| disease | Dengue Fever and Dengue Hemorrhagic Fever |
| alias | Dengue Fever, Dengue Henorrhagic Fever, DHF |
Dengue fever and dengue hemorrhagic fever (DHF) are acute pestilential diseases caused by the dengue virus and transmitted by mosquitoes. The former is primarily characterized by fever, rash, severe muscle and bone joint pain, swollen lymph nodes, and leukopenia, with a low mortality rate; the latter is mainly characterized by fever, rash, bleeding, and shock, with a high mortality rate.
bubble_chart Epidemiology
(1) Source of Pestilence: Patients and asymptomatic carriers are the main sources of pestilence. The pestilence is most potent from one day before the onset of the disease to five days after. Monkeys in the forests of Southeast Asia often do not develop the disease after infection but can become sources of pestilence.
(2) Pestilence Vectors: The Aedes aegypti mosquito is the primary vector for this disease, followed by the Aedes albopictus mosquito. The former is mainly distributed in the southern coastal areas of China, such as Hainan Island, and prefers indoor habitats. The latter is more widely distributed in China, especially south of the Yangtze River, and is often active outdoors. After a mosquito becomes infected by feeding on blood, it takes 8 to 12 days to become pestilent, and it can transmit the disease by biting again. Once infected, Aedes mosquitoes remain pestilent for life. The virus can replicate extensively in the salivary glands and nerve cells of Aedes albopictus.
(3) Susceptibility: Humans are generally susceptible. Once an outbreak occurs in an area previously free of the disease, the epidemic can spread rapidly within a short period, infecting most residents. Children are more likely to contract the disease. In tropical regions, the disease often becomes endemic. Immunity to the same subtype can last 1 to 4 years after an infection, but individuals can still be infected by another subtype. Infection with two subtypes can confer long-lasting immunity.
(4) Epidemiological Characteristics: The disease is prevalent in tropical and subtropical regions, particularly Southeast Asia, followed by North Africa, equatorial Africa, northern South Africa, Australia, the Mediterranean region, Pacific islands, and Caribbean islands. Before liberation, outbreaks occurred in Taiwan and the southeastern coastal regions of China. After liberation, an outbreak occurred in Foshan, Guangdong, in 1978, and by 1980, it had spread to Guangdong, Guangxi, and other regions, with Hainan Island being the most severely affected. Since then, outbreaks of varying severity have occurred frequently.The disease is transmitted by mosquitoes, so its prevalence is seasonal, generally occurring from May to November each year, with the peak between July and September.
Dengue viruses are group B arboviruses, classified under the Togaviridae family and the Flavivirus genus. The virus has an RNA genome capsid, appearing in dumbbell, rod, or spherical shapes, with a diameter of 40-50nm. It can be cultured and propagated in the brains of suckling mice and tissue cells, with the Aedes albopictus cell line (C6/36) being the most sensitive. Dengue virus has four serotypes: I, II, III, and IV, which can be differentiated using methods such as neutralization, complement fixation, and hemagglutination inhibition tests. There are cross-reactions among the serotypes, so paired serum samples from patients should be taken, and a fourfold or greater rise in antibody titer is required for diagnostic value.
Dengue virus can be inactivated by ether, 0.25% formic acid, ultraviolet irradiation, or exposure to temperatures of 40-45℃ for about half an hour.
The mechanisms of dengue fever and dengue hemorrhagic fever have not yet been fully elucidated. Recent research has provided the following insights.
(1) Immune mechanism: Halstead et al. believe that individuals infected with the dengue virus for the first time clinically present with typical dengue fever without bleeding or shock. However, upon reinfection with a different type of dengue virus, the virus in the blood binds with pre-existing antibodies to form immune complexes, which activate complement and cause tissue injury, clinically manifesting as bleeding and shock.
Experiments on monkeys infected with the dengue virus for the first time revealed that the virus invades nearby lymphatic tissues before viremia occurs, then rapidly spreads to all lymphatic tissues. Even after viremia disappears, the virus can still replicate in white blood cells and other tissue cells, re-entering the bloodstream to form immune complexes with antibodies. During the second infection, the amount of virus in tissue cells significantly increases compared to the first infection. When dengue virus antibodies were injected into monkeys and then challenged with the dengue virus, the viral load was 51 times higher than in the control group (monkeys without dengue virus antibodies). Additionally, it was found that white blood cells from individuals with dengue virus antibodies had a significantly higher rate of virus replication compared to those without antibodies. These experiments demonstrate that the significant increase in virus replication is related to the presence of antibodies.
