European Journal of Cardiovascular Medicine

Dengue is a viral illness caused by viruses of the family Flaviviridae. It is transmitted by the bite of an infected Aedes mosquito. Four serotypes of the virus have been described: DNV-1 to DNV-4.[1] Outbreaks usually occur around the rainy season when conditions are conducive for vector buildup and survival.[2] Dengue epidemics have been known to occur regularly for at least three centuries. Cartographic estimates reveal 390 million dengue infections per year, of which 96 million manifest clinically.[3] In India, dengue fever was first reported in 1956 in Vellore. The annual estimated incidence is around 7.5 to 32.5 million.[4]

The clinical syndrome varies from asymptomatic or acute febrile illness (dengue fever) to dengue hemorrhagic fever and dengue shock syndrome. The clinical features of dengue fever include high fever, facial flushing, headache, rash, retro-orbital pain, nausea, and abdominal pain. Hemorrhagic manifestations may be rarely seen.[2] Dengue hemorrhagic fever and dengue shock syndrome are characterized by high fever, hemorrhagic manifestations, hepatomegaly, and circulatory disturbances. There is increased vascular permeability leading to plasma leakage, often manifested by a rising hematocrit.

Dengue, having a wide spectrum of presentation, has to be differentiated from other febrile illnesses with non-localizing signs.[5] Diagnosis is confirmed by detection of dengue NS1 antigen or dengue IgM antibody using the ELISA method.[6] However, these facilities may not be accessible in remote areas. Diagnosis using simple hematological and biochemical tests may aid physicians in early diagnosis and initiation of treatment.

The common hematological abnormalities include thrombocytopenia, leucopenia, atypical lymphocytes, and a rise in hematocrit.[7] The common biochemical finding is a rise in transaminases.[8] Electrolyte derangement secondary to dehydration may also be present.

In this study, we attempted to evaluate parameters such as WBC count, differential count, platelet count, serum transaminases, and serum electrolytes. Observation of trends in certain hematological parameters may provide a diagnostic clue and help differentiate dengue from other febrile illnesses with non-localizing symptoms.

This was a 2 months retrospective study was conducted in the months of September and October 2022. 50 cases of febrile illness which was confirmed as Dengue by serology (ELISA NS1 or IgM) were enrolled as cases.  They included 33(66%) males and 17(34%) females. Cases having thrombocytopenia or leucopenia due to other causes were excluded from the study. 42 patients having fever with non localising signs were enrolled as controls. Hematological parameters of Dengue patients like platelet count, WBC count, lymphocyte and neutrophil differential were serially measured in Dengue patients from day 3 to day 7 of illness and there trends were plotted on a graph. Rise in hematocrit was calculated as [(Highest HCT– Recovery HCT) / Recovery HCT] X 100. A rise of 20% or more is considered significant hemoconcentration.  Leucopenia was defined as wbc count less than 4000 per mm³. Thrombocytopenia was defined as platelet count less than 1,50,000 per mm³ . Platelet count and WBC count on admission was compared between cases and controls using the student T test. Biochemical parameters including serum transaminases, electrolytes , blood urea and serum creatinine were measured on day of admission and compared between cases and controls using student T test.

Among the 50  Dengue patients,  there were 33(66%)males and 17(34%) females. The age ranged from 12 years to 70 years. There were 42 controls including 26 males(62%) and 16(38%) females. Table 1 demonstrates the demographic characteristics of cases and controls. Mean age of cases was 27.5 years. Among the Dengue patients  26(52%) were positive for NS1, 19(38%) were positive for IgM and 5(10%) were positive for both NS1 and IgM. The hematological findings in Dengue patients included rise in hematocrit, thrombocytopenia, leucopenia and relative lymphocytosis. (Table 2 )

We have observed a significant rise in hematocrit  of more than 20% in 2 cases (4 %). In 96%(48 cases) of the cases the rise in hematocrit was not significant. Thrombocytopenia was seen in 96% of dengue patients., leucopenia was seen in 88% cases. Mean platelet count progressively fell from the day 3(1,09,300/mm³) onwards to reach a nadir on day 6 (66,100/mm³). The count gradually increased from day 7  (1,21,940 /mm³) onwards. Figure 1 demonstrates the trend in platelet count. The Wbc count fell from day 3(4,068/ mm³) with a nadir on day 4(3,810/ mm³) and count gradually recovered from day 5 (4,386/ mm³) onwards.(Figure 2)

Neutrophil count progressively declined and the lymphocyte count gradually increased with the disease progression. (Figure 3) There was also an increased percentage of atypical lymphocytes in dengue patients(82%) . The platelet count and wbc count on admission was significantly lower in cases when compared with controls ( p value <0.0001).

