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Dengue infection is a common disease in tropical country. It is not new, but it is a re-emerging infectious disease that has aroused the concern of medical and public-health personnel worldwide. Dengue viruses (DENV) cause dengue infection. DENV are transmitted by members of the arbovirus group. The four antigenically distinct dengue serotypes (DEN-1, DEN-2, DEN-3, and DEN-4) are closely related viruses that cause infection. Dengue infection involves a combination of factors related to host (human), virus (dengue virus), vector (mosquito), and the environment.
The Aedes aegypti mosquito is the main transmitter of dengue virus. Moreover, the environment is a key factor for dengue infection spread, especially in tropical and sub-tropical countries. Global warming is a catalyst for the faster and short life cycle of mosquito.
Southeast Asia has a high incidence of dengue infection compared with other continents of the world. In Thailand, dengue infection is a major public-health problem. Survey data have revealed that transmission rates are highest in northeast and upper center Thailand, because of the scarcity of private water wells. In contrast to the transmission intensity in Bangkok has decreased rapidly since the mid-1990s. It seems that dengue cases are generally lower than in other provinces.
In the past, patient with dengue infection occurs mainly among children under the age of 15 years, with the highest attack rate among those aged 5-9 years. Nowadays, the peak for patient with dengue infection has shifted to the 10-14 age groups. A gradual increase in dengue infection has been reported among adults, who account for 30-40% of dengue cases in recent years. The severity of disease vary according to each age group; however, dengue virus, itself may contribute a role of pathological mechanisms and clinical presentations.
After a human is bitten by an infected A. aegypti mosquito, the dengue virus spreads through the blood circulation and lymphatic system, implicating human hepatocytes as target cells. They then redistribute through the blood circulation. The dengue virus infects the dendritic cells (DC) and triggers vascular leakage processes via matrix metalloproteinase (MMP)-9 substances. Afterward, it directly attacks the endothelial cells and increases vascular permeability. These conditions lead to circulatory failure and hypovolemic shock. The effects on the endothelial cells may contribute to the severity of dengue infection. Moreover, dengue virus also affects the monocyte cells, which release cytokine (tumor necrosis factor; TNF) with subsequent activation of the endothelial cells.
Varying degrees of thrombocytopenia are common in DHF. Some of the mechanisms responsible for this include IgM type antiplatelet antibodies, dengue viral specific antibodies, bone marrow hypocellularity (leading to increases in defective megakaryocytes production), or destruction of platelets in the liver and spleen. Antiplatelet antibodies cause lysis of platelets in the presence of complement. They are found in higher concentrations in patients with dengue hemorrhagic fever (DHF)/ dengue shock syndrome (DSS) than dengue fever, which probably accounts for the greater degree of thrombocytopenia seen in DHF. The DEN-2 serotype binds to human platelets only in the presence of virus-specific antibody, supporting a role for immune-mediated clearance of platelets. White blood cell counts for patient with dengue infection are characterized by increased numbers of atypical lymphocytes.
The incubation period of Dengue infection ranges from 4 - 10 days (WH0, 2009). After the incubation period, the infection from virus may be asymptomatic or can cause variety of symptoms depending on whether primary or secondary infection.
The clinical staging can be divided into 3 phases; febrile, critical or shock and recovery phase. The clinical and laboratory profile in each phase has difference. A viraemic stage follows where the patient becomes febrile phase. Thereafter, the patient may either recover or progress to the leakage phase, leading to DHF and/or DSS (WHO, 2009).
This phase begins with sudden onset intermittent high grade fever, associated with rigors or rashes. During the febrile phase, patients may develop other signs and symptoms including headache, myalgia and variable forms of hemorrhagic tendency such as easy brusing, petechiae and other mucosal bleeding. There may also be other associated symptoms for example cough, sore throat, myalgia, and abdominal pain. These symptoms make dengue fever difficult to distinguish from other non- specific febrile illness. A positive tourniquet test may help to make diagnosis of dengue infection (Malavige et al., 2004, WHO, 2009). Other features such as decreased white cell count and organomegaly mostly hepatomegaly are very common (Malavige et al., 2004). Platelet counts decline during this phase and reach the lowest point around the time of defervescence ( Srikiatkhachorn, 2009).
