Dengue is the most important arthropod-borne viral infection affecting humans, caused by four serotypes (DENV-1 to DENV-4) of a Flaviviridae RNA virus transmitted by Aedes aegypti and Aedes albopictus.[1,2] An estimated 390 million infections occur annually worldwide, of which approximately 96 million produce clinical illness.[3] India accounts for a substantial share of this burden: a national serosurvey found evidence of past infection in roughly half of those aged 5–45 years,[4] and transmission has extended from metropolitan centres into peri-urban and rural districts across the country.[5]

Since no licensed antiviral agent exists, management is entirely supportive and rests on judicious fluid replacement guided by close monitoring.[6] The therapeutic challenge is one of timing. Deterioration characteristically occurs at defervescence, between the third and seventh day of illness, when increased microvascular permeability produces plasma leakage; patients may decompensate rapidly at the very moment their fever settles and they appear to be recovering.[1,7] Identifying who will follow this trajectory is therefore the central clinical problem, and the WHO 2009 classification incorporates two laboratory criteria — a rising haematocrit accompanied by a rapidly falling platelet count — precisely because these changes precede overt haemodynamic compromise.[1]

The haematological derangements of dengue are well characterised. Leucopenia is the earliest and most consistent abnormality, followed by progressive thrombocytopenia and, in patients developing plasma leakage, haemoconcentration reflected by a rising haematocrit.[8,9] The mechanisms underlying thrombocytopenia are multiple: direct dengue virus-induced suppression of bone marrow progenitors during the acute phase,[10] increased peripheral platelet consumption through disseminated intravascular coagulation, complement-mediated lysis, antiplatelet antibodies and accelerated apoptosis.[11] Alterations in the differential count — relative neutrophilia early, followed by lymphocytosis with atypical lymphocytes — reflect the evolving cellular immune response.[12]

Hepatic involvement in dengue has been recognised since 1967 and is now understood to be near-universal in some degree. Injury ranges from asymptomatic transaminitis to fulminant hepatic failure, and arises both from direct viral cytotoxicity to hepatocytes and Kupffer cells and from the host immune and cytokine response, with hypoxic injury contributing in patients who develop shock.[13,14] In a large Brazilian series of 1,585 patients, aminotransferase elevation was documented in the great majority, with AST typically exceeding ALT — a pattern distinguishing dengue hepatitis from viral hepatitis.[15] Studies from Vietnam and Thailand have shown that the magnitude of transaminase elevation correlates with disease severity and with bleeding manifestations.[16,17] Renal dysfunction, though less frequently emphasised, occurs in the context of hypovolaemia, rhabdomyolysis and direct viral injury, and independently predicts mortality.[18]

Despite this substantial literature, comparatively few Indian studies have simultaneously examined haematological, hepatic and renal parameters within a single adult cohort classified prospectively by the WHO 2009 scheme, and fewer still from district-level hospitals where the majority of Indian dengue admissions now occur. The present study was undertaken to quantify these parameters in adults admitted with serologically confirmed dengue and to determine which of them correlate most strongly with disease severity.

This was a longitudinal, hospital-based observational study conducted in the Department of General Medicine, McGann District Teaching Hospital, Shivamogga, Karnataka — a public teaching hospital serving a predominantly semi-urban and rural catchment in the Malnad region of southern India — over an 18-month period from January 2021 to June 2022. Study population. All consecutive patients admitted with serologically confirmed dengue during the study period and satisfying the eligibility criteria were enrolled. Because the study was time-bound rather than powered to a pre-specified effect size, no formal sample size calculation was performed; the final sample comprised 130 participants. Inclusion criteria. Men and women aged more than 18 years testing positive for dengue-specific IgM antibody by enzyme-linked immunosorbent assay (ELISA) and/or for dengue non-structural protein 1 (NS1) antigen by ELISA. Exclusion criteria. To ensure that biochemical derangements could be attributed to dengue rather than to confounding hepatic pathology, the following were excluded: any documented history of hepatic dysfunction; alcoholic hepatitis, operationally defined by an AST:ALT ratio ≥2:1; any co-infection independently capable of raising hepatic transaminases; and known hepatotoxic drug use within the preceding six months. Data collection. Written informed consent was obtained from every participant in their own language. A pre-tested, semi-structured proforma was used to record sociodemographic data, duration of fever, presenting symptoms, past history and findings on general physical and systemic examination. Patients were examined daily until discharge. Laboratory investigations. A venous blood sample was drawn at admission. Complete haemogram — haemoglobin, haematocrit, total leucocyte count, differential leucocyte count and platelet count — was performed on an automated haematology analyser, with platelet counts below the analyser threshold confirmed by peripheral smear examination. Liver function tests included AST, ALT, alkaline phosphatase, serum bilirubin and serum proteins; renal function tests included blood urea and serum creatinine; both were performed on an automated clinical chemistry analyser using standard kinetic and colorimetric methods. Coagulation studies (prothrombin time, international normalised ratio, activated partial thromboplastin time), chest radiography (postero-anterior view) and ultrasonography of the abdomen were performed in all patients, and further investigations were undertaken as clinically indicated. Classification of severity. Each patient was assigned to one of three mutually exclusive categories according to the WHO 2009 classification: dengue without warning signs, dengue with warning signs, or severe dengue (defined by severe plasma leakage, severe bleeding or severe organ involvement).[1] For analysis, platelet counts were additionally grouped as <20,000, 20,000–50,000 and 50,000–100,000/mm³, and total leucocyte counts as <4,000, 4,000–11,000 and >11,000/mm³. Statistical analysis. Data were entered in Microsoft Excel and analysed using IBM SPSS Statistics version 24.0 (IBM Corp., Armonk, NY, USA). Qualitative variables were expressed as frequencies and proportions and quantitative variables as mean ± standard deviation. Categorical associations were tested with the chi-square or Fisher’s exact test; differences in means across the three severity groups were tested with one-way analysis of variance. The relationship between each laboratory parameter and severity grade was quantified using the Pearson correlation coefficient. A p-value <0.05 was considered statistically significant and <0.001 highly significant. Ethical considerations. The protocol was approved by the Institutional Ethics Committee and the study was conducted in accordance with the Declaration of Helsinki. Participation was voluntary and data were anonymised.

