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Symptoms and treatment of dengue fever caused by dengue virus

Dengue virus belongs to the family Flaviviridae. Mosquito Aedes is its vector and mostly Aedes aegypti causes about two-thirds of the global dengue. There are four serotypes of this virus which includes DENV-1, DENV-2, DENV-3 and DENV-4.

By Iram Ghaffar1, Muhammad Dilawaiz Khan2, Nargis Naheed3*, Fasiha Kamran3

The symptoms of dengue infection vary from mild flu-like illness to severe haemorrhagic manifestations and shock. The tourniquet test is used in the diagnosis of dengue and is vital parameter suggested by the WHO. The immunological test and viral RNA detection by PCR is also helpful in the diagnosis of disease. The fluid therapy is the basic management in dengue and is given to the patient on the basis of severity of illness. The antiviral drugs are preferred for definitive treatment of dengue. The more people who know about causes and prevention of this disease, the better their lives will be.

Keywords: serotype, flu-like, vector, shock

Introduction:

The family of dengue virus is Flaviviridae, and is transfer to humans by Aedes mosquitoes. The chief carrier is Aedes aegypti that causes about two-thirds of the global dengue. On the basis of neutralization assay data, there are four serotypes of this virus including DENV-1, DENV-2, DENV-3 and DENV-4. Dengue virus mostly causes disease in tropical and subtropical areas and according to estimation about 50 million people infected every year and 2.5 billion people are at risk (Guha-Sapir et al., 2005).  

Infection caused by any DENV serotype may be asymptomatic or have broad spectrum symptoms including mild flu-like illness (known as dengue fever DF) or dangerous varieties of the illness such as increased vascular fragility, coagulopathy and increased vascular permeability (dengue haemorrhagic fever DHF) and ultimately results in hypovolemic shock (dengue shock syndrome DSS) (Harris et al., 2000). In Asian countries children of age less than 15 years are at higher risk of disease development than adults (Carlos et al., 2005) (Guzman et al., 2002) (Kittigul et al., 2007) (Nguyen et al 2004).

On the other hand, in Americas the adult population is more affected, initially mild symptoms of disease appear (Halstead, S.B. 2006) (Pinheiro et al., 1997) (Pongsumpun et al., 2002) later progressing to DHF and DSS (Guzman et al., 2003) (Lancet. 1997). It is evidenced that dengue fever is a serious disease in children, adolescents and adults. The disease first attacks in the form of fever then progress to retro-orbital pain, myalgia, severe headache, arthralgia, GIT discomfort and rash. Mild haemorrhagic symptoms appear in the form of epistaxis, petechiae and gingival bleeding.

In the patients of DF with haemorrhagic symptoms, thrombocytopenia occurs at times but leukopenia is very common (Guilardi et al., 2008) (Kittigul et al., 2007). The DHF has been classified into four grades by World health organization (WHO). In grade 1 and 2, symptoms are mild without shock but grade 3 and 4 are accompanied by severe symptoms with shock. In DHF all the symptoms of DF are present along with haemorrhagic manifestations. The most dangerous DSS stage appears just after defervescence, that is classified as hypotension (<20mm Hg) rapid pulse, cold skin during early stage of shock (grade 3). If proper treatment is not given to the patient in this stage, he may go to the next stage in which his pulse and BP become undetectable (grade 4) and patient died within next 12 to 36 hours after onset of shock.

Epidemiology: Dengue virus infection is known as one of the world’s progressive and rising infectious disease. Every year approximately 50 to 100 million cases of dengue fever and about 500,000 cases of DHF are reported, as a result almost 24,000 deaths accounted annually. A pandemic of disease started in Southeast Asia after World War 2 and then circulated worlds wide.

Virulence of virus:  On the basis of virus virulence hypothesis, some strains of DENV cause life-threating disease. There are further four genotypes of DENV serotypes which are classified on the basis of nucleotide variations. The virulence of DENV is related to these genetic differences (Cologna et al., 2003) (Leitmeyer et al., 1999) (Sanchez et al., 1996) (Ubol et al., 2008). The more virulent Southeast Asian genotype DENV-2 was introduced in the first outbreak of DHF in 1981 in Americas, whereas the less virulent DENV-2 genotype was already spreading in the area (Kouri et al., 1987) (Rico-Hesse et al, R. 1990) (Rico-Hesse et al., 1997).

