Dr. Stephen Thomas (State University of New York): capturing subjective patient experience of dengue
In a recent paper published in PLOS NTDs*, a group of researchers is capturing a more thorough and realistic overview of the true burden of dengue based on the subjective experiences of the patients infected with the dengue virus. Spanning a wide spectrum of infection, from the vast majority of asymptomatic cases to the fewer cases of severe dengue, the authors are developing a Dengue Illness Card to record patient experiences in view of developing a quantitative Dengue Illness Index to provide robust data on the true cost and burden of dengue in endemic regions, and to ultimately improve the tools available to evaluate the benefit of measures to counter dengue including drugs and vaccines. In this Infectious Thoughts interview, we speak to Dr. Stephen Thomas from the Division of Infectious Diseases at the State University of New York, whose career spans work as a medical doctor, a world-renowed researcher in infectious diseases and dengue in particular, and chief operating officer of all the US Army's medical labs, about the innovative thinking underpinning the Dengue Illness Index and its role in accelerating the understanding and control of dengue infection.
* Dengue illness index—A tool to characterize the subjective dengue illness experience
Stephen J. Thomas, Liane Agulto, Kim Hendrickx, Martin Erpicum, Kay M. Tomashek, M. Cristina Cassetti, Catherine Laughlin, Alexander Precioso, Alexander C. Schmidt, Federico Narvaez, João Bosco Siqueira, Hasitha Tissera, Robert Edelman
