Dengue hemorrhagic fever may arise from repeated infection with different serotypes of the dengue virus. It is a vasculopathy that consists in endothelial lesions which allow plasma leakage and hemorrhages.
DHF initially manifests as dengue fever and thus patients show fever (< 40°C), headaches and generalized pain as well as rash. This acute phase lasts up to one week and cannot easily be distinguished from other tropical infectious diseases such as malaria, leptospirosis and typhoid as well as viral pathologies. In uncomplicated cases of dengue fever, symptoms diminish after this time.
In contrast, additional symptoms are manifested, fever reappears and the patient's condition deteriorates in cases of DHF. Symptoms indicating circulatory failure caused by plasma leakage, hemoconcentration and edema development can usually be detected in between 24 hours before or after the initial fever peak drops. Patients frequently experience acute abdominal pain before going into shock. Dengue shock syndrome may result from plasma leakage or, less frequently, from hemorrhages and blood loss . Patients suffering from dengue shock syndrome are severely hypotensive (< 20 mm Hg), their pulse is nearly undetectable, they present petechial hemorrhages, perioral cyanosis and tachycardia as well as decreased consciousness. Dengue shock syndrome is associated with a very high mortality if left untreated.
Recommended procedures depend on the condition of the patient upon admission.
During the acute dengue fever-like stage of the disease, alterations detected in laboratory analyses may be less severe than after remission of the initial fever peak.
Hemogram, blood chemistry and coagulation tests should be realized and most frequently show the following alterations:
Plasma leakage and eventually hemorrhages are often associated with the following pathological findings:
These symptoms aggravate upon onset of dengue shock syndrome. For this reason, blood analyses should be repeated at least daily to monitor disease progress or remission and to be able to act as soon as possible when the patient threatens to go into shock. Worse condition justifies an even more frequent evaluation of these parameters.
A thorough clinical examination and possibly imaging techniques may reveal a bleeding diathesis (petechial bleedings, ecchymoses, purpura, positive tourniquet test ), pleural effusion, ascites, hepatomegaly and a thickened gallbladder wall. Ultrasonography is available at most places and provides reliable results . Surprisingly, the prevalence of hepatomegaly in DHF patients seems to depend on the specific strain of dengue virus. Distinct serotypes apparently cause different degrees of liver damage .
Because DHF and dengue shock syndrome may be accompanied by life-threatening edema formation and hemorrhages, the patient should be closely monitored and, if necessary, thoroughly examined to determine if those conditions affect vital organs, e.g., in form of cerebral edema or intracranial bleedings.
Hydration, fluid therapy and maintenance of water and electrolyte balances are the mainstays of DHF therapy. Hemodynamic and metabolic parameters have to be constantly monitored in order to be able to react rapidly. Isotonic solutions are usually administered to compensate hemoconcentration. Bicarbonate may be given to correct the acid-base balance. More severe cases of DHF and dengue shock syndrome may require transfusion of blood products.
Non-steroidal anti-inflammatory drugs are not recommended as analgesics and antiphlogistics because they may enhance the patient's bleeding diathesis. Furthermore, they have been associated with the development of Reyes syndrome in children. In order to manage pain and fever, acetaminophen should be administered.
Of note, effectivity of methylprednisolone in dengue shock syndrome has been refuted in a prospective clinical trial .
Prognosis is good when adequate treatment is provided during early stages of the disease. DHF, however, is associated with high mortality rates when left untreated or after patients go into shock.
Dengue fever is a tropical infectious disease caused by a positive single-stranded RNA virus pertaining to the family Flaviviridae and the genus Flavivirus. The virus is termed dengue virus.
There are four distinct serotypes of dengue virus that are indicated with numbers one to four. Evolutive studies suggest that all serotypes originate from one common ancestor presumably distributed in primate populations. Nowadays, all four serotypes are transmitted in urban cycles . Dengue virus serotypes present distinct antigenic determinants and may be further subdivided into different genotypes. These virus properties, serotype and genotype, as well as the sequence of infection with different virus strains presumably triggers DHF and determines the severity of the disease.
Dengue virus is transmitted by mosquitos and dengue fever may be contracted in endemic areas. People living in such areas have an increased risk of repeated infection and are therefore more likely to develop DHF .
About 40% of the world population live in subtropical and tropical climates and are at constant risk to be infected with dengue fever. Virus and vectors are present on every continent with the exception of Europe and Antarctica. The worldwide incidence of dengue fever has been estimated to range between 50 and 100 million per year, with this figure set to increase in the future. Indeed, case numbers have been increasing 30-fold during the last 50 years. Annually, about half a million individuals develop DHF and about 20.000 deaths occur due to DHF. Mortality is increased in children .
About one million cases of dengue fever are registered every year on the American continent. Approximately 2.5% of the affected patients developed DHF. All four serotypes have been detected in the northern countries of South America, with Brazil, Colombia and Venezuela reporting the majority of cases. Increasing case numbers have been registered in the Caribbean. With regards to Asia, most cases of dengue fever and DHF are registered in South-East Asia, particularly in Indonesia. While currently a significant share of cases corresponds to children, the average age at time of infection and mortality are augmenting. Interestingly, in all other continents DHF is equally distributed among all ages. Less reliable data are available regarding the African continent. It is known that many countries located in sub-Saharan Africa and the Arabian subcontinent harbor all subtypes of dengue virus as well as transmitting mosquitos.
The dengue virus replicates inside of different target cells, e.g. in endothelial cells, hepatocytes and cells pertaining to the reticulo-endothelial system. It is not yet known why some patients develop a coagulopathy and present with the more severe clinical picture of DHF after repeated infection with distinct serotypes and genotypes of the virus.
