Dengue fever risk factors; causes


The original WHO-sponsored DF/DHF/DSS classification system for dengue, first introduced in the 1970s, proved to be invaluable in focusing attention on the urgent need for volume resuscitation for patients with shock (Nimmannitya et al., 1969; WHO, 1986, 1997). However, over the ensuing years increasing concerns have been voiced regarding the applicability and complexity of the system, particularly in the face of the ongoing geographical expansion of dengue such that a much greater range of countries and patient populations now experience symptomatic disease (Sumarmo et al., 1983; Deen et al., 2006; Rigau-Perez, 2006; Bandyopadhyay et al., 2006; Santamaria et al.2009). As a result of these concerns, and in the light of a large multicenter study intended to evaluate the system across a range of endemic countries, a revised case classification system was adopted by WHO in 2009 (WHO, 2009; Alexander et al., 2011). The new system recognizes dengue to be one disease entity with different clinical presentations, often with unpredictable clinical evolution and outcome. Patients are classified according to their overall level of clinical severity, as having either dengue or severe dengue without recourse to specific cutoffs for laboratory parameters such as the platelet count or the degree of hemoconcentration. Additionally, while accepting that the group who progress to severe disease can be difficult to define, the new classification also identifies two sub-categories within the dengue group, i.e. patients with and without warning signs for progression. The revised classification system is considerably simpler to apply than the original scheme and has been welcomed in many countries (Basuki et al., 2010; Barniol et al., 2011; Narvaez et al., 2011; van de Weg et al., 2012; Tsai et al., 2013), although the old system continues to be used in some Southeast Asian countries (Srikiatkhachorn et al., 2011). Efforts are ongoing, through large prospective studies involving partners in a number of endemic countries across Southeast Asia and Latin America, to further refine the system, focusing in particular on improving the identification of warning signs for progression to severe disease.


Dengue with warning signs

During the transition from febrile to critical phases it is crucial for clinicians to be aware of warning signs that the patient may be developing significant vascular leakage. These signs of impending deterioration include persistent vomiting, increasingly severe abdominal pain, tender hepatomegaly, a high or rising hematocrit concurrent with a rapid decrease in platelet count, serosal effusions, mucosal bleeding and lethargy or restlessness. However, it is also important to remember that some patients may progress to severe dengue whether or not they have warning signs. In principle, development of any warning sign should flag the need for hospitalization, close observation and consideration of early intervention.

Severe dengue

Patients who experience any one of the following problems at any time in their illness course are classified as having severe dengue: plasma leakage resulting in shock and/ or fluid accumulation sufficient to cause respiratory distress; severe bleeding; severe organ impairment (such as severe liver involvement, myocarditis). A system in which any single serious manifestation classifies the patient as severe is considered to be preferable for surveillance and should facilitate more standardized reporting. DSS remains prominent on the list of complications, focusing attention on altered capillary permeability, plasma leakage and shock as the primary manifestations of severe disease. Severe bleeding is also included, as a well recognized though less common complication, while the incorporation of severe organ involvement as a specific entity gives clinicians the opportunity to report cases that were previously ignored. Final definitions as to what should qualify for severe involvement of specific organs (for example, hepatic involvement) are likely to require further refinement over time (Lee et al., 2012b), but the current system is designed to allow the full extent of severe syndromes associated with dengue infection to be described.

Major Host Factors Influencing

Clinical Presentation


Symptomatic dengue with or without complications may be seen at all ages. The clinical features and type of complications that occur in individual patients are influenced by a complex interplay between factors including

prior exposure/dengue immune status at the time of the current infection, and a number of intrinsic physiological factors that vary with age.


Female subjects generally have a lower threshold for vascular leakage than males (Gamble et al., 2000), and there is evidence to suggest that, although dengue is diagnosed more frequently in male than female patients (Anders et al., 2011; Anker and Arima, 2011), female patients have a higher risk of developing DSS and of dying from this complication than male patients (Kabra et al., 1999; Anders et al., 2011).


Co-morbidities are seen more frequently with increasing age (Lee et al., 2008; Wang et al., 2009; Lye et al., 2010). Work from Cuba originally suggested that conditions such as bronchial asthma, sickle cell anemia and diabetes

mellitus could be risk factors for development of severe disease forms (Bravo et al., 1987; Gonzalez et al., 2005). Subsequently studies in Singapore and Taiwan also found that diabetes mellitus and hypertension were associated with severe disease (Lee et al., 2006; Pang et al., 2012). Not surprisingly, individuals with bleeding disorders such as hemophilia may experience more bleeding than other patients.

Pregnancy and transplacental infection

With the increasing burden of dengue seen among young adults, exposure to infection during pregnancy is becoming more frequent. Although the evidence is limited to case reports and small series, the presenting signs and symptoms during pregnancy are fairly typical (Carles et al., 2000; Ismail et al., 2006; Waduge et al., 2006; Basurko et al., 2009; Adam et al., 2010). However, identification of vascular leakage may be masked by the normal physiological changes that occur during pregnancy, and diagnosis of severe complications can be difficult given the similarities with conditions such as HELLP syndrome and eclampsia (Chye et al., 1997; Chhabra and Malhotra, 2006; Waduge et al., 2006; Tagore et al., 2007).

Differential Diagnosis

Early and accurate diagnosis of dengue is im - portant for several reasons. Firstly, appropriate case management can be instituted and arrangements made for suitable follow-up and monitoring of true dengue cases; currently large numbers of patients with possible dengue, potentially at risk for severe disease, are admitted to healthcare facilities primarily for observation, overburdening the system such that the often limited local resources are not used to maximal advantage. Secondly, other potentially serious diagnoses can be identified and treated properly from an early stage. Both infectious and noninfectious diseases must be included in the differential diagnosis. The particular disorders that should be considered vary, depending partly on the phase of illness and the age of the patient, as well as the epidemiological pattern of other febrile illnesses that are common locally. During the febrile phase many viral infections need to be considered, among them measles, rubella, enterovirus infections, adenovirus infections, influenza, infectious mononucleosis, other arboviral infections, and, occasionally, human immunodeficiency virus (HIV) seroconversion illness. If present, the characteristics and natural evolution of the rash can be helpful. In measles and rubella, for example, the rash is often florid and typically extends from the head to the trunk and extremities, while in dengue the early rash can be quite difficult to see and usually starts on the trunk, later extending to the face and extremities (Dietz et al., 1992). Upper respiratory symptoms with headache and myalgia are common features in many systemic viral infections – by contrast patients with dengue tend to experience gastrointestinal rather than respiratory symptoms, although younger children do sometimes complain of cough, sore throat and occasionally rhinorrhea (Phuong et al., 2004).

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