MfA - Dengue fever

Medicine for Africa - Medical Information Service

ENGUE FEVER

Definition:

Dengue fever is an acute viral disease that used to be called ‘break-bone fever’ or ‘dandy fever’, due to the often excruciating joint and muscle pains that are associated with the disease, creating the feeling of one’s bones that appear to break. The second name, ‘dandy fever’ originates from the peculiar postures and gait of slaves in the West Indies.

Dengue fever (DF) and its more severe form, called dengue hemorrhagic fever (DNF) are viral diseases, caused by the genus Flavivirus, a single-stranded enveloped RNA arbovirus, which is most prevalent in tropical and sub-tropical areas of the world. The disease is transmitted to humans by the bite of a mosquito of the so-called Aedes mosquito family. The particular type that is responsible for dengue fever relates to the most common representative of this family, the Aedes (Ae.) aegypti mosquito, which is particularly active during the daytime and loves to live near human residents. The mosquito has well adapted to human habitation, and preferably breeds in standing waters, especially artificial water containers, such as flower vases or pots, cisterns, standing water in uncovered barrels, cisterns and even the interior of discarder tires.

The Ae. aegypti mosquito is also one of the transmitting vectors for yellow fever.

At this time, there are four known serotypes of the flavivirus that causes dengue fever, termed DEN-1, DEN-2, DEN-3 and DEN-4. While the viral subtypes are in fact closely related, they are also anti-genetically rather distinct. Thus, while infection with one specific dengue serotype provides lifelong ‘homotypic’ immunity against a re-infection by this serotype, and a brief period of some partial heterotypic immunity, it does not provide permanent immunity or protection against the potential infection by any of the other serotypes. During an epidemic, several serotypes may circulate concurrently within an exposed population.

This is especially important in view of the fact that DF, a viral disease that may produce just some minor nonspecific viral symptoms, may also progress towards its more aggressive and often fatal variant, ‘dengue hemorrhagic fever’ (DHF).

Once a human being has become infected by the bite of the Aedes mosquito, the incubation period is anywhere between three and 14 days (with an average lag time of four-to-seven days), during which time the viral replication takes place. The virus primarily targets the reticuloendothelial system, including dendritic cells, endothelial cells and hepatocytes. After a five-to-seven day acute febrile illness, recovery is usually complete within one-to-two weeks.

Historic review

Dengue fever has been known for well over 200 years. As a matter of fact, the first dengue-like fever illness was described in medical writings from China as far back as 265 AD. Since then, outbreaks of ‘febrile illnesses’ compatible with dengue fever have been described over and over again. However, it took until 1789, when Dr. Benjamin Rush published the first precise account of a probable dengue fever in Philadelphia, USA, in 1780. Similar reports surfaced from Africa and Asia at nearly the same time, thus enforcing the assumption that the disease has been around for many years prior to these outbreaks. Dr. Rush also coined the alternative name of the disease – break-bone fever – resulting from the description of symptoms by one of his patients.

While the disease was generally considered to be a mild, non-fatal viral disease with long intervals of 10 to 40 years between major epidemics, early ‘globalization’ in regard to travelling habits, changed this perception. The development of different serotypes, resistant to the immunity response, occurs within an individual who had been infected by another serotype, and can ultimately lead to the much more serious and fatal variant of dengue hemorrhagic fever. DHF first emerged after World War II in the Pacific region and the Americas, soon spreading to South East Asia and beyond.

At this point in time, DHF is one of the leading causes of hospitalization and death in children in many countries in Southeast Asia, with Indonesia reporting the bulk of cases. The Ae. aegypti mosquito is prevalent in both the Middle East and sub-Saharan Africa, being present in over 19 countries on the African continent. The mosquito is also abundantly present in most countries and islands of the Caribbean – significant outbreaks occurred in 2005 and 2006 in Barbados, Cuba, Curacao, the Dominican Republic, Guadeloupe, Martinique, Puerto Rico, as well as on all US Virgin Islands. Furthermore, the mosquito is also present in all of South America, except Chile, while a close cousin, Ae. albopictus, which originated from Asia, is now also found in widespread areas of Central and South America.

Overall, an estimated 2 ½ to 3 billion people in over 110 countries are at risk for dengue fever infection. About 100 million people become infected with dengue fever every year, of which 250,000 develop dengue hemorrhagic fever (DHF). Worldwide, about 24,000 deaths are attributed to dengue fever.

Symptoms:

After about 10 days (plus/minus two days) of viral replication within the mosquito’s salivary gland, the mosquito becomes infectious for the rest of its lifetime – somewhere between 15 and 65 days. The mosquito’s eggs, however, can survive for as long as one year and at temperatures as low as 10ºC (50ºF).

The initial dengue infection may be asymptomatic and result in a nonspecific febrile illness, or it may produce the symptom complex of classic dengue fever. The so-called ‘dengue-triad’, a characteristic presentation of symptoms, includes the sudden onset of fever, accompanied by severe frontal headaches, and joint (arthralgias) and muscle pains (myalgias). Some patients will also experience nausea and vomiting, and develop a skin rash. This rash will appear three to five days after the initial infection, and spread from the torso to the extremities and face.

Some patients, who have previously been infected by one of the dengue serotypes, may develop bleeding and endothelial leakage upon infection with another dengue serotype. This syndrome is termed dengue hemorrhagic fever (DHF). Subsequently, some patients with dengue hemorrhagic fever may develop shock (dengue shock syndrome – DSS), which may be lethal.

The symptoms of DHF and/or DSS are much more severe than in DF, and usually occur within three to seven days of the illness, coinciding with the time of defervescence (the decline or interruption of the phase of fever). The primary symptoms of DHF and DSS consist of plasma leakage and bleeding, which are potentially lethal, as plasma leakage is caused by an increase of capillary permeability, often resulting in hemoconcentration, pleural effusions and ascites; and bleeding, caused by capillary fragility and thrombocytopenia (a marked decrease of platelets) may result in bleeding incidents into the skin (petechial skin hemorrhages), or even life-threatening bleeding into the gastrointestinal tract.

DHF or DSS usually develop in patients who had previously been infected by one or more of the other Dengue serotypes. Furthermore, certain dengue strains are considered more virulent, such as DEN-2, as this serotype has been associated with more epidemics of DHF than other serotypes.

Typically, the basic dengue fever lasts for about six to seven days, with a trailing end of the fever curve after a small peak (‘biphasic’ fever pattern). The patient’s thrombocytes (platelets) will keep dropping until the patient’s temperature has returned to normal.

Diagnosis:

In general, the diagnosis of dengue fever is made clinically, based on the clinical picture of the disease – high fever with no local source of infection, pinpoint skin (petechial) rash, and thrombocytopenia and relative leucopenia (low white blood cell count) on a CBC (complete blood count).

Additional laboratory criteria for a positive diagnosis include one or more of the following:

Demonstration of a four-fold or more increase in reciprocal IgG (immunoglobulin G) or IgM (immunoglobulin M) antibody titers to one or more dengue virus serotype antigens;
Isolation of the dengue virus from serum, plasma or leukocytes;
Demonstration of dengue virus antigens or viral genomic sequences, derived from autopsy tissues.

A ‘confirmed case’ of dengue fever is based on the compatibility of symptoms (its clinical definition) and confirmatory tests by the laboratory.

The World Health Organization (WHO) established guidelines for the diagnosis of dengue fever in 1975, calling for all criteria that must be fulfilled for a positive diagnosis:

Fever;
Hemorrhages – positive tourniquet test, spontaneous bruising, mucosal bleeding, vomiting blood or bloody diarrhea;
Thrombocytopenia – less than 100,000 platelets/mm³ (or less than three platelets/high power microscopy field);
Plasma leakage – evident by a hematocrit level of more than 20% higher than expected (thus confirmed the loss of plasma fluids), or a drop of the hematocrit level by 20% or more, following IV fluid therapy; hypoproteinemia, pleural effusion and ascites (collection of fluids in the thoracic cavity and/or abdominal cavity).

In addition to the symptoms of dengue fever, DSS is defined as including the following;

A rapid, weak pulse;
A narrow pulse pressure (<20 mm Hg);
Hypotension;
An altered mental status;
Cool, clammy skin.

Other basic laboratory findings of DF include:

Hyponatremia (low level of sodium), the most common electrolyte abnormality in DF or DSS;
Metabolic acidosis in DSS – requires immediate correction;
Increased BUN (blood urea nitrogen) levels in DSS;
Liver function tests may reveal low albumin levels (secondary to the hemoconcentration), and slightly elevated transaminase levels;
Coagulation studies in patients with DSS may show a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT);
Low fibrinogen levels in combination with elevated fibrin degradation product levels are indicative of disseminated intravascular coagulation (DIC), a medical emergency.

Additional diagnostic tests, such as chest radiography (X-rays) may show a typical (right-) sided pleural effusion or bilateral effusions in DSS. Serial ultrasonography can be used as a cost-effective method to identify fluid collections in the thoracic and abdominal cavities, or pericardial effusion.

Treatment:

Since dengue fever is a virus disease, there is no direct therapy available. It is usually a self-limited illness, thus, the mainstay of treatment consists of supportive therapy, including oral and intravenous fluid intakes, in order to maintain an adequate blood pressure, and to prevent dehydration and subsequent concentration of the blood. Platelet transfusions are indicated, if the platelet count falls below 20,000 per µl (normal level: 200,000 to 400,000/ µl), or if significant episode(s) of bleeding occur.

Blood in the stool (melena) may indicate gastrointestinal bleeding and require platelet and/or red blood cell transfusions.

To manage the febrile episodes, acetaminophen containing drugs are preferred over aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids, which should be avoided.

Patients with DHF or DSS require close observation, including intravenous (IV) fluids, such as Ringer lactate solution, starch, dextran 40 or albumin 5%, all of which may be of value to the patient.

Blood transfusions to replace blood loss or fresh frozen plasma for patients with a coagulopathy may be necessary in individual cases.

Prevention:

At this point in time – there is no vaccine available for the prevention of dengue fever.

Although, recently, attenuated candidate vaccine viruses have been developed, they are still very early in efficacy trials, determining their safety and efficiency. Other research is trying to develop so-called second-generation recombinant vaccine viruses, also still far away from early safety and efficiency trials.

Thus, the only currently available and reliable way of prevention is to avoid being bitten by the Ae. aegypti mosquito or one of its ‘relatives’. Preventive measures may include:

Wear protective light-colored clothing, ideally impregnated with permethrin insecticide;
Use DEET- (N,N-diethyl-3-methylbenzamide) containing mosquito repellants if traveling to tropical and/or subtropical regions;
Remain in air-conditioned or well-screened places, especially during the day;
Use indoor sprays to eliminate the mosquito;
Prevent the mosquito from finding breeding places by eliminating sources of stagnant water around human habitats (such as [flower] pots, old tires or any other kind of potentially water-holding containers).

Community Education

In endemic or potentially endemic areas, the community should be educated to the potential sources of the disease, and how to prevent the mosquito from breeding. This is especially important for patients and/or communities with a previous history of dengue fever, as this group appears to be at the highest risk to develop DHF or DSS upon a re-infection by a different subtype of the virus.

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