ICMR STS PROJECT FORMAT1. Reference ID- 2018-014282. Title- THE SERUM IgE LEVEL IN CHILDREN WITH DENGUE INFECTION AND ITS CORRELATION WITH THE SEVERITY OF ILLNESS3. Introduction- • Dengue fever (DF) is currently a huge epidemiological and clinicopathological challenge, not only in our country but also all over the world1.• It is caused by an RNA arbovirus belonging to the Flaviviridae family which is transmitted by the female Aedes aegypti mosquito and leads usually to a passing flu-like illness but sometimes (in 10-15% of cases) progresses to severe disease with its potentially lethal complications of the dengue haemorrhagic (DHF) and shock syndromes (DSS)2,3.• Over the last 6-7 years of managing children with DF in this institution, we have noted that adolescents develop more serious symptoms, more severe disease and complications more often than younger children significantly endangering their lives. Consequently, these children are noted to require more intense monitoring and therapy leading to extended hospital stay and unacceptable morbidity and mortality. The commonest explanation for this phenomenon is said to be a robust immune reaction to dengue viremia in adolescents and its role in enhancing the vascular leak characteristic of the disease4,5.

• However, this aspect of the pathogenesis has neither been studied adequately. The Serum IgE level is one of the more easily available marker for quantifying immune response to any antigen entering the body and challenging the immune system6,7,8,9.• We have undertaken this study to assess whether the adolescents serologically diagnosed with DF have higher levels of IgE during the course of their illness as compared to younger children and correlate the same with the severity of illness as determined by the degree of thrombocytopenia, requirement of component transfusion, need for inotropic support, duration of hospital stay and mortality (if any).• If this does indeed correlate, the exciting prospect of using anti-inflammatory agents (steroids, anti-histamines, intravenous immunoglobulin therapy, etc.) as adjuvants to standard therapy in this subgroup of children may be explored which may then result in saving precious lives10,11.4. Objectives- • To assess the serum levels of IgE in two groups of children (pre – adolescent and adolescent) serologically diagnosed with dengue and to correlate the same with the haematological recovery, progression to severe disease duration of hospital stay and mortality (if any) in these children.

 Hypothesis- Based on a study done by Koraka P et al.6 who concluded that serum IgE levels can be used as a prognostic marker for the progression to severe dengue, we postulated that adolescent children may mount an exaggerated immune response to the dengue virus as compared to pre-adolescent subjects due to their possessing a well-developed and robust immune system. This in turn may lead to severe disease and complications as it is universally known that most of the complications of severe DF occur because of a immunological storm ‘the cytokine tsunami’12 that causes a significant and severe vascular leak resulting in the loss of platelets and coagulant factors into the third space. In addition, due to the loss of plasma, the blood pressure falls and the child goes into shock. Thus, we intend to correlate the serum IgE levels (a reliable marker of immune response) with the severity of the disease in adolescents.5. Methodology- • Study design: Prospective observational study• Study period: 2 months• Inclusion criteria: • Dengue NS1 or IgM positive patients presenting within the first 3 days of fever.• Age: 5 – 15 years.

• Exclusion criteria: • Children below 5 years of age. • Children with history of known allergies / asthma / atopy / urticaria / angioneuritic edema• Children with confirmed helminthic infestations.• Children with an increased Absolute Eosinophil count.• Children with prior haematological conditions associated with thrombocytopenia /thrombasthenia.• Children with haematological malignancies.• Sample size: • Sample size: 92• Rationale: The Hammond et al study has observed that children formed 35% of the population that was severely affected by Dengue. In the present study expecting similar results in the 5-10 year age group and a 22% difference in the 11-15 year age group with 80% power and 95% confidence level, the study requires a minimum of 46 subjects in each age group3.

• Detailed description of procedure: • A written informed consent will be obtained from the parents of the participants who are admitted to the Tertiary care Teaching Hospital fulfilling the inclusion criteria. These participants will be divided into two groups – Group 1 (age: 5-10 years) and Group 2 (age: 11-15 years). The first serum sample for IgE titre will be collected on the 1st day of fever (or upon admission) and the second serum sample will be collected 24 to 36 hours after defervescence (or 72-96 hours after the collection of the first sample). Both these samples will be collected along with routine blood samples collected daily to monitor the progress of the patient. The samples for IgE titre will be stored at -800C for collective analysis on a later date.• Platelet counts will be followed up serially.

