|High hematocrit with low platelets|
The diagnosis of dengue is typically made clinically, on the basis of reported symptoms and physical examination; this applies especially in endemic areas. However, early disease can be difficult to differentiate from other viral infections. A probable diagnosis is based on the findings of fever plus two of the following: nausea and vomiting, rash, generalized pains, low white blood cell count, positive tourniquet test, or any warning sign (see table) in someone who lives in an endemic area. Warning signs typically occur before the onset of severe dengue. The tourniquet test, which is particularly useful in settings where no laboratory investigations are readily available, involves the application of a blood pressure cuff for five minutes, followed by the counting of any petechial hemorrhages; a higher number makes a diagnosis of dengue more likely. It can be difficult to distinguish dengue fever and chikungunya, a similar viral infection that shares many symptoms and occurs in similar parts of the world to dengue. Often, investigations are performed to exclude other conditions that cause similar symptoms, such as malaria, leptospirosis, typhoid fever, and meningococcal disease.
The earliest change detectable on laboratory investigations is a low white blood cell count, which may then be followed by low platelets and metabolic acidosis. In severe disease, plasma leakage results in hemoconcentration (as indicated by a rising hematocrit) and hypoalbuminemia. Pleural effusions or ascites can be detected by physical examination when large, but the demonstration of fluid on ultrasound may assist in the early identification of dengue shock syndrome. The use of ultrasound is limited by lack of availability in many settings.
The World Health Organization’s 2009 classification divides dengue fever into two groups: uncomplicated and severe. This replaces the 1997 WHO classification, which needed to be simplified as it had been found to be too restrictive, though the older classification is still widely used. The 1997 classification divided dengue into undifferentiated fever, dengue fever, and dengue hemorrhagic fever. Dengue hemorrhagic fever was subdivided further into grades I–IV. Grade I is the presence only of easy bruising or a positive tourniquet test in someone with fever, grade II is the presence of spontaneous bleeding into the skin and elsewhere, grade III is the clinical evidence of shock, and grade IV is shock so severe that blood pressure and pulse cannot be detected. Grades III and IV are referred to as “dengue shock syndrome”.
Dengue fever may be diagnosed by microbiological laboratory testing. This can be done by virus isolation in cell cultures, nucleic acid detection by PCR, viral antigen detection or specific antibodies (serology). Virus isolation and nucleic acid detection are more accurate than antigen detection, but these tests are not widely available due to their greater cost.All tests may be negative in the early stages of the disease.
These laboratory tests are only of diagnostic value during the acute phase of the illness with the exception of serology. Tests for dengue virus-specific antibodies, types IgG and IgM, can be useful in confirming a diagnosis in the later stages of the infection. Both IgG and IgM are produced after 5–7 days. The highest levels (titres) of IgM are detected following a primary infection, but IgM is also produced in secondary and tertiary infections. The IgM becomes undetectable 30–90 days after a primary infection, but earlier following re-infections. IgG, by contrast, remains detectable for over 60 years and, in the absence of symptoms, is a useful indicator of past infection. After a primary infection the IgG reaches peak levels in the blood after 14–21 days. In subsequent re-infections, levels peak earlier and the titres are usually higher. Both IgG and IgM provide protective immunity to the infecting serotype of the virus. In the laboratory test the IgG and the IgM antibodies can cross-react with other flaviviruses, such as yellow fever virus, which can make the interpretation of the serology difficult. The detection of IgG alone is not considered diagnostic unless blood samples are collected 14 days apart and a greater than fourfold increase in levels of specific IgG is detected. In a person with symptoms, the detection of IgM is considered diagnostic.
