocytopenia. 

Dengue virus: A global human threat: Review of literature  Shamimul Hasan et al
Oral features are infrequently seen in dengue virus infection and are more commonly associated with DHF. Erythema, crusting of lips, and tongue and soft palatal vesicles constitute the prominent oral features in dengue virus infection. …... Petechiae, purpura, ecchymoses, and nasal bleeding have also been reported

Haemorrhage, dilatation and congestion of vessels, and oedema of arterial walls are commonly found, and haemorrhagic manifestations in other organs combined with fluid accumulations in body cavities may be substantial – including the gastrointestinal tract, and heart. 
Controversy surrounds the role of endothelial cells as the target for DENV infection. Severe dengue disease is characterized by systemic endothelial dysfunction accompanied by vascular leakage, even though destructive vascular lesions are generally absent in fatal cases

These symptoms  may progress to the severe illnesses of dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS)

  •  Severe Dengue: Dengue fever with severe plasma leakage, haemorrhage, organ dysfunction including transaminitis greater than 1000 international units per liter, impaired consciousness, myocardial dysfunction, and pulmonary dysfunction.
  • Dengue shock syndrome clinical warnings: include rapidly rising hematocrit, intense abdominal pain, persistent vomiting, and narrowed or absent blood pressure.

The recovery phase  - entails the gradual reabsorption of extravascular fluid in two to three days. The patient will display bradycardia at this time.

Viral latency

Although the findings are somewhat tentative, evidence seems to point to the possibility that the Dengue virus exhibits latency, as such it may be responsible for far more diseases than just the ones outlined above.  Several in vitro studies have shown that viral replication occurs in endothelial cell cultures.

Localization of Dengue Virus in Naturally Infected Human Tissues, by Immunohistochemistry and In Situ Hybridization - Kala Jessie et al

We studied tissue specimens from patients with serologically or virologically confirmed dengue infections …. to localize viral antigen and RNA, respectively. IHC was performed on specimens obtained from 5 autopsies and 24 biopsies and on 20 blood-clot samples. …. Viral antigens were demonstrated in Kupffer and sinusoidal endothelial cells of the liver; macrophages, multinucleated cells, and reactive lymphoid cells in the spleen; macrophages and vascular endothelium in the lung; kidney tubules; and monocytes and lymphocytes in blood-clot samples. Positive-strand viral RNA was detected in the same IHC-positive cells found in the spleen and blood-clot samples. The strong, positive ISH signal in these cells indicated a high copy number of viral RNA, suggesting replication.

Cause

The DENVs are old viruses that have re-emerged during the latter half of the 20th century.  The four dengue viruses originated in monkeys and independently jumped to humans in Africa or Southeast Asia between 100 and 800 years ago.  Dengue remained a relatively minor, geographically restricted disease until the middle of the 20th century.  The disruption of the second world war – in particular the coincidental transport of Aedes mosquitoes around the world in cargo –  are thought to have played a crucial role in the dissemination of the viruses.  DHF was first documented only in the 1950s during epidemics in the Philippines and Thailand.  It was not until 1981 that large numbers of DHF cases began to appear in the Carribean and Latin America

Part of the Flavivirus family, the dengue virus is a 50 nm virion with three structural and seven nonstructural proteins, a lipid envelope, and a 10.7 kb capped positive sense single strand of ribonucleic acid.  Dengue fever is caused by any of four distinct serotypes (DENV 1-4) of single-stranded RNA viruses. Infection by one serotype results in lifelong immunity to that serotype but not to others.  All four DENV serotypes have emerged from sylvatic strains in the forests of South-East Asia and all four serotypes of DENV can be found worldwide.

The exact course of events following the dermal injection of dengue virus by a mosquito bite is unclear. Skin macrophages and dendritic cells appear to be the first targets. It is thought that the infected cells then move to the lymph nodes and spread through the lymphatic system to other organs. Viremia may be present for 24 to 48 hours before the onset of symptoms. A complex interaction of host and viral factors then occurs and determines whether the infection will be asymptomatic, typical, or severe. Severe dengue fever with increased microvascular permeability and shock syndrome is thought to be associated with infection due to a second dengue virus serotype and the patient's immune response. However, cases of severe dengue do occur in the setting of infection by only a single serotype.

Diagnosis, Prevention and treatment

There is no vaccine available against dengue, and there are no specific medications to treat a dengue infection. This makes prevention the most important step, and prevention means avoiding mosquito bites if you live in or travel to an endemic area.

Prevention

The only way to avoid contracting dengue is to prevent mosquito bites and not travel to its endemic areas. Other preventative measures include the use of DEET insecticide, wearing protective clothing, sleeping under a mosquito net, and eliminating stagnant water around the home.