Biochemical findings included a significant rise in serum Transaminases (p value <0.001) in cases compared to controls.  There was a significant lower mean value of serum sodium levels(134.5 mmol/L in cases compared to controls(139.6 mmol/L) Mean potassium levels were also comparatively lower in cases(3.8 mmol/L) compared to controls (4.27 mmol/L). Mean urea levels were significantly higher in cases(32.35 mmol/L ) when compared to controls (25 mmol/l) (p value<0.05). Table 3 compares the various biochemical abnormalities in cases and controls.

Dengue has a wide spectrum of presentation ranging from asymptomatic or a febrile illness with non localising signs to a severe form like Dengue hemorrhagic fever and Dengue shock syndrome. When it presents as a febrile illness it is difficult to differentiate it from other febrile illnesses which present with non localising signs. In such cases, in the absence of Dengue NS1 and IgM testing, certain hematological and biochemical parameters can prove to be a useful diagnostic aid.

In our study, we have observed a predominance of Male patients similar to Joshi et al.[10] The mean age was 27.4 years comparable with Chaloemwong et al (27 years).[6]

Among the hematological parameters, we observed hematocrit, total wbc count, platelet count, and  Percentage of neutrophils and lymphocytes. We have observed a higher hematocrit in our cases but it was significant hemoconcentration (more than 20%) in only 4% cases. A rise in hematocrit more than 20% can be considered as definite evidence of  increased vascular permeability and plasma leakage.[4] Endothelial dysfunction leading to increased vascular permeability may be caused by cytokines such as tumour necrosis factor‐α,  Dengue NS 1 antigen, lipid mediators like Platelet activating factor and leukotrienes.[11] A rise in  hematocrit  less than 20% could be secondary to dehydration as a result of vomiting which is common in Dengue.

We have observed thrombocytopenia in 96% of the cases Comparable with Babuji et al (97%).[12]  platelet count started to decline  from day 3 onwards and recovery was observed from day 6 onwards. A similar trend was observed by Chaloemwong et al. [6]. Thrombocytopenia has been hypothesised due to viral infection of Hematopoietic progenitor cells leading to bone marrow hypoplasia, increased apoptosis, anti platelet antibodies and complement mediated lysis.[13]

We have observed leucopenia in 88% of the cases. Rao et al have reported leucopenia in 76% of the cases. Others like Tahlan et al  have reported lower rates of leucopenia(34.78%)[14]. Some studies have also reported leucocytosis at the beginning of illness.[15]The higher percentage of leucopenia in our study can be explained by the fact that we have observed the cases over a certain period.  The cases which had normal wbc count initially have shown leucopenia subsequently.  The wbc count fell from day 3 onwards and recovered from day 5 onwards similar to Chaloemwong et al.  Gupta et al have observed that though leucopenia can be a useful guide for diagnosis of dengue , leucopenia and thrombocytopenia together have high specificity.[16]Leucopenia is caused by virus induced suppression of hematopoietic stem cells.[17]. The percentage of lymphocytes gradually increased associated with a gradual fall in the percentage of neutrophils. There was an inverse correlation between them. A similar finding was observed by Chaloemwong et al.[6]

In our study of biochemical parameters  we have observed a significant elevation of transaminases similar to Azin et al.[15] We have observed that our cases had significantly lower mean sodium(134.5mmol/L) and potassium(3.8 mmol/L) levels when compared to controls (139.6 mmol/L and 4.27 mmol/L). Khandelwal et al have observed mild hyponatremia and mild hypokalemia to be the most common electrolyte abnormalities whereas hyperkalemia was the least common abnormality.[18] We have observed a statistically significant difference in mean urea levels between cases (32.35mg/dl) and controls (25mg/dl) ( p value<0.05). Ali et al also have made a similar observation [19].

Dengue with it’s varied spectrum can mimic many other febrile illnesses. Our study aimed to elucidate certain common biological parameters in the evolution of this disease from day 3 to day 7 which can serve as diagnostic pointers even in the absence of confirmatory tests like ELISA.

Table 1: Gender and age of control subjects and Dengue patients

*Minimum and Maximum years of age

Table 2: Hematological abnormalities in Dengue

Figure 1: Platelet count changes in dengue patients from day 3 to day 7

Figure 2: WBC count changes in dengue patients from day 3 to day 7

Figure 3: Neutrophil % and lymphocyte % changes in dengue cases from day 3 to day 7

Table 3: The concentration of Blood Urea, Serum creatinine, Na, K, Cl, AST and ALT in Control and Dengue patients

Statistical analysis done by student T-test

Values are Mean ± SD;

*= p< 0.05 and **= p<0.001 compared to corresponding control group

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