Table 1. Baseline characteristics of the study population (n=130)

The cohort comprised predominantly young and middle-aged adults with a male preponderance (male:female 1.36:1). Mean age did not differ significantly across the three severity strata (41.53, 41.80 and 39.44 years respectively; p=0.724).

Table 2. Haematological parameters across severity groups (mean ± SD)

Mean total leucocyte count was low in all three groups (overall 4164.62/mm³), reflecting the leucopenia characteristic of dengue, but did not differ significantly between severity strata (p=0.396) and therefore has limited value as a severity marker once dengue is established.

The two parameters embedded in the WHO warning-sign definition behaved as expected. Mean haematocrit rose stepwise from 39.65% in patients without warning signs to 41.83% in those with warning signs and 42.49% in severe dengue (p=0.021), consistent with progressive haemoconcentration from plasma leakage. Conversely, mean platelet count fell from 40,920/mm³ to 39,250/mm³ and then sharply to 27,667/mm³ in severe dengue (p=0.006) — a difference of approximately 13,000/mm³ between the extremes of severity. Haemoglobin, in contrast, showed no significant variation (p=0.164), indicating that the haematocrit changes reflected plasma volume contraction rather than any change in red cell mass.

Neutrophil percentage rose (58.56% → 60.15% → 64.20%; p=0.029) and lymphocyte percentage also rose (34.83% → 37.05% → 40.33%; p=0.032) with increasing severity. Both differential counts were statistically significant but the absolute differences were modest and the wide standard deviations in the severe dengue group indicate considerable overlap between strata.

Table 3. Distribution of platelet counts across severity groups

Every patient in the cohort had a platelet count below 100,000/mm³, so thrombocytopenia was universal and by itself non-discriminatory. Its depth, however, differed markedly: profound thrombocytopenia (<20,000/mm³) occurred in 47% of severe dengue cases compared with 10% and 1% in the warning-sign and no-warning-sign groups. The categorical comparison did not reach significance (p=0.645), most likely because of the small number of severe cases distributed across three cells; the continuous analysis in Table 2 was significant (p=0.006), and the continuous measure should be regarded as the more reliable of the two.

Table 4. Distribution of total leucocyte counts across severity groups

Leucopenia was present in 78 of 130 patients (60.0%) overall and was somewhat more frequent with increasing severity, but the association was not statistically significant (p=0.579). Leucocytosis was rare (3 patients, 2.3%), all within the warning-sign and severe groups, and may indicate secondary bacterial infection rather than dengue itself.

Table 5. Hepatic transaminases across severity groups (mean ± SD, U/L)

The transaminases showed the steepest and most orderly gradient of any parameter measured. Mean AST in severe dengue (132.93 U/L) was 3.6 times that in patients without warning signs (36.96 U/L), and mean ALT (113.87 U/L) was 3.2 times higher (35.52 U/L); both differences were statistically significant (p=0.036 and p=0.021). AST exceeded ALT at every level of severity, giving an AST:ALT ratio of approximately 1.1–1.2 — a pattern typical of dengue hepatitis and distinct from that of chronic viral hepatitis. Patients without warning signs had mean values within or close to the reference range, indicating that clinically meaningful transaminitis was largely confined to the warning-sign and severe groups.

Table 6. Renal parameters across severity groups (mean ± SD)

Renal parameters behaved differently from the haematological and hepatic markers. Rather than rising progressively, urea and creatinine were essentially identical in the warning-sign and no-warning-sign groups (30.30 vs 29.96 mg/dL and 0.79 vs 0.77 mg/dL) and then rose abruptly in severe dengue, where mean urea was more than double and mean creatinine more than twice the values in the other groups (p=0.019 and p=0.012). This threshold pattern suggests that renal impairment is a consequence of established circulatory compromise rather than an early marker of impending deterioration.

