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Dengue fever

Pathogen: RNA viruses →flaviviruses →dengue virus
Transmission: Aedes aegypti mosquito
Geographical range: Warm regions in the Americas, Africa and Eurasia
Incidence: 40 million infections per year

Case history

A 23-year old man from Indonesia with a fever (38°C) visited physician five days after the initial onset of his fever. The man reported to the clinician these symptoms: headache, malaise, vomiting, abdominal pain and small joints pain. Considering the man’s symptoms, a complete blood count with WBC differential analysis was performed to investigate a possible Dengue fever infection.

Dengue fever pathophysiology and clinical course

Dengue fever is an infectious tropical disease caused by the dengue virus (RNA virus, Flaviridae family). The virus is transmitted to humans by the bite of Aedes mosquito. The virus has 5 different serotypes and infection with a given serotype often provides lifelong immunity to that serotype, but only short time immunity for other serotypes. Subsequent infection with a different serotype increases the risk of severe complications.

When a person is infected, the virus enters and reproduces in white blood cells. The infected white blood cells respond by producing a number of signaling proteins, that raises a number of defenses against viral infection through the innate immune system. Cytokines and interferons produced during innate immune responses are the activators of the adaptive immune responses, which leads to the generation of antibodies against the virus as well as T cells that directly attack cells infected with the virus.

The course of Dengue infection is divided into 3 phases: febrile, critical, and recovery. The febrile phase involves high fever and is associated with a muscle and joint pains and a headache. The phase usually lasts 2–7 days (1). In case of secondary infection with a different serotype, the disease proceeds to a critical phase. The critical phase is characterized by a significant leakage of plasma typically lasting 1–2 days. Plasma from the bloodstream leaks into body cavities due to capillary permeability. Less blood volume circulates in the blood vessels and thus the blood pressure becomes low. The leakage can result in pulmonary edema and ascites, as well as hypovolemia and shock (2). The dysfunction of the bone marrow due to infection and immune mediated increased peripheral platelet destruction lead to reduced numbers of platelets. This may lead to severe bleeding, typically from the gastrointestinal tract.

It is not completely understood why secondary infection with a different Dengue serotype increase a risk of dengue hemorrhagic fever and dengue shock syndrome for the patient. The most widely accepted is the antibody-dependent enhancement (ADE) hypothesis. A memory B cells (specific for one serotype) are activated by a new serotype to produce antibodies that ineffectively bind to the new serotype. The presence of these antibodies inhibits activation of a naïve B cells that produces more effective antibodies against the new serotype. This leads to an attenuated immune response against the new serotype and highly increase the risk of a serious infection course.

 

Laboratory results

              
4th of September6th of September
Blood countELISA IgM anti-Dengue (+)
Blood culture (-)ELISA IgG anti-Dengue (+)
 

Case interpretation

Although leukopenia is in the febrile or critical phase often present in patients with Dengue fever, the presented patient had a normal WBC count. However, there was an abnormally large cluster of cells with high fluorescence in the area of the WDF scattergram where atypical lymphocytes are located when present. This triggered the flag ’Atypical Lympho?’.  High values of parameters AS-LYMPH (14.5%) and total RE-LYMPH (18.4%) are indicative of suspected reactive lymphocytes and the values can be interpreted as the humoral immune response dominates over the cell-mediated immune response. In case of the Dengue infection this pattern can also be indicative of critical phase infection due to the high count of plasma cells (secondary infection with different serotype). The WPC scattergram show in the FSC-SSC view two different lymphocytes populations (W1/W2) with a ratio of 0.45. This confirms the humoral lymphocytosis response. The SFL-SSC view from WPC channel does not revealed cells in the high-fluorescence area above the lymphocytes and therefore the presence of abnormal neoplastic lymphocytes could be excluded.

The monocyte population showed an increased fluorescence intensity in the WDF scattergram without cells in the WPC blast gating area which confirms the inflammatory state. The extremely high percentage of reactive lymphocytes and activated monocytes and not an increased neutrophil/ lymphocyte ratio, exclude a non-infectious inflammatory response or bacterial infection and make a viral infection more likely.

The patient showed further a significant increase in the values of red blood cell parameters (RBC, HGB and HCT) which pointed to the plasma vessel leakages. The PLT count originating from the PLT-F channel was very low (14 x 109/L) and a very high immature platelet fraction (IPF, 12.4%) suggested the destruction/ activation of platelets in the peripheral blood.

The increased HCT, severe thrombocytopenia and the presence of many plasma cells suggests that the sample was obtained during the critical phase of the infection (at day 5 after the onset of fever). The observed results such as not increased neutrophil/ lymphocyte ratio, activation of monocytes and high IPF are also all characteristic for a patient in the critical phase of Dengue hemorrhagic fever infection. The Dengue fever was confirmed 2 days later by the positive anti-Dengue IgG and IgM ELISA tests.

In the following recovery phase, the leaked fluid is resorbed back into the bloodstream, leading to the normalization of the HCT value. At this stage of the disease, the number of PLT also tends to increase from a severe to a mild thrombocytopenia or normal PLT counts. At day 28 after the onset of fever, the patient was in the recovery phase and the blood count of the patient was normalized (data not shown).

Literature

1.       World Health Organization (2015): Dengue and severe dengue.

http://www.who.int/mediacentre/factsheets/fs117/en/

2.       World Health Organization (2009): Dengue Guidelines for Diagnosis, Treatment, Prevention and Control

http://apps.who.int/iris/bitstream/10665/44188/1/9789241547871_eng.pdf

Advanced clinical parameters

Reference ranges

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