Serological studies have confirmed that there are two different antigenic determinants on the surface of the dengue virus: group-specific determinants and type-specific determinants. The group-specific determinants are common to flaviviruses (including the dengue virus), and the antibodies they produce have a strong enhancing effect on dengue virus infection, known as enhancing antibodies. The type-specific determinants produce antibodies with strong neutralizing effects, known as neutralizing antibodies, which can neutralize reinfection by the same type of dengue virus and also have some neutralizing ability against different types of viruses. During a second infection, if the enhancing antibody activity in the serum is weak and the neutralizing antibody activity is strong enough to neutralize the invading virus, viremia is quickly eliminated, and the patient may not develop symptoms. Conversely, if the enhancing antibody activity is strong, it binds with the virus to form immune complexes, promoting virus replication in these cells through Fc receptors on monocyte or macrophage membranes. This phenomenon is known as Antibody-dependent enhancement (ADE), leading to the occurrence of dengue hemorrhagic fever. It has been found that type II dengue virus strains have multiple antigenic determinants related to ADE, while other types of virus strains do not have these enhancing antigenic determinants, making type II dengue virus more likely to cause dengue hemorrhagic fever than other types.
Monocytes containing dengue virus proliferate extensively and are transported throughout the body in the presence of dengue virus antibodies, becoming target cells for immune responses. Activated T cells stimulate monocytes to release various chemical mediators, and the activated T cells themselves can also release a series of lymphokines. These bioactive substances activate the complement system and the coagulation system, increasing vascular permeability, leading to the formation of DIC, resulting in bleeding and shock. Histamine levels in the patient's blood increase, which can dilate blood vessels and increase vascular permeability, with type I hypersensitivity reactions also involved. Dengue virus antigens bind to platelets with Fc receptors and virus receptors, and dengue virus antibodies bind to viral antigens on platelets, causing platelet aggregation and destruction, leading to thrombocytopenia. The patient's bone marrow is suppressed, reducing platelet production. Thrombocytopenia can lead to bleeding and also affect the function of vascular endothelial cells. Immune complexes deposit on the vascular walls, activating the complement system and causing immune injury to the vascular walls, with type III hypersensitivity reactions also involved in the pathogenesis.
(II) Virus Variation
Hammon believes that the different clinical manifestations of dengue fever and dengue hemorrhagic fever are related to the variation of the virus. Through epidemiological observations in Pacific islands such as Tahiti and Fiji, it was found that many people with their first dengue Rebing infection also exhibited the clinical course of dengue hemorrhagic fever. The serum reactions of these patients were also of the primary infection type, with children constituting the majority. Some believe that the severity of the clinical condition of dengue virus infection is related to the virulence of the virus. The emergence of more virulent strains of the dengue virus through variation may be an important factor in the occurrence of dengue hemorrhagic fever.
bubble_chart Pathological Changes
1. Dengue Fever: In this disease, degenerative changes are observed in the liver, kidneys, heart, and brain. Hemorrhages of varying degrees are found in the endocardium, pericardium, pleura, peritoneum, gastrointestinal mucosa, muscles, skin, and central nervous system. In the skin rash, there is swelling of the endothelium of small blood vessels, perivascular edema, and mononuclear cell infiltration. Extravasation of blood is widespread in the ecchymoses.
2. Dengue Hemorrhagic Fever: The main pathological changes in this disease are vascular dilation and congestion caused by systemic vascular damage, leading to hemorrhage and plasma extravasation. Hemorrhages occur in the digestive tract, subendocardium, subcutaneous tissue, subcapsular liver, lungs, and soft tissues. There is hemorrhage, edema, and lymphocyte infiltration around small visceral blood vessels and capillaries. Lymphocytes and plasma cells proliferate in the liver, spleen, and lymph nodes, with active phagocytosis. The lungs are congested and hemorrhagic, with increased interstitial cells. The liver parenchyma shows fatty changes and focal necrosis, with lymphocyte, histiocyte, and plasma cell infiltration in the portal areas. The adrenal glands show capillary dilation, congestion, focal hemorrhage, loss of fat in the zona glomerulosa, and focal necrosis. The bone marrow shows impaired maturation of megakaryocytes.
bubble_chart Clinical Manifestations
The incubation period is 2 to 15 days, with an average of about 6 days, and its length is related to the amount of virus that invades.
(1) Dengue Fever The typical course can be divided into the invasion period, stage of remission, and stage of full eruption.
1. Invasion period (fever period) Most patients have an acute onset, while a few may have brief prodromal symptoms such as headache, back pain, fatigue, and loss of appetite. The temperature rapidly rises above 39°C, accompanied by fear of cold, severe headache, back pain, muscle and joint pain (all extremely intense, hence the disease was once called "breakbone fever"), orbital pain, and retro-orbital pain (especially when moving the eyes). The face and conjunctiva are significantly congested, and the skin of the neck and upper chest is flushed. There may be grade I swelling of the lymph nodes throughout the body, the spleen is palpable and soft, and the liver is also enlarged. Other symptoms include hypersensitivity, nausea, vomiting, abdominal pain, poor appetite, and both diarrhea and constipation may occur. There may be a relatively moderate pulse.
