Tuesday, October 15, 2013

NIAID-DVI: Dengue Cohort Studies in Thailand -- Tim Endy

As a intermittent blogger...or rather any type of blogger, I get an absolute thrill when I see my pageviews jump from a few dozen to a couple hundred at any given time especially since my blog goes "inactive" if I've nothing to say (ie. no conference, no workshop, no training to write about or I'm being lackadaisical about reviewing literature on a blog). On October 9th I hit 244 pageviews...and when I checked today I saw that on Oct 13th I had 488...it was indeed thrilling. The last time I experienced a thrill such as this was when I got into the thousands after I live-blogged the Workshop on Genomics Blog Series in Jan 2013.

It's always nice to know one's blog is proving useful from time to time...

Back to NIAID-DVI!

Human immune responses to dengue infection: lessons from cohort studies in Thailand
Tim Endy
State University of New York Upstate Medical University

Tim Endy like Dr. Kuhn is another one of those individuals in the field I could listen to for hours and not get bored. He's been a long time collaborator of my postdoc mentor, MAJ Jarman and WRAIR, where I work now. He also a retired COL did a stint at AFRIMS in Bangkok and is highly involved and I would contend a pillar in dengue work in Thailand.

Additionally, it's always exciting when someone you look up to in your field uses figures you generated in his presentation...huzzah!

That all being said...

 Abstract: DENV is now the most common arboviral infection of humans in the subtropical and tropical regions of the world. Thailand was one of the first countries to describe a new manifestation of severe dengue illness, dengue hemorrhagic fever (DHF), during the late 1950's and has been the epicenter of DENV evolution and transformation in the last 60 years. The evolutionary change of DENV to be able to utilize pre-existing heterotypic flavivirus antibody to enhance its own infection, antibody enhancement, is a unique feature of DENV and specifically a characteristic of Southeast Asian strains. Thai and US scientists studied dengue in Thailand that spanned over a half a century producing many of the seminal concepts of dengue virus transmission and disease severity. Early studies on DHF in Thailand established this as a unique clinical syndrome of DENV infection. Careful clinical studies of hospitalized children in Bangkok, Thailand demonstrated the clinical severity of DHF in producing thrombocytopenia, leukopenia, coagulopathy and plasma leakage. Classic studies in Thailand children first established the role of enhancing antibody in the peripheral blood mononuclear cells of children in producing severe dengue illness and DHF. Prospective studies in hospitalized Thai children and in long-term cohort studies demonstrated the importance of dengue viral load and the T-cell response in determining dengue severity, the diversity of all four dengue serotypes circulating spatially and temporally in a well-defined geographic area and the role of subclinical dengue infection and its contribution to the overall burden of dengue illness.

There is a really nice book: Frontiers in Dengue Virus Research where Tim was involved in writing the introductory chapter on Dengue Virus: Past, Present and Future. For those that have no desire to pay $100+ to read this book you can find it on google books for free, although some of the figures will be blocked out as 'copyrighted' material.
  • Reports of symptoms consistent with dengue fever date back over two millennia
  • So why do we continue to care about dengue? Because despite being such an old disease in recent decades it has expanded it's range, incidence and severity
  • Increased urbanization and population density has increased the number of breeding sites for the urban mosquito Ae. aegypti...which consequently LOVE humans. I witnessed this myself during a blood feeding with Ae. aegypti mosquitoes who went nuts when you blew carbon dioxide on them or put your hand near them. Some of the entomologist told me that to get the mosquitoes to feed off the membranes they'd rub the membrane on their skin to get the human scent on it.
  • Ae. aegypti and Ae. albopictus, both of which can transmit dengue have increased their range and overlap in the recent decades as well.
Melendrez, MC. 2013. presentation slide.
  • Additionally the increased interaction between serotypes in subsequent seasons of dengue has shown an increase in severity over time.
So we still need to care about this virus...

For another nice rundown of the historical impact and surveillance of dengue in Thailand see: Nisalak A, Endy TE et al., 2003. Serotype-specific dengue virus circulation and dengue disease in Bangkok, Thailand from 1973 to 1999. AJTMH 68:191.

In one of Tim Endy's studies, (from the abstract/study) findings are reported from the first 3 years of a prospective study of dengue virus transmission and disease severity conducted in a cohort of 2,119 elementary school children in northern Thailand.
  • The incidence of inapparent and of symptomatic dengue virus infection was 4.3% and 3.6% in 1998, 3.2% and 3.3% in 1999, and 1.4% and 0.8% in 2000. 
  • Symptomatic dengue virus infection was responsible for 3.2%, 7.1%, and 1.1% of acute-illness school absences in 1998, 1999, and 2000. 
  • The early symptom complex of acute dengue virus infection is protean and difficult to distinguish from other causes of febrile childhood illnesses

So let's break down the abstract and put some studies to it...
"The evolutionary change of DENV to be able to utilize pre-existing heterotypic flavivirus antibody to enhance its own infection, antibody enhancement, is a unique feature of DENV and specifically a characteristic of Southeast Asian strains."
"Careful clinical studies of hospitalized children in Bangkok, Thailand demonstrated the clinical severity of DHF in producing thrombocytopenia, leukopenia, coagulopathy and plasma leakage."
"Prospective studies in hospitalized Thai children and in long-term cohort studies demonstrated the importance of dengue viral load and the T-cell response in determining dengue severity..."
"...the diversity of all four dengue serotypes circulating spatially and temporally in a well-defined geographic area..."
Note: there are many more studies and examples and sites...I am focusing on a few representative examples...

Clustering into genotypes/lineages loosely associated with geographic region

Cite:
Clustering by 'school'/geography 

Cites:
Clustering by houses

Cites:
"...the role of subclinical dengue infection and its contribution to the overall burden of dengue illness."
There have been a lot of lessons learned from long-term prospective cohort studies and other studies on the epidemiology of DENV in Thailand and it's pathogenesis in humans. All add to the base of knowledge that will contribute to development of an effective vaccine...