The most characteristic symptom of DHF is plasma leakage that occurs due to increased vascular permeability. This condition causes hemoconcentration as well as edema development. Fragile blood vessels may break and give rise to hemorrhages that become visible in form of petechiae when the skin is affected, but that may also affect the gastrointestinal tract or other organ system. Hemorrhages may become life-threatening, particularly when the patient suffers from disseminated intravascular coagulopathy and subsequent deficiency of thrombocytes and coagulation factors. To date, complex interactions between viruses, the host immune system, its antibodies, inflammatory cells and cytokines is presumed to be responsible for the development of DHF.
As has been mentioned above, viruses also replicate in hepatocytes and reticulo-endothelial cells. This may cause severe hepatic damage. It has been shown that up to 90% of all hepatocytes and Kupffer cells are infected with the viral agent in cases of fatal dengue hepatitis . Of note, only very low levels of pro-inflammatory cytokines could be detected here. Less severe hepatic damage, although not fatal, may aggravate the deficiency of coagulation factors that is initially caused by the above mentioned coagulopathy.
There are no specific measures to avoid contracting dengue fever and subsequently DHF other than avoiding the mosquitos that serve as vectors for the dengue virus.
Travelers can be advised to take preventive measures, to wear adequate clothing that covers arms and legs, to use repellents, to impregnate clothes with repellents and to stay in rooms that dispose of window screens. Sleeping under mosquito nets is recommended but not sufficient because the most of the mosquitos that transmit the virus, the genus Aedes, is active during the day. If possible, journeys should not be realized when large mosquito populations have to be expected, especially during rainy seasons.
However, these recommendations are of limited help to billions of people living in endemic areas. Moreover, many endemic areas correspond to developing countries where large shares of the population do not have access to the required articles. It has repeatedly been tried to eliminate mosquitos from larger areas by spraying whole cities, but these measures have not proven effective. General efforts to eliminate the insects' habitat, to implement hygienic measures, to remove garbage and other reservoirs of stagnant water may be helpful to decrease the incidence of the disease. Water in reservoirs that cannot be eliminated because they are needed by the population should regularly be changed, ideally daily.
Current research focuses on the possibility of biological mosquito control. Predatory copepods may eventually be used in this context .
Finally, general measures such as raising the awareness of health care givers and the general public are as necessary as surveillance systems to stop the increasing incidence of dengue fever and DHF.
Dengue hemorrhagic fever (DHF) is a severe complication of dengue fever. The causative agent of the latter, the dengue virus, replicates in endothelial and other types of cells. It is not yet fully understood why some patients suffering from dengue fever develop severe vasculopathies that result in DHF. It has been speculated that repeated infection with distinct serotypes and genotypes of dengue virus predisposes individuals for DHF. Children seem to be more susceptible to DHF .
DHF is characterized by plasma leakage due to increased vascular permeability and edema formation. More severe lesions to the endothelial cells may even result in hemorrhages. Hemoconcentration and hemorrhages contribute to circulatory failure and provoke the potentially lethal dengue shock syndrome .
Symptoms of DHF usually set in with some delay in relation to acute dengue fever symptoms. During this acute phase, it is difficult to distinguish DHF from uncomplicated dengue fever and even other tropical infectious diseases. About 24 hours after dengue fever-associated fever subsides, DHF patients will start to show signs of hemoconcentration and edema development.
Treatment aims at stabilizing the patient and preventing dengue shock syndrome. Therefore, fluid therapy and correction of electrolyte imbalances are the mainstays of therapy. If adequate treatment is provided, prognosis is good.
Dengue hemorrhagic fever (DHF) is a severe form of dengue fever, an infectious disease transmitted by mosquitos in subtropical and tropical regions. A small share of dengue fever patients develops DHF.
Patients may develop DHF after repeated infection with distinct types of the dengue virus. It seems the specific types, the sequence of infection as well as the patient's immune system contribute to the development of DHF, but the precise background is not yet completely understood.
In cases of DHF, the inner layer of the blood vessels, called the endothelium, is damaged in the course of the disease. This allows fluids and certain solutes to pass from the vessel into the surrounding tissue. The same condition may also cause an overall bleeding tendency.
Similarly to an uncomplicated case of dengue fever, DHF patients develop fever, headaches and generalized pain as well as rash. The fever usually subsides after a few days, but contrary to the uncomplicated cases, it will return soon after and be accompanied by additional symptoms.
Due to the above mentioned damage to the endothelium, edema may form in different parts of the body, e.g. in the abdomen or around the lungs. Hemorrhages may be recognized as differently sized spots of blood on the skin and an overall tendency to bleed due to minimal traumas.
The cardiovascular system will be lacking those fluids and blood that leave the intravascular space through the damaged endothelium. The body may try to compensate this by increasing the heart rate but may not be able to make up for the severely decreasing blood pressure. At this point, patients may start to sweat but feel cold and clammy and go into shock. If not adequately treated, shock can lead to death.
Diagnosis is based on clinical examination and laboratory tests. Blood samples are particularly helpful to confirm viral infection and to identify hemoconcentration, electrolyte imbalances and coagulation disorders that result from an increased vascular permeability. Treatment will be adjusted to the results obtained in blood analyses. Therefore, such analyses may not only be realized to verify the diagnosis of DHF, but also to monitor disease progress and recovery after treatment has been started.
Chest X-rays or ultrasound examinations may be conducted to check the condition of the liver and to see if fluids are accumulated in thorax or abdomen.
There is no specific treatment against dengue fever or DHF. Thus, any treatment will be symptomatic and focus on compensating for plasma and blood loss. Therefor, isotonic solutions may be administered in mild cases and blood or blood product transfusions may be required in more severe cases. Oxygen might be supplemented to increase the amount of oxygen distributed to the body's tissues and cells.
Additional drugs may be prescribed in order to alleviate pain and fever.