A few cases develop transient, pinpoint-like macules and papules all over the body within 24 to 48 hours of onset, mainly seen on the elbows, knees, and face, which fade upon pressure. This period lasts about 2 to 4 days.
2. Stage of remission This usually occurs on the 4th day of illness and lasts about 1 to 2 days. Generally, symptoms lessen, and the temperature returns to normal. However, there can be significant variation between outbreaks, and many cases do not have a stage of remission, with fever persisting without a downward trend.
3. Stage of full eruption The rash appears 2 to 5 days after the onset of illness, initially on the palms and soles, or first on the trunk and abdomen, gradually extending to the neck and limbs, with some patients experiencing facial eruptions. The rash is quite noticeable, mostly measles-like, with a few being scarlet fever-like, or somewhere in between; it is slightly itchy and fades upon pressure. If the temperature had dropped, it rises again at this time, showing a saddleback fever, and systemic symptoms worsen accordingly. The second fever can be higher than the first and often drops abruptly. The rash disappears within 1 to 5 days (average 3 days), usually subsiding with the temperature, but there are cases where the rash becomes more pronounced after the temperature drops.
There are also cases where fine petechiae appear on the back of the legs, ankles, back of the wrists, armpits, etc., on the last day of fever or after the fever subsides, which do not fade upon pressure; they disappear within 1 to 3 days, leaving behind transient brown spots.
A relatively moderate pulse is quite noticeable during this period. Severe cases may have a tendency to bleed, such as epistaxis, petechiae, gastrointestinal bleeding, etc.
The entire course lasts about 5 to 7 days. Patients often feel weak and depressed after the illness, and full recovery usually takes several weeks.
(2) Dengue Hemorrhagic Fever The course of this disease can be divided into the fever period, shock period, and stage of convalescence.
1. Fever period The main symptoms of this period include fever, upper respiratory symptoms, headache, vomiting, diarrhea, etc. The onset is acute, with the temperature rapidly rising to above 40°C, though some cases have a slower onset with 2 to 4 days of prodromal symptoms such as low fever, headache, nausea, anorexia, etc. The face is flushed, and the pharynx is congested with a dry cough. Petechiae appear on the 2nd to 3rd day of illness, commonly on the forehead or distal parts of the limbs, with maculopapular rashes being rare. The tourniquet test is positive before the appearance of petechiae. There may be severe abdominal pain and tenderness.
2. Shock period Severe patients often suddenly go into shock, usually occurring on the 4th day of illness (2 to 5 days), lasting 12 to 24 hours. Symptoms include dysphoria, restlessness, cold limbs, drop in body temperature, rapid and irregular breathing, weak pulse, and some patients may have massive gastrointestinal bleeding, large skin petechiae, etc., with occasional unconsciousness. A few patients may develop complications such as bronchopneumonia, cerebral edema, intracranial hemorrhage, etc.
2. Stage of convalescence With timely rescue, patients can improve 1 to 2 days after shock and bleeding are controlled, recovering quickly and completely, without weakness or depression. Occasionally, there may be bradycardia, premature beats, etc.
bubble_chart Auxiliary Examination
(1) General Routine Examinations
1. Peripheral Blood Picture In dengue fever patients, the total white blood cell count decreases at the onset of the disease and becomes particularly evident during the stage of full eruption; the percentage of neutrophils also decreases, with a noticeable left shift, and abnormal lymphocytes are present. The blood picture returns to normal one week after the fever subsides.
In dengue hemorrhagic fever patients, the total white blood cell count is normal or increased, with the latter seen in severe cases and those with secondary infections, generally above 10,000/mm3. Platelet count decreases, with the lowest reaching below 10,000/mm3.
2. Urine Routine Examination May show a small amount of protein, red blood cells, white blood cells, and sometimes casts.
(2) Virus Isolation Take blood from early-stage patients and inoculate it into Aedes albopictus cell line (C6/36). After virus isolation, it must be identified through type-specific neutralization tests or hemagglutination inhibition tests.
(3) Serum Immunological Tests Take paired sera for complement fixation tests, neutralization tests, or hemagglutination inhibition tests. The hemagglutination inhibition test is more sensitive, while the complement fixation test is the most specific. During the stage of convalescence, a single specimen with a complement fixation antibody titer of 1:32 or higher is diagnostically significant; a fourfold or greater rise in titer in paired sera confirms the diagnosis.