It is very difficult to control or eliminate Ae. aegypti mosquitoes because they have adaptations to the environment that make them highly resilient, or with the ability to rapidly bounce back to initial numbers after disturbances resulting from natural phenomena (e.g., droughts) or human interventions (e.g., control measures). One such adaptation is the ability of the eggs to withstand desiccation (drying) and to survive without water for several months on the inner walls of containers.  It is likely that Ae.aegypti is continually responding or adapting to environmental change. For example, it was recently found that Ae. aegypti is able to undergo immature development in broken or open septic tanks.

Diagnosis

The clinical diagnosis of dengue can be challenging as many other illnesses can present similarly early in the disease course - malaria, influenza, Zika, chikungunya, measles, and yellow fever – all have similar symptoms on initial presentation.   Diagnosis can be aided by knowing a history of immunizations, travel, and exposures.  If the patient presents at a late stage, diagnosis becomes even more difficult

Dengue virus: A global human threat: Review of literature  Shamimul Hasan et al
Dengue virus gains entry into the host organism through the skin following an infected mosquito bite. Humoral, cellular, and innate host immune responses are implicated in the progression of the illness and the more severe clinical signs occur following the rapid clearance of the virus from the host organism. Hence, the most severe clinical presentation during the infection course does not correlate with a high viral load.

Rapid laboratory identification of dengue fever includes NS1 antigen detection and serologic tests.

“The virus antigen can be detected by ELISA, polymerase chain reaction, or isolation of the virus from body fluids. Serology will reveal a marked increase in immunoglobulins.  It is vital to assess pregnant patients with dengue as the symptoms may be very similar to preeclampsia.

Serologic tests are only useful after several days of infection and may be associated with false positives due to other flavivirus infections, such as yellow fever or Zika virus.

Metagenomic testing is also possible in those countries that have the equipment.

Treatment

Dengue Fever - Timothy J. Schaefer et al

Supportive management includes giving the patient fluids,  and a blood transfusion for haemorrhage. Avoid giving aspirin and nonsteroidal anti-inflammatory drugs and other anticoagulants. No antiviral medications are recommended.  Patients with thrombocytopenia or bleeding may require platelets and fresh frozen plasma.   No laboratory tests can predict the progression to severe disease.

Patients should be encouraged to consume ample liquids. The return of a patient's appetite is a sign that the infection is subsiding.

References and further reading

  • Timothy J. Schaefer; Robert W. Wolford. Un of IL College of Med, OSF Med Center, - Dengue Fever - August 14, 2018. StatPearls Publishing
  • Bäck AT, Lundkvist A. Dengue viruses - an overview. Infect Ecol Epidemiol. 2013 Aug 30;3 [PMC free article]
  • Henchal EA, Putnak JR. The dengue viruses. Clin. Microbiol. Rev. 1990 Oct;3(4):376-96. [PMC free article]
  • Guo C, Zhou Z, Wen Z, Liu Y, Zeng C, Xiao D, Ou M, Han Y, Huang S, Liu D, Ye X, Zou X, Wu J, Wang H, Zeng EY, Jing C, Yang G. Global Epidemiology of Dengue Outbreaks in 1990-2015: A Systematic Review and Meta-Analysis. Front Cell Infect Microbiol. 2017;7:317. [PMC free article]
  • Mayer SV, Tesh RB, Vasilakis N. The emergence of arthropod-borne viral diseases: A global prospective on dengue, chikungunya and zika fevers. Acta Trop. 2017 Feb;166:155-163. [PMC free article]
  • Muller DA, Depelsenaire AC, Young PR. Clinical and Laboratory Diagnosis of Dengue Virus Infection. J. Infect. Dis. 2017 Mar 01;215(suppl_2):S89-S95.
  • WHO. Geneva: WHO; 1997. Dengue haemorrhagic fever. Diagnosis, treatment, prevention and control; pp. 12–23.
  • Gubler DJ. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends Microbiol. 2002;10:100–3. [PubMed]
  • WHO. Geneva: World Health Organization; 2009. Dengue: guidelines for diagnosis, treatment, prevention and control – New ed
  • J Int Soc Prev Community Dent. 2016 Jan-Feb; 6(1): 1–6.  doi:  10.4103/2231-0762.175416 PMCID: PMC4784057  PMID: 27011925  Dengue virus: A global human threat: Review of literature  Shamimul Hasan, Sami Faisal Jamdar,1 Munther Alalowi,2 and Sadun Mohammad Al Ageel Al Beaiji3
  • Localization of Dengue Virus in Naturally Infected Human Tissues, by Immunohistochemistry and In Situ Hybridization - Kala Jessie Mun Yik Fong Shamala Devi Sai Kit Lam K. Thong Wong  The Journal of Infectious Diseases, Volume 189, Issue 8, 15 April 2004, Pages 1411–1418, https://doi.org/10.1086/383043  Published: 15 April 2004

 

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