The Growing Menace of Dengue - Is Detection and Diagnosis Enough?

The July, 1968 issue of Indian Pediatrics included five original research papers related to a variety of topics; dengue and West Nile viruses, infantile tremor syndrome, sickle cell hemoglobinopathy, dermato-glyphics in congenital heart disease, and chromosomal abnormalities in measles. Given that the Dengue season is looming ahead ominously, it is not difficult to guess which study was selected this month. The somewhat lengthily entitled article ‘Arthropod-borne Viral Infections in Children in Vellore, South India, With Particular Reference to Dengue and West Nile Viruses’ [1] deals primarily with the establishment of diagnosis and clinical profile. Thus, we shall trace the evolution of both of these over the past five decades up to present day practice.

The study: The authors were affiliated with the Rockefeller Foundation, Christian Medical College, Vellore and the Virus research centre in erstwhile Poona. The primary objective was to perform arboviral profiling in children under 14 years of age with febrile illnesses, followed by clinical profiling of the cases that were confirmed. The study population included 396 eligible children recruited from both urban and rural centres. Acute phase sera were inoculated in infant white mice for virological isolation, which was processed in research laboratories at Poona and the US. Subsequently 268 paired acute and convalescent sera (collected between 14 days to a few weeks) underwent serologic testing by complement fixation using different arboviral antigens, hemagglutination inhibition assay (HIA) and neutralization techniques. Dengue viruses were isolated in three children, whereas serologic evidence was found in 17 children. This clinical data was compiled with existing data from previous cases of Dengue from Vellore (1956 -1966) that had been confirmed by either virus isolation (5) or serology (9). Thus, the clinical description pertained to a total of 34 children.

In recent times, the magnitude of Dengue has escalated to frightening proportions. This can be exemplified by comparing a state of 34 cases over 11 years in Vellore with 9,169 cases reported in a single season (2017) in Delhi [4]. Not surprisingly, the understanding of Dengue fever has evolved considerably since Carey’s paper. It is now known that the severe presentation usually occurs after secondary infection with heterologous serotypes, due to a cytokine storm [5]. Severe thrombocytopenia and capillary leakage are the hallmarks of the most life-threatening complications and death [5]. The recognition of global epidemics prompted the development of the first World Health Organization (WHO) guidelines for management in 1975 [6]. Since then it has undergone multiple revisions, with the most recent update being released in 2012 [7]. In India, the National Vector Borne Disease Control Programme (NVBDCP) published the National Guidelines for Management of Dengue Fever in 2014, which were adapted from the 2009 and 2011 WHO guidelines on dengue [8].

The 2012 WHO guideline classified the disease as Dengue with or without warning signs (Group A and Group B respectively) and severe Dengue (Group C) [7]. The latter includes all severe cases including hemorrhage, capillary leak, hepatic failure, and encephalopathy [9]. It also serves as a case management guide with an easy-to-follow decision-making algorithm for management.

Cases of dengue fever without warning signs are advised domiciliary care with increased oral intake, antipyretics, and recognition of danger signs. Children with warning signs warrant hospitalization for monitoring of hemodynamic status coupled with judicious fluid therapy (oral or intravenous). Cases of severe dengue require emergency management with crystalloids and if need be, colloids, depending upon the type of shock, the presence of a capillary leak and/or end organ failure [7]. There is growing scientific evidence that fluid overload loads to more deaths than shock and hemorrhage [6,7].

The main implications of a laboratory diagnosis are confirmation of the clinical diagnosis (especially when there are many dengue-like illnesses) and generating epidemiological data, rather than case management. Newer virological and serologic diagnostic tools for dengue are now available that depend upon the phase of illness. Detection of the virus or its components is possible during the first five days of fever and can be done by isolation in mosquito cell-culture, detection of nucleic acid (RT-PCR and real-time RT-PCR) and detection of antigen (NS1 rapid tests, NS1 Ag ELISA, Immuno-histochemistry). Serological tests are performed after the fifth day of fever by either paired sera (ELISA, HIA, Neutralization tests) or single serum samples that can detect IgM (ELISA rapid tests) or IgG (ELISA, HIA) [7]. The antigen detection methods and IgM and IgG ELISA have the shortest turnaround time making results available within a day. NVBDCP recommends ELISA-based antigen detection tests (NS1) for diagnosis the first day onwards and antibody detection test IgM capture ELISA (MAC-ELISA) after the fifth day of onset of clinical illness [8]. Haematocrit has emerged as an important monitoring tool while following the WHO decision-making algorithm for fluid management [9].

We have come a long way in the last 50 years. Unfortunately, the same cannot be said for the public health measures that should be undertaken to prevent this vector-borne disease. The increase in cases over the years cannot be ascribed to better clinical recognition and diagnostics. Let us hope that the new vaccine, that is currently licensed in twenty countries and indicated for individuals between 9-45 years who are dengue-seropositive [10], proves to be a better preventive strategy than curbing the breeding of mosquitoes.

1. Carey DE, Rodrigues FM, Myers RM, Webb JK. Arthropod-borne viral infections in children in Vellore, South India, with particular reference to dengue and West Nile viruses. Indian Pediatr. 1968;5:285-96.

2. Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev. 1998;11:480-96.

3. Halstead SB. Dengue haemorrhagic fever—a public health problem and a field for research. Bull World Health Organ. 1980;58:1-21.

4. Dengue/DHF situation in India. Available from: http://nvbdcp.gov.in/den-cd.html. Accessed May 10, 2018.

5. Yacoub S, Mongkolsapaya J, Screaton G. The pathogenesis of dengue. Curr Opin Infect Dis. 2013;26:284-9.

6. World Health Organization. Technical Guides for Diagnosis, Treatment, Surveillance, Prevention and Control of Dengue Haemorrhagic Fever. Geneva: WHO (Southeast Asian and Western Pacific Regional Offices), 1975.

7. World Health Organization (WHO). Handbook for clinical management of dengue. Geneva: WHO, 2012. Available from: http://www.wpro.who.int/mvp/documents/handbook _for_clinical_management_of_dengue.pdf. Accessed May 10, 2018.

8. National Guidelines for Clinical management of Dengue Fever. Directorate of National Vector Borne Diseases Control Programme, Dte General of Health Services, Ministry of Health & Family Welfare, Government of India; 2015. Available from: http://www.nvbdcp.gov.in/Doc/Dengue-National-Guidelines-2014.pdf. Accessed May 10, 2018.

9. Srikiatkhachorn A, Rothman AL, Gibbons RV, Sittisombut N, Malasit P, Ennis FA, et al. Dengue-how best to classify it. Clin Infect Dis. 2011;53:563-7.