It has suggested that during epidemic, the development of circulating DENV caused more severe form of the disease. It was observed during DENV-2 epidemic in 1981 in Cuba that the disease severity and fatality rates were raised by the end of the epidemic proposing that the virulence of DENV-2 might has increased by passing in hosts during epidemic. In 1992 during DENV epidemic in Townsville, Australia (Streatfield et al., 1993) and during 1997 again in Cuba epidemic (Guzman et al., 2000), similar situation was noticed. Genomic analysis of DENV has proven that virus undoubtedly develops during an epidemic (Chen et al., 2008) (Rodriguez et al., 2005), nevertheless more studies and data are required to build a connection between disease severity and intra-epidemic virus development.

Epidemiological studies were conducted in Singapore and Americas proposed that specific serotypes that cause disease in a sequence and the time period between primary and secondary infection play a significant contribution in evolution of DHF. Epidemics with greater incidences of DHF have been associated to primary infection caused by DENV-1 accompanied by infection with DENV-2 or DENV-3. Studies were also showed that as long as the time interval between primary and secondary infection increases, the chances of evolving serious disease also increases.

Mode of transmission: Aedes Aegypti mosquito sucks the blood of an infected person and then transfers the virus to a healthy individual by biting him. It usually lives close to the human habitation and usually a daytime feeder. The mosquito lives in dark places such as inside the cupboards. While outside it lives in shadowed and cool places. Eggs are laid by female mosquitos in water containers. Approximately in 10 days these eggs go to adult stage. Mosquitos breed in exposed water collections. The preferred breeding spots include buckets, plant saucers, pots, drums and places where rain water collects.  The disease usually starts with symptoms of headache and fever after bite of infective mosquito when incubation period of 2 to 8 days completes.

Clinical features: Dengue fever is a serious disease which begins with flu-like symptoms affecting infants, young children and adults and rarely causes death. The severity of the symptoms depends on age of patient. The infants and young children may present with non-specific febrile illness along with rash while older children and adults either have mild febrile syndrome or definitive severe symptoms of disease which appear abruptly including high grade fever, maculopapular rash, headache, severe pain behind the eyes and also pain in joints and muscles (Naseem S et al., 2005).

High fever may persist for 5 to 6 days. Other clinical sing and symptoms include chilliness, photophobia, abdominal pain, nausea and vomiting, enlarged lymph nodes, splenomegaly and hepatomegaly. In case of DHF additional symptoms include petechiae, epistaxis and GIT bleeding. The symptoms may sustain to several weeks and patient goes to depression due to asthenia.

In DHF, body’s vascular system is impaired results in bleeding from different sites of the body. Bleeding takes place due to decreased vascular integrity, vascular instability and dysfunction of platelets (Guzman MG, Kouri G. 2002).

Essential Criteria for DHF:

  • Patient presents with fever or with recent history of acute fever.
  • Haemorrhagic symptoms.
  • Platelet count 100,000 mm3 or less.
  • Demonstration of leaky capillaries
  • Increased haematocrit (20% or greater than normal)
  • Decreased albumin level
  • Pleural effusion or other effusions.

According to grading of DHF:

Grade 1 DHF: Fever and general organic symptoms, positive tourniquet test is exclusive evidence. Presence of thrombocytopenia and increase in haematocrit level (more than 20%)

Grade 2 DHF: Signs of grade 1 plus bleeding and circulatory failure accompanied by rapid and week pulse with pulse pressure of (20mmHg or less then that), decreased blood pressure with cold clammy skin and unease of the patient. Capillary refill time is of 2 seconds or more.

Grade 3 DHF (Also called DSS): It includes signs of vascular system failure with hypotension, weak rapid pulse and cold sweaty skin.

Grade 4 DHF (DSS): Acute onset of shock (BP and pulse become undetectable), severe abdominal pain, vomiting and patient’s temperature falls suddenly and he becomes restless or drowsy and then collapse.

Diagnosis: Diagnosis is usually make on the basis of clinical symptoms such as acute febrile illness and decreased platelet count. The principal screening test for dengue is tourniquet test. The use of tourniquet test in the diagnosis of dengue is vital parameter suggested by the WHO. This test was proved very helpful in diagnosis of dengue infection in rural areas in endemic countries (Cao et al., 2002). The chief reason for that is after definite diagnosis only small changes are required to make in therapeutic management and it is also helpful in limited resources.

