41Objectives: To identify suitable biomarkers during early stages of dengue to predict which 42 patients would develop severe forms of dengue before the warning signs appear. 43Methods: Expression of inducible nitric oxide synthase (iNOS) and resultant changes in nitric 44 oxide (NO) and oxidized low density lipoprotein (oxLDL) levels in plasma and saliva were 45 analyzed. 46Results: Expression of iNOS in patients who later developed dengue hoemorrhagic fever (DHF) 47 showed significant (P<0.05) down regulation compared to dengue fever (DF) patients while 48 those who later developed DHF showed a corresponding significant (P<0.05) decrease of plasma 49 NO levels (18.1±3.1 µM) compared to DF patients (23.6±4.4 µM) within 4 days from fever 50 onset. OxLDL levels in plasma showed a decrease in patients who later developed DHF 51 compared to DF patients although this value was significantly different only within 3 days from 52 fever onset. The salivary NO levels did not show a significant difference. However, salivary 53 oxLDL levels were significantly (P<0.05) low in patients who later developed DHF (0.6±0.2 54 ng/mL) compared to DF patients (1±0.4 ng/mL) collected within 4 days from fever onset. 55Conclusions: The expression level of iNOS, plasma NO and salivary oxLDL levels may serve as 56 early markers of severity of dengue infection. 57 58 Keywords: Dengue, Dengue Hemorrhagic Fever, inducible nitric oxide synthase, nitric oxide, 59 oxidized LDL, salivary biomarkers 60 61 Highlights 62 Severity of dengue infection correlates with early differential expression of iNOS 63 Plasma NO and salivary oxLDL levels may also serve as early markers of severe dengue 64 Saliva may serve as a non-invasive source of early biological markers for severity of 65 dengue infection 66 67 68 Dengue is an extremely prevalent mosquito-borne viral disease in many tropical countries 69 including Sri Lanka. It is the second most important tropical disease (after malaria) with 284 -70 528 million dengue infections resulting in 67 -136 million clinically manifested dengue cases 71 with half the global population at-risk posing a significant public health threat worldwide. 1,2 In 72 2017, 1,86,101 suspected dengue cases were reported to the Epidemiology Unit of Sri Lanka 73 from all over the island. 3 Most people infected with dengue viruses are asymptomatic while 74 others may suffer a wide range of clinical manifestations from mild fever to severe dengue. 75 Although a serious, debilitating condition, dengue fever (DF) is not fatal while severe 76 manifestations of the disease such as dengue hoemorrhagic fever (DHF) and dengue shock 77 syndrome (DSS) are major causes of hospitalization and death, globally. 1,4 Currently, the number 78 of DHF cases in Sri Lanka has dramatically increased. 5 Unlike DF, severe dengue is 79 characterized by severe possibly lethal vasculopathy marked with plasma leakage, intrinsic 80 coagulopathy and massive internal bleeding. 6,7 81 Despite the social and clinical impact, there are no antiviral thera...
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