Patients recover from this phase uneventfully but sometimes may progress to severe form. Shock phase occurs when the temperature reaches normal within 24-48 hours of defervescence. This phase occurs on 3rd-7th days later is called as defervescence phase or critical phase. During defervescence, some patients develop a transient increase in vascular permeability there by increasing the risk of plasma leakage usually lasting for 24-48 hrs manifesting as rise in haematocrit, tachycardia and hypotension (WHO, 2009). Leakage of albumin rich fluid in the pleural and abdominal cavities presents commonly as right side pleural effusion and ascites respectively (Malavige et al., 2004).
When patients recover from this phase, return of appetite is considered as a good indicator of recovery. Nevertheless, some patients can still progress to state of shock that called as DSS as manifested by narrow pulse pressure, cold clammy skin, hypotension and organ failure. These patients usually carry greater risk of mortality (Malavige et al., 2004).
Classification of dengue infection
Most dengue infections are symptomless. The World Health Organization (WHO, 1997) scheme classifies symptomatic infections into three categories: undifferentiated fever (viral syndrome), dengue fever (DF), and dengue hemorrhagic fever (DHF).
Figure 1; classification of dengue infection according to WHO, 1997
Clinical diagnosis is defined as an acute febrile illness with two or more manifestations
Hemorrhagic manifestations, such as petechiae and positive tourniquet test
Dengue Hemorrhagic Fever:
A case must meet all 4 of the following criteria to be defined as DHF:
Fever lasting 2-7 days
Hemorrhagic tendency, such as
Positive tourniquet test
Petechiae, ecchymosis or purpura
Bleeding from mucosa (mostly epistaxis or bleeding from the gums), injection sites or other sites
Hematemesis or melena
Thrombocytopenia (platelets 100,000/cu.mm or less) and
Evidence of plasma leakage due to increased capillary permeability manifested by one or more of the following:
- >20% rise in hematocrit for age and sex
- >20% drop in hematocrit following treatment with fluids, compared with baseline
- Signs of plasma leakage (pleural effusion, ascities or
Grading of Dengue Hemorrhagic Fever:
DHF is further classified into four severity grades according to the presence or absence of spontaneous bleeding and the severity of plasma leakage (as table 1). DSS refers to DHF grades III and IV, in which shock is present as well as all 4 DHF-defining criteria. Moderate shock, identified by narrowing of the pulse pressure or hypotension for age, is present in DHF grade III, whereas profound shock with no detectable pulse or blood pressure is present.
A prospective study, conducted in a hospital setting in Dhaka, Bangladesh, found that a total of 150 clinically and serologically diagnosed dengue infections were classified into 3 groups, 12% DF, 84.67% DHF, and 3.33% DSS. A study among adults in Sri Lanka found 30.6% DF and 69.4% DHF. Of those with DHF, grades I, II, III and IV were seen in 44, 37.4, 13.3, and 5.3% of cases, respectively. A study of dengue patients classified according to WHO criteria found 81.9% DF, 13.6% DHF, and 4.5% DSS. Another study by Makroo et al. found 88.4% DF, 9.3% DHF, and 2.2% DSS using the WHO criteria.
Table 1; Grading of dengue fever and dengue hemorrhagic fever (Modify form WHO, 1997)
2 - 7 days
Positive TT or easy bruising
Spontaneous bleeding +/- positive TT
Spontaneous bleeding +/- positive TT
Rapid weak pulse and
PP <20 mmHg
Restless with cold clammy skinand
Hypotension (<90mmHg if age >5y, <80mmHg if age <5y
Spontaneous bleeding +/- positive TT
Pulse and BP undetectable
Several risk factors have been proposed for the development of DHF, including serotype and virulence of the infecting dengue virus, age, sex, immune status, and the genetic background of the host.
Case fatality and hospitalization rates due to DHF/DSS are highest among infants and the elderly. For instance, following a secondary DEN-2 infection, the risk of death for children is nearly 15-fold higher than adults. DHF is also reported to be more severe among females.