Application of viral study and immunological based test is possible by concentrating on the present absolute diagnosis. Nevertheless, immunological based test is more broadly used while viral study is scarcely as it involves the complex process of virus isolation. In spite of the fact that immunological based test is beneficial for disease control program and for epidemiological records but it does not markedly change the management of the diseased person. The specific examples of immunological test used for confirmed diagnosis of dengue infection are IgM, IgG ELISA assays, neutralization and heamagglutination inhibition. Still the results of the test should be analysed carefully by keeping in view the timing of serum collection (Kowitdamrong E et al., 2001).

A more instant test is required for the diagnosis of dengue infection because most of the patients visit the physician in later stages of the disease losing the chance of carrying out serological test. In order to diagnose dengue rapidly, the combination of IgM antibody detection with virus or viral RNA detection using PCR was required (Schilling S et al., 2004).

Management: The treatment of dengue infection involves the concept of eliminating the infective agent and minimizing the complications. The complications of dengue can be reduced by using supportive and symptomatic treatment and it is broadly used. The fluid therapy is the basic management in dengue and is given to the patient on the basis of severity of illness. The patient is not required to be hospitalized in simple dengue as fluid replacement therapy is enough in this case. While in case of severe dengue infection, the patient should be hospitalized and fluid replacement therapy must be given under strict observation.

Shock can be prevented by giving intravenous (I/V) fluid replacement through colloids or crystalloids (Soni A et al., 2001). In fluid replacement therapy it is recommended that 0.9% normal saline solution is given at a rate of 20ml/kg/h in the first two hours accompanying 10ml/kg/h for the next 6 hours and then by observing the condition of the patient, rate of fluid administration is adjusted (Ngo NT et al., 2001). During treatment to prevent less or more than required fluid administration, water and electrolytes should be monitored carefully. At the same time, to assess the haematocrit and platelet count the physician should also recommend basic laboratory tests.

The antiviral drugs are preferred for definitive treatment of dengue. In phytomedicine a number of sulphated polysaccharides have been taken out from the seaweeds and their high antiviral activity against dengue virus was studied and observed (Damonte EB et al., 2004).

In modern medicine, it has been revealed that 6-azauridin, ribavirin and glycyrrhizin have suppressive and cytostatic effects on the dengue virus (Crance JM et al., 2003). Nowadays, the favourable drug being studied is adenosine analogue and its best example is the chemical ‘‘NITDOO8’’ (Yin Z et al., 2009).

Conclusion: Dengue is a viral infection which is transmitted from the mosquitos in human beings. Now it has become an international public health issue. Children in Asian countries are more at risk while in Americas the adult population is affected more. The symptoms vary from mild febrile illness to the shock. In order to cope with this disease, public health campaigns should be initiated to promote the great understanding of the causes, effects and prevention of the disease.

References:

  • Cao X T, Ngo TN, Wills B et al. Paediatric Hospital Study Group. Evaluation of the World Health Organization standard tourniquet test and a modified tourniquet test in the diagnosis of dengue infection in Vietnam. Trop. Med. Int. Health 7, 125–132 (2002).
  • Carlos, C. C., K. Oishi, M. T. Cinco, C. A. Mapua, S. Inoue, D. J. Cruz, M. A. Pancho, C. Z. Tanig, R. R. Matias, K. Morita, F. F. Natividad, A. Igarashi, and T. Nagatake. 2005. Comparison of clinical features and hematologic abnormalities between dengue fever and dengue hemorrhagic fever among children in the Philippines. Am. J. Trop. Med. Hyg. 73: 435– 440.
  • Chen, H. L., S. R. Lin, H. F. Liu, C. C. King, S. C. Hsieh, and W. K. Wang. 2008. Evolution of dengue virus type 2 during two consecutive outbreaks with an increase in severity in southern Taiwan in 2001–2002. Am. J. Trop. Med. Hyg. 79: 495–505.
  • Cologna, R., and R. Rico-Hesse. 2003. American genotype structures decrease dengue virus output from human monocytes and dendritic cells. J. Virol. 77: 3929–3938.
  • Crance JM, Scaramozzino N, Jouan A, Garin D. Interferon, ribavirin, 6–azauridine and glycyrrhizin: antiviral compounds active against pathogenic flaviviruses. Antiviral Res. 58, 73–79 (2003).

Authors:

Iram Ghaffar1, Muhammad Dilawaiz Khan2, Nargis Naheed3*, Fasiha Kamran3

1Department of Eastern Medicine, Government College University Faisalabad-38000, Pakistan

2Department of Agronomy, University of Agriculture, Faisalabad-38000, Pakistan

3Department of Zoology, Wildlife & Fisheries, University of Agriculture, Faisalabad-38000, Pakistan

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