A 1920s photograph of efforts to disperse standing water and thus decrease mosquito populations
There are no approved vaccines for the dengue virus. Prevention thus depends on control of and protection from the bites of the mosquito that transmits it. The World Health Organization recommends an Integrated Vector Control program consisting of five elements: (1) Advocacy, social mobilization and legislation to ensure that public health bodies and communities are strengthened, (2) collaboration between the health and other sectors (public and private), (3) an integrated approach to disease control to maximize use of resources, (4) evidence-based decision making to ensure any interventions are targeted appropriately and (5) capacity-building to ensure an adequate response to the local situation.
The primary method of controlling A. aegypti is by eliminating its habitats. This is done by emptying containers of water or by adding insecticides or biological control agents to these areas, although spraying with organophosphate or pyrethroid insecticides is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effect from insecticides and greater logistical difficulties with control agents. People can prevent mosquito bites by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective).
There are no specific treatments for dengue fever. Treatment depends on the symptoms, varying from oral rehydration therapy at home with close follow-up, to hospital admission with administration of intravenous fluids and/or blood transfusion. A decision for hospital admission is typically based on the presence of the “warning signs” listed in the table above, especially in those with preexisting health conditions.
Intravenous hydration is usually only needed for one or two days. The rate of fluid administration is titrated to a urinary output of 0.5–1 mL/kg/hr, stable vital signs and normalization of hematocrit. Invasive medical procedures such as nasogastric intubation, intramuscular injections and arterial punctures are avoided, in view of the bleeding risk. Paracetamol (acetaminophen) is used for fever and discomfort while NSAIDs such as ibuprofen and aspirin are avoided as they might aggravate the risk of bleeding. Blood transfusion is initiated early in patients presenting with unstable vital signs in the face of a decreasing hematocrit, rather than waiting for the hemoglobin concentration to decrease to some predetermined “transfusion trigger” level. Packed red blood cells or whole blood are recommended, while platelets and fresh frozen plasma are usually not.
During the recovery phase intravenous fluids are discontinued to prevent a state of fluid overload. If fluid overload occurs and vital signs are stable, stopping further fluid may be all that is needed. If a person is outside of the critical phase, a loop diuretic such as furosemide may be used to eliminate excess fluid from the circulation.
Dengue distribution area
Red: Epidemic dengue
Most people with dengue recover without any ongoing problems. The mortality is 1–5% without treatment, and less than 1% with adequate treatment; however severe disease carries a mortality of 26%. Dengue is endemic in more than 110 countries. It infects 50 to 100 million people worldwide a year, leading to half a million hospitalizations, and approximately 12,500–25,000 deaths.
The most common viral disease transmitted by arthropods, dengue has a disease burden estimated to be 1600 disability-adjusted life years per million population, which is similar to other childhood and tropical diseases such as tuberculosis. As a tropical disease dengue is deemed only second in importance to malaria, though the World Health Organization counts dengue as one of sixteen neglected tropical diseases.
The incidence of dengue increased 30 fold between 1960 and 2010. This increase is believed to be due to a combination of urbanization, population growth, increased international travel, and global warming. The geographical distribution is around the equator with 70% of the total 2.5 billion people living in endemic areas from Asia and the Pacific. In the United States, the rate of dengue infection among those who return from an endemic area with a fever is 2.9–8.0%, and it is the second most common infection after malaria to be diagnosed in this group.
Until 2003, dengue was classified as a potential bioterrorism agent, but subsequent reports removed this classification as it was deemed too difficult to transfer and only caused hemorrhagic fever in a relatively small proportion of people.
Like most arboviruses, dengue virus is maintained in nature in cycles that involve preferred blood-sucking vectors and vertebrate hosts. The viruses are maintained in the forests of Southeast Asia and Africa by transmission from female Aedes mosquitoes—of species other than A. aegypti—to her offspring and to lower primates. In rural settings the virus is transmitted to humans by A. aegypti and other species of Aedes such as A. albopictus. In towns and cities, the virus is primarily transmitted to humans by A. aegypti, which is highly domesticated. In all settings the infected lower primates or humans greatly increase the number of circulating dengue viruses. This is called amplification. The urban cycle is the most important to infections of humans and dengue infections are primarily confined to towns and cities. In recent decades, the expansion of villages, towns and cities in endemic areas, and the increased mobility of humans has increased the number of epidemics and circulating viruses. Dengue fever, which was once confined to Southeast Asia, has now spread to Southern China, countries in the Pacific Ocean and America, and might pose a threat to Europe.