Generally, malnutrition predisposes to many infectious diseases (for example, measles, or tuberculosis) and tends to correlate positively with severity of disease. However, malnutrition appears to be significantly uncommon among patients with DHF, compared with patients with other infectious diseases, or healthy children.
DHF tends to be common among patients suffering from other chronic illnesses (e.g. diabetes mellitus or bronchial asthma). Further investigation of these different factors should help us better understand the pathogenesis of DHF and may in turn allow us to identify possible therapeutic options.
Hemorrhagic manifestations in DHF can present in a variety of ways, e.g. bleeding skin, such as petechiae, epistaxis, mild mucosal bleeding (hemetemesis, melena), to fatal hemorrhages such as intracranial bleeding. Moderate to severe thrombocytopenia (< 100,000/µl) causes the contributing factor of tendency to hemorrhage.
The study by Wiwanitkit (2003) showed that 26.6% had bleeding manifestations, including petechiae (23.3%), and melena (3.3%). Among 38% with bleeding manifestations, the most frequent was petechiae (15.7%), melena (9.3%), ecchymoses (7.4%), bleeding gums (6.5%), and hematemesis (5.6%). In a study of females at Colombo South Teaching Hospital, Sri-Lanka, bleeding per vagina was seen in 15.9% of cases, none of whom was menstruating at the time of infection.
Among hospitalized adult dengue patients, 42.9% had upper gastrointestinal bleeding manifestations (27%) and epistaxis (12.9%) associated with thrombocytopenia. Of the total, 98 patients presented with hemorrhagic manifestations. Gastrointestinal (GI) tract was the most common site of hemorrhage (46.9%), melena (37.8%), hematemesis (12.2%), hematochezia (2.04%), followed by petechiae (31.6%), gum bleeding (19.4%), and epistaxis (10.2%). Moreover, the common bleeding manifestations were GI tract bleeding (22%), and petechiae (18%).
In most cases of dengue fever, leucopenia, thrombocytopenia, and raised liver enzymes, may be seen. In contrast, DHF is always accompanied by a platelet count <100 x 109/l, hemoconcentration (a rise in packed cell volume >20% of base level), leucopenia, and raised liver enzymes. Both alanine and aspartate aminotransferase levels are raised. A leucopenia of 5 x 109/l has been suggested to predict the onset of DHF. Initial leucopenia is followed by a relative lymphocytosis (with > 15% atypical lymphocytes) towards the end of the febrile phase. Abnormal coagulation profiles (prolonged partial thromboplastin time and prothrombin time, raised fibrinogen degradation products), and hypoalbuminemia, are also seen.
A study conducted in Chonburi hospital found that patients (both adults and children) with severe DHF/DSS infections had significantly higher hematocrit levels than those with DF during hospitalization, and DSS patients had significantly higher peaks of hematocrit than the non-shock groups. Hemoconcentration, thrombocytopenia (< 50,000/mm3), leucopenia (< 4000 cells/ mm3) and atypical lymphocytes (>10%), were predominant laboratory findings associated with elevated liver enzyme tests (AST and ALT) among adult dengue patients admitted to hospitals in Thailand.
Platelet count and bleeding profiles
A study at Chonburi showed the median platelet count of all patients on admission was 85,000; DHF patients had significantly lower median platelet counts than those with DF. Regardless of disease severity, platelet counts decreased significantly during hospitalization. The mean time (SD) for platelet levels to reach their lowest point, for all patients, was 4.8 days after onset of fever. Moreover, a study among children in India showed that platelet counts were significantly lower in DHF and DSS groups. There was no correlation between platelet count and bleeding in classical dengue fever (DF vs DHF).