(4) Others In dengue hemorrhagic Rebing cases, blood concentration, prolonged bleeding and clotting times, elevated serum aspartate aminotransferase, prolonged prothrombin time, electrolyte disturbances, decreased blood albumin, and metabolic acidosis may also be observed. Various coagulation factors are reduced to grade I, fibrinogen is decreased, and fibrinogen degradation products are mildly to grade II increased. Additionally, more than half of the shock cases show signs of DIC.
A comprehensive analysis should be conducted based on epidemiology, clinical manifestations, and laboratory tests. Individuals in or having visited epidemic areas during the epidemic season, who suddenly develop symptoms such as fever, severe muscle and bone arthralgia, facial flushing, relatively moderate pulse, superficial lymph node enlargement, rash appearing two days after fever, and decreased white blood cells and platelets, should be considered for dengue fever. Early appearance of significant petechiae or ecchymosis on the face and limbs, a positive tourniquet test, rapid onset of shock, and obvious bleeding are of significant reference value for the diagnosis of dengue hemorrhagic fever. Virus isolation and serological testing are the main bases for confirmation. A history of not having suffered from group B viral diseases, a high antibody titer in serological tests, a hemagglutination inhibition test >1:640, a complement fixation test >1:32, or a fourfold or greater increase in antibody titer during the convalescent stage are all helpful for diagnosis.
bubble_chart Treatment Measures
There is no specific treatment for dengue fever and dengue hemorrhagic fever, and comprehensive treatment measures are mainly adopted. Patients in the acute phase should rest in bed, and during the {|###|}stage of convalescence{|###|}, they should not engage in activities too early. The diet should consist of liquid or semi-liquid foods, which should be nutritious and easy to digest. For patients with high {|###|}Rebing{|###|}, intravenous fluid infusion can be considered, with a daily volume of 1000～1500ml, but care must be taken to prevent infusion reactions. If an infusion reaction occurs, immediately administer 200mg of hydrocortisone or 10mg of dexamethasone intravenously, and closely monitor the patient's condition. {|###|}Dengue hemorrhagic fever presents with severe symptoms such as shock and bleeding, which require active management. For patients in shock, timely replenishment of blood volume is essential, and options include low molecular weight dextran, balanced salt solution, and glucose saline. The initial fluid volume should be 300～500ml, administered rapidly intravenously, and plasma transfusion or vasoactive drugs may be used if necessary (refer to Section 20 "Epidemic Hemorrhagic Fever"). Patients with massive bleeding should receive fresh blood transfusions. For those with {|###|}upper consumptive thirst{|###|} and gastrointestinal bleeding, aluminum hydroxide gel, Yunnan Baiyao, and cimetidine can be administered orally. In severe cases, ice saline or diluted norepinephrine can be used for gastric lavage. For uterine bleeding, uterine contraction agents can be used. For patients with cerebral {|###|}edema{|###|}, 250ml of 20% mannitol and 10mg of dexamethasone can be administered intravenously. For those with {|###|}spasm{|###|}, diazepam can be slowly injected intravenously. The value of adrenal corticosteroids remains controversial.
Dengue fever is a self-limiting disease with a good prognosis, and the mortality rate is below 0.1%. The prognosis is poorer in the elderly with stirred pulse sclerosis and severe bleeding. Dengue hemorrhagic fever has a higher mortality rate, especially in cases of shock, where the mortality rate can be as high as 10-40%; however, if shock or bleeding is properly managed, the mortality rate can be reduced to 5-10%. Dengue hemorrhagic fever differs from dengue fever in that recovery is rapid and complete, with few cases of post-recovery suppression and weakness. A platelet count below 50,000/mm3 should alert one to the possibility of major bleeding, and a decrease in pulse pressure is a precursor to shock.
Mosquito eradication and prevention are the primary measures to prevent dengue fever and dengue hemorrhagic fever. For more information, refer to Section 79 "Malaria" and Section 12 "Japanese Encephalitis," etc. Mosquito eradication mainly involves eliminating mosquito breeding grounds. Aedes mosquitoes often lay eggs and breed in small stagnant water. Measures include overturning pots, jars, and caves, filling in depressions, and dredging ditches. Spraying various organophosphorus {|###|} insecticides to reduce mosquito density to the lowest level.
Suspected patients should be placed under medical observation. Patients should be isolated in wards with screen windows and doors, and the isolation period should be no less than 5 days.
Opinions on the use of vaccines are still not unified.
Dengue fever needs to be differentiated from epidemic common cold, yellow Rebing, leptospirosis, macula and papule cold-damage disease, malaria, cold-damage disease, measles, scarlet fever, and drug efficacy. Dengue hemorrhagic fever needs to be distinguished from epidemic hemorrhagic fever, meningococcal septicemia, rickettsial diseases, etc. The Chikungunya virus belongs to the arbovirus group A and can cause clinical manifestations similar to dengue fever, but the condition is generally milder. Differentiation mainly relies on virus isolation and serological tests.