Table 7. Correlation of laboratory parameters with severity of dengue (n=130)

Correlation analysis reproduced and refined the group comparisons. The strongest associations with severity were seen for AST (r=0.663) and ALT (r=0.635), followed closely by creatinine (r=0.630) and urea (r=0.616), all highly significant. Haematocrit showed a moderate positive correlation (r=0.434) and platelet count a weak inverse correlation (r=−0.241). Neutrophil and lymphocyte percentages, although statistically significant, correlated only weakly (r≈0.22), and age, total leucocyte count and haemoglobin showed no meaningful correlation. Taken together, the hepatic transaminases emerged as the single most informative laboratory group in this cohort.

This study of 130 adults hospitalised with serologically confirmed dengue found that hepatic transaminases correlated more strongly with disease severity than any haematological parameter, and that haematocrit and platelet count behaved in the manner anticipated by the WHO 2009 classification.

Thrombocytopenia was universal, every patient having a platelet count below 100,000/mm³, but its depth rather than its presence distinguished severity: mean counts fell to 27,667/mm³ in severe dengue against 40,920/mm³ in patients without warning signs (p=0.006), and 47% of severe cases had counts below 20,000/mm³. This accords with Azin et al., who described progressive thrombocytopenia paralleling clinical deterioration,[9] and with Chaloemwong et al., who documented progressively lower counts from day 3 to day 10 of illness.[20] Indian series by Patel and Patel[23] and Deshwal et al.[24] have likewise identified thrombocytopenia as the commonest laboratory abnormality in adult dengue, present in over 90% of admissions. The pathogenesis is multifactorial, combining dengue virus-induced marrow suppression during the acute phase[10] with peripheral consumption, complement-mediated lysis, antiplatelet antibodies and accelerated apoptosis.[11] The modest correlation coefficient we observed (r=−0.241) is nonetheless a reminder that a single admission platelet count is an unreliable severity marker; the WHO emphasises the rate of fall alongside a rising haematocrit, and serial measurement remains essential.[1]

Haematocrit rose stepwise with severity (39.65% → 41.83% → 42.49%; p=0.021; r=0.434) while haemoglobin remained unchanged (p=0.164), an internally consistent pattern indicating haemoconcentration from plasma leakage rather than any alteration in red cell mass. Total leucocyte count was uniformly low but did not discriminate between strata (p=0.396), consistent with leucopenia being a marker of dengue infection itself rather than of its severity — indeed, it is one of the features most useful in distinguishing dengue from other undifferentiated febrile illnesses.[19,20] Our finding that both neutrophil and lymphocyte percentages rose with severity should be interpreted cautiously, since these two fractions are largely reciprocal; the wide standard deviations and weak correlation coefficients suggest limited discriminatory value.

The most striking finding was the transaminase gradient. Mean AST rose from 36.96 U/L in dengue without warning signs to 132.93 U/L in severe dengue, and ALT from 35.52 to 113.87 U/L, with correlation coefficients of 0.663 and 0.635 respectively. AST consistently exceeded ALT, the pattern described by Souza et al. in 1,585 Brazilian patients and attributed to concomitant release from injured myocytes and erythrocytes in addition to hepatocytes.[15] Kuo et al. first established the relationship between transaminase elevation and dengue haemorrhagic fever,[13] and Trung et al. subsequently confirmed in Vietnamese adults that the magnitude of hepatic injury tracks with severity and bleeding risk.[16] Ayaz and Furrukh similarly reported significantly higher ALT in patients with dengue haemorrhagic fever and shock syndrome than in classical dengue.[21] Jayadas et al., in a comparable South Asian cohort of NS1-positive adults, also found transaminase elevation to be the most consistent biochemical abnormality.[22] Our absolute values are somewhat lower than several of these series, plausibly because patients with pre-existing liver disease and alcoholic hepatitis were excluded by design, and because a substantial proportion of our cohort was sampled early in the illness before peak transaminase levels — which typically occur around the second week — had been reached.[17]

Urea and creatinine were more than double in severe dengue (p=0.019 and p=0.012) but were indistinguishable between the two milder groups, a threshold rather than graded pattern consistent with renal impairment arising from hypoperfusion once circulatory compromise is established.[18]

In this cohort of 130 adults admitted with serologically confirmed dengue, thrombocytopenia was universal and leucopenia common, but neither presence of thrombocytopenia nor total leucocyte count distinguished between severity grades. Disease severity was significantly associated with the depth of thrombocytopenia, a rising haematocrit, and — most strongly of all — with elevated hepatic transaminases. AST and ALT showed the highest correlations with severity of any parameter measured, followed by serum creatinine and blood urea, while haematocrit showed a moderate positive and platelet count a weak negative correlation. These findings support a simple, inexpensive admission panel for risk stratification in district hospital settings: haematocrit, platelet count, AST, ALT, urea and creatinine. An AST or ALT above roughly three times the upper reference limit, or a platelet count below 20,000/mm³, should prompt intensified monitoring and early consideration of referral, while serial rather than single measurements should guide fluid management. Larger multicentre studies with serial sampling and serotyping are needed to establish the predictive thresholds and to define whether transaminase measurement adds value beyond the existing WHO warning-sign criteria.

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