Bleeding manifestations were seen in 62.8% of adult patients with platelet counts <50 x 109/l. Platelet count <50 x 109/l and PCV >50 were significantly associated with bleeding manifestations. Furthermore, a significant negative correlation was seen between disease severity (grade of DHF) and platelet count in a study of hospitalized adult dengue patients in Sri Lanka. Ninety percent of patients were observed to have platelet levels < 100 x 103/μl , 60.6% < 50 x 103/μl, and 1.5% < 10 x 103/μl. The mean platelet counts in DF, DHF, and DSS groups were 51.6 ± 38.7, 40.0 ± 26.8, and 34.7 ± 20.5 x 103/μl, respectively. The mean platelet counts for patients with and without hemorrhagic manifestations were 47.2 ± 34.4 and 50.5 ± 38.4 x 103/μl, respectively and showed no association between hemorrhagic manifestation and degree of thrombocytopenia. In addition, the mean platelet counts of patients with and without hemorrhagic manifestations were not significantly different.
Among the laboratory indices it was seen that patients who had platelet counts < 50,000/cu.mm developed shock more frequently and those with counts > 100,000/cu.mm developed shock less frequently. Bleeding was significantly related to severe thrombocytopenia (platelet count < 50,000/cu.mm). However, bleeding was not related to moderate thrombocytopenia (platelet counts between 50,000 and 100,000/cu.mm).
Severe dengue infections may give rise to many complications, such as liver failure, disseminated intravascular coagulation (DIC), encephalopathy, myocarditis, acute renal failure, and hemolytic uremic syndrome (HUS).
Virus isolation and molecular techniques, such as reverse transcriptase-polymerase chain reaction (RT-PCR) are the gold standard. The popularity laboratory tests are NS1 and dengue IgM. However, the accuracy of these laboratory tests depends on investigation time.
According to severity of clinical symptoms, DHF is divided into 4 grades. Adequate fluid administration, regular assessment of fluid and electrolyte balance, and monitoring for the development of complications, are necessary. Management of dengue infections is mainly symptomatic, as there are no specific drugs effective against the dengue virus. Proper maintenance of fluid balance is a cornerstone of management. Early identification of the leakage phase, with prompt resuscitation, helps to reduce complications and improve outcome.
- Management of dengue fever
Both dengue fever and the febrile phase of DHF are managed similarly. Paracetamol is the only antipyretic recommended for use, since other non-steroidal anti-inflammatory drugs may provoke gastrointestinal bleeding. The recommended dose of paracetamol (60 mg/kg/day) should not be exceeded, since the liver injury that accompanies dengue viral infections may be aggravated.
- Management of DHF
Controversy exists regarding the type of fluid to be used for fluid replacement in DHF. Platelet transfusions may be given to patients who develop serious hemorrhagic manifestations or have very low platelet counts, although the exact platelet count at which platelet transfusions should be given is debatable. Transfusion requirements correlate with the occurrence of bleeding in the gastrointestinal tract, but not with platelet counts. A significant reduction in active bleeding is observed following platelet transfusions. A study among adult dengue patients showed that 30.9% needed platelet concentrates. 8% with DHF were given FFP for profound shock that was not controlled with crystalloid solutions. Of 42.6% of dengue patients who received platelet transfusion therapy, of whom 39.69% were DF, 71.42% were DHF and 40% DSS. Patients with platelet counts <10,000 /cu.mm received platelet transfusions. Patients with abnormal PT were transfused with FFP. PRBC were also transfused.
The dose of platelet concentrates is 0.2 - 0.4 unit/kg with a maximum of 8-10 units. On average, about 6 units of platelets were required per patient. A total of 826 platelet concentrates were transfused to 245 dengue patients (3.4 units/patient) and 882 units of FFP were transfused to 66 DHF/DSS patients (13.3 units/patient), resulting in significant rises in post-transfusion platelet counts. In unresponsive cases of massive bleeding, recombinant activated factor VII is suggested.
- Management of DSS:
Patients who develop disseminated intravascular coagulation need supportive therapy with blood products (blood, fresh frozen plasma, and platelet transfusions).
Of the total, 19.7% recovered completely, and 78.5% had improved at time of discharge from hospital within 2 weeks. Mortality due to dengue was only 0.9% in a study among adults in Thailand. Most patients receiving platelet transfusions recovered were discharged earlier, and their counts increased substantially.
The eradication of mosquito infestations may interrupt transmission. This outbreak underscores the importance of maintaining surveillance and control of potential vectors to control emerging infectious diseases.