The first record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (265–420 AD) which referred to a “water poison” associated with flying insects. There have been descriptions of epidemics in the 17th century, but the most plausible early reports of dengue epidemics are from 1779 and 1780, when an epidemic swept Asia, Africa and North America. From that time until 1940, epidemics were infrequent.
In 1906, transmission by the Aedes mosquitoes was confirmed, and in 1907 dengue was the second disease (after yellow fever) that was shown to be caused by a virus. Further investigations by John Burton Cleland and Joseph Franklin Siler completed the basic understanding of dengue transmission.
The marked spread of dengue during and after the Second World War has been attributed to ecologic disruption. The same trends also led to the spread of different serotypes of the disease to new areas, and to the emergence of dengue hemorrhagic fever. This severe form of the disease was first reported in the Philippines in 1953; by the 1970s, it had become a major cause of child mortality and had emerged in the Pacific and the Americas. Dengue hemorrhagic fever and dengue shock syndrome were first noted in Central and South America in 1981, as DENV-2 was contracted by people who had previously been infected with DENV-1 several years earlier.
The origins of the word “dengue” are not clear, but one theory is that it is derived from the Swahili phrase Ka-dinga pepo, which describes the disease as being caused by an evil spirit. The Swahili word dinga may possibly have its origin in the Spanish word dengue, meaning fastidious or careful, which would describe the gait of a person suffering the bone pain of dengue fever. However, it is possible that the use of the Spanish word derived from the similar-sounding Swahili. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy, and the disease was known as “dandy fever”.
The term “break-bone fever” was first applied by physician and Founding Father Benjamin Rush, in a 1789 report of the 1780 epidemic in Philadelphia. In the report he uses primarily the more formal term “bilious remitting fever”. The term dengue fever came into general use only after 1828. Other historical terms include “breakheart fever” and “la dengue”. Terms for severe disease include “infectious thrombocytopenic purpura” and “Philippine”, “Thai”, or “Singapore hemorrhagic fever”.
Public health officers releasing P. reticulata fry into an artificial lake in the Lago Norte district of Brasília, Brazil, as part of a vector control effort.
Research efforts to prevent and treat dengue include various means of vector control, vaccine development, and antiviral drugs.
With regards to vector control, a number of novel methods have been used to reduce mosquito numbers with some success including the placement of the guppy (Poecilia reticulata) or copepods in standing water to eat the mosquito larvae.
There are ongoing programs working on a dengue vaccine to cover all four serotypes. One of the concerns is that a vaccine could increase the risk of severe disease through antibody-dependent enhancement. The ideal vaccine is safe, effective after one or two injections, covers all serotypes, does not contribute to ADE, is easily transported and stored, and is both affordable and cost-effective. As of 2009, a number of vaccines were undergoing testing. It is hoped that the first products will be commercially available by 2015.
Apart from attempts to control the spread of the Aedes mosquito and work to develop a vaccine against dengue, there are ongoing efforts to develop antiviral drugs that would be used to treat attacks of dengue fever and prevent severe complications. Discovery of the structure of the viral proteins may aid the development of effective drugs. There are several plausible targets. The first approach is inhibition of the viral RNA-dependent RNA polymerase (coded by NS5), which copies the viral genetic material, with nucleoside analogs. Secondly, it may be possible to develop specific inhibitors of the viral protease (coded by NS3), which splices viral proteins. Finally, it may be possible to develop entry inhibitors, which stop the virus entering cells, or inhibitors of the 5′ capping process, which is required for viral replication.