The day of reversal of the downward trend will be noted and thereafter normalization of platelet count would be recorded to have occurred when the platelet count exceeds 1,00,000 cells / mm3. • Subjects will be clinically followed up to assess progression to severe disease, use of component therapy, inotropic requirement along with duration of hospital stay and mortality (if any)• Potential risks and benefits: a. The blood samples for serum IgE will be collected as a part of the routine investigations for dengue as required for monitoring and management. Hence there is no additional risk to the patient.b. By conducting this study, we intend to provide justification for further studies on the use of anti-inflammatory agents as adjuvants to standard therapy in a particular sub group of children with DF (adolescents) with an aim to reduce the morbidity and mortality often associated with severe disease.• Biological materials needed with quantity: 5ml of blood will be collected with due aseptic precautions in plain vacutainer tubes and the serum separated and stored at a temperature of -800C till further collective analysis for IgE levels by the ELISA method in the central research laboratory.

(Reference range: 0-160 IU/ml)• Investigations: as mentioned earlier • Outcome measures: a. Haematological recovery – i. The day of reversal of platelet trend and the day of normalization of platelet count.           b.     Progression to complications / severe disease – ii.

Development of DHF and DSS.           c.     Interventions  iii. Component therapy iv.

Inotropic requirement   d.       Duration of hospital stay. e.        Mortality (if any)• Statistical methods: (i) Independent t test would be used to compare IgE levels between the 2   groups.(ii) Descriptive statistics of IgE will be analysed and summarized in terms of mean with standard deviation.(iii) Chi-square test would be used to compare the progression of subjects of each group to severe disease and the odds ratio would be estimated.

• Ethical considerations: A written consent from the parents of the participants would be obtained before enrolment. The parents will also be informed about the procedure before collection of the blood sample.6. Implications- To determine the possible role of anti-inflammatory agents as an addition to the standard of care in the management of dengue illness in adolescent children with a view to reduce the morbidity and mortality from the disease.

7. References-1. Nivedita Gupta, Sakshi Srivastava, Amita Jain, and Umesh C.

Chaturvedi. Dengue in India. Indian J Med Res 2012 Sep; 136(3): 373–390. 2.

Anne Tuiskunen Bäck, PhD and Åke Lundkvist. Dengue viruses: an overview. Infect Ecol Epidemiol. 2013; 3: 10.

3402/iee.v3i0.19839. 3. Samantha Nadia Hammond, Angel Balamaseda, Leonel Perez, Yolanda Tellez, Saira Indira Saborio and Juan Carlos Mercado. Differences in dengue severity in infants, children, and adults in a 3-year hospital-based study in Nicaragua. Am J Trop Med Hyg.

2005 Dec;73(6):1063-70.4. Wahala M. P. B. Wahala and Aravinda M. de Silva.

The Human Antibody       Response to Dengue Virus Infection Viruses. 2011 Dec; 3(12): 2374–2395.5.  J. Boesiger, M.

Tsai, M. Maurer, M. Yamaguchi, L. F.

Brown, K. P. Claffey, H. F.

Dvorak, S. J.Galli. Mast cells can secrete vascular permeability factor/ vascular endothelial cell growthfactor and exhibit enhanced release after immunoglobulin E-dependent upregulation of fc epsilon receptor I expression, J Exp.Med (1998) 1135-1145.6. Koraka P, Murgue B, Deparis X, Setiati TE, Suharti C, van Gorp EC, Hack CE, Osterhaus AD and Groen J. Elevated levels of total and dengue virus-specific immunoglobulin E in patients with varying disease severity.

J Med Virol. 2003 May;70(1): 91-8. 7. María José Míguez-Burbano, Carlos A.

Jaramillo, Carol J. Palmer, Gail Shor-Posner, Luz Stella Velásquez, Hong Lai, and Marianna K. Baum. Total Immunoglobulin E Levels and Dengue. 1999 Jul; 6(4): 624–626.8. L. Borish, J.

J. Mascali, L. J. Rosenwasser. IgE-dependent cytokine production by human peripheral blood mononuclear phagocytes. J Immunol.

(1991) 63-67.9. H. Gascan, J. F. Gauchat, G. Aversa, P.

Van Vlasselaer, J. E. de Vries. Anti-CD40 monoclonal antibodies or CD4+ T cell clones and IL-4 induce IgG4 and IgE switching in purified human B cells via different signaling pathways. J Immunol. (1991) 8-13.9.

 10. Arnau Navinés-Ferrer, Eva Serrano-Candelas, Gustavo-J Molina-Molina, and Margarita Martín. IgE-Related Chronic Diseases and Anti-IgE-Based Treatments.

J Immunol Res. 2016; 2016: 8163803. 11. J. M. Carballido, D. Schols, R.

Namikawa, S. Zurawski, G. Zurawski, M. G. Roncarolo, J.

E. deVries, IL-4 induces human B cell maturation and IgE synthesis in SCID-hu mice. Inhibition of ongoing IgE production by in vivo treatment with an IL- 4/IL-13 receptor antagonist, J Immunol. (1995) 4162-4170.

12. U. C. Chaturvedi, R. Agarwal, E. A. Elbishbishi, A.

S. Mustafa, Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol.Med Microbiol (2000) 183-188 


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