Dengue is a viral illness which is transmitted by the female mosquito of the species Aedes aegypti and less commonly Aedes albopictus that is rampant throughout the world especially in the tropics. It causes a wide spectrum of disease severity ranging from subclinical to severe flu-like symptoms in those infected [1]. The incidence of Dengue has increased considerably around the world in the last few decades. According to an estimate made by the World Health Organization [WHO], dengue incidence nearly amounts to about 390 million cases per year, of which 96 million manifests clinically [2]. Estimates of around 500,000 people with severe dengue require hospitalization each year and about 2.5% of those affected die. In India during the last few decades, there have been increased number of outbreaks and most of the states in India are currently almost endemic to dengue fever. Though the predominant serotype of the virus keeps changing each year, almost all the four serotypes are seen circulating in the environment [1].
Dengue has been classified by the WHO into 2 major categories: Non-severe dengue [with/without warning signs] and severe dengue. Non-severe dengue involves a high fever[1040F/400C] accompanied by any 2 of the following symptoms during the febrile phase –nausea, vomiting, rash, aches and pains, positive tourniquet test, leucopenia. Three to seven days after the onset of the illness, the fever drops to below 1000 F [380C] and the warning signs such as abdominal pain or tenderness, persistent vomiting, fluid accumulation, mucosal bleed, lethargy, restlessness, hepatomegaly and rising hematocrit with thrombocytopenia start to appear requiring strict medical intervention. Inevitable cases progress towards severe dengue evidenced by severe plasma leakage, fluid accumulation with respiratory distress, shock, severe bleeding and organ impairment [3].
Previous studies have shown the role of chemokines, cytokines and several other types of biomarkers that could be involved in the symptom severity of dengue fever [4–5]. Over the years the World Health Organization has attempted to find potential markers which could indicate the progression of dengue to its severe form. In view of this, few studies and reviews have been proposed to indicate potential markers of severity. Noteworthy among them is a meta-analysis conducted by Kuan-Meng Soo et al which proposed the role of IL-7, IL-8, IL-10, TGF-β and VEGFR2 as early indicators of severe dengue infection [6]. Although there have been studies reporting raised levels of cytokines, TNF-α, IL-2, IL-6, IL-10, IL-12 and IFN-ϒ involved in the pathogenesis in severe dengue cases, these markers have not proven to be beneficial in differentiating the early stages of dengue from the severe form [7–11]. Hence the diagnosis based on these markers and clinical symptoms help to distinguish severe dengue from non-severe only after the person has presented to the hospital with symptom severity. Hence there exists the need for markers to identify dengue during the early febrile phase before it progresses to the severe form so as to effectively manage the disease, reduce the rate of complications and death due to dengue. In a developing nation like India, mitigating the healthcare related costs due to outbreak of dengue is detrimental.
In addition to the biomarkers mentioned above, a study among the paediatric population showed that ferritin [an acute phase reactant] expressed by the reticuloendothelial cells as a response to inflammation and infection is allied with the severity of the disease [12]. A previous study by Ho T et al has deduced that ferritin is a discriminatory marker to differentiate dengue associated febrile illness from other causes for the same [13]. Serum ferritin in dengue fever shows marked levels in contrast to any other viral or bacterial illness and these high levels correspond to an exaggerated risk of developing complications. Some studies have shown a very strong relationship between the severity of dengue infection and rising ferritin levels [12]. During the course of dengue fever, there exists a period during which the Immunoglobulin M [IgM] antibody for dengue, the NS1 antigen and several other biochemical and blood parameters ruling out other febrile illnesses may be absent. During this phase the physicians are in a dilemma regarding the acceptable line of management. Since the progression of the dengue into its severe form can be prevented by optimal fluid correction, thereby preventing dehydration, there is a need to look for adjunct biomarkers which help us predict the progression of the disease during the early stages [14]. The present study tried to look for ferritin levels done on the third or fourth day of the febrile phase, as an early predictor of severity of the disease
Hypovolemic shock due to the leakage of plasma into serosal cavities is prominent feature of severe dengue. Clinically it is difficult to determine leakage of plasma and quite often serum hematocrit is used as an adjunct to detect significant plasma leak [15]. Gallbladder wall thickening due to significant plasma leakage is one of the commonest findings in dengue fever [16]. A few studies indicate that ultrasonography plays an important role in detecting patients who progress to a critical phase by measuring the thickness of the gallbladder wall [17–19]. Very few studies have been undertaken regarding the validity of gallbladder wall thickening determined on the third or fourth day of febrile illness as a prognostic indicator of severity.
Hence, we undertook this study to determine if the serum ferritin levels and gallbladder wall thickness detected on the third or fourth day of the febrile phase could predict the severity of illness. Early identification of such patients could improve overall case outcome and facilitate more efficacious use of hospital reserves.