Evaluation of the importance of fever with respect to dengue prognosis according to the 2009 WHO classification: a retrospective study

Dengue is an infectious disease that exhibits acute evolution [1]. The incidence of dengue has increased across all age groups [2] to become a clear public health problem [3]. The causative dengue virus (DENV) belongs to the Flaviviridae family within the Flavivirus genus [4], and harbors RNA genetic material that encodes three structural (capsid [C], membrane protein [M] and glycoprotein for the viral envelope [E]) and seven non-structural (NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5) proteins [5] essential for viral replication in host cells [4, 6]. DENV is transmitted by a bite from a female Aedes aegypti mosquito [7] that caries one of the four virus serotypes [4]. The viremic period of the disease is defined as the period during which dengue virus can be detected in the blood of an infected human [6]. Following inoculation of the virus into the host, the incubation period may vary from 4 to 10 days [8, 9], after which various clinical signs and symptoms will emerge [9]. Infection with a specific virus serotype initiates permanent, or homotypic, immunity against that serotype [5, 6, 9]. Reinfection with a different strain may induce a cross-reaction in which existing antibodies from the first infection bind but do not abolish the virus; this process generally leads to more severe disease [5, 10].

The 1997 World Health Organization (WHO) guidelines on dengue presented three disease categories: dengue fever, dengue hemorrhagic fever, and dengue shock syndrome [3]. Investigations intended to classify the disease and facilitate the initiation of treatment are necessary when a patient is suspected to have dengue. Patients with dengue fever usually presents with an abrupt-onset high fever [11] and two or more other symptoms, such as headache, retro-orbital pain, myalgia, and arthralgia. Laboratory tests may indicate leukopenia and thrombocytopenia without plasma leakage. In addition to the classic symptoms of dengue fever, patients with dengue hemorrhagic fever present with a positive result on the tourniquet test and signs of spontaneous bleeding. This disease is divided into four grades, of which grades three and four are defined as dengue shock syndrome, indicated by the presence of signs of circulatory deficiency such as a weak pulse and hypotension, or even an absent pulse and blood pressure, as a result of plasma leakage [8].

Owing to difficulties with the application of this classification to patients with more severe symptoms, the WHO revised its guidelines in 2009 to include three categories: dengue without warning signs, dengue with warning signs, and severe dengue [2, 3, 12]. Symptoms of dengue with warning signs may include abdominal pain, vomiting, fluid retention, bleeding from mucous membranes, lethargy, and hepatomegaly. Laboratory tests may indicate an increase in erythrocytes with thrombocytopenia. Patients with severe dengue experience plasma leakage, bleeding, and organ failure [2, 3, 8]. Notably, fever is the core symptom of both classifications. Patients who do not present with fever or who develop fever later are difficult to classify according to these guidelines. Furthermore, dengue may present with symptoms similar to other acute febrile illnesses, especially those caused by other arboviruses such as the Zika and Chikungunya viruses, which were both recently detected in Brazil (in 2015 and 2014, respectively), thus contributing to the complicated diagnosis of dengue [13].

The main objective of the present study was to evaluate the importance of fever in patients with dengue, to analyze clinical data related to fever, and to assess associations between fever and the severity indices listed in the 2009 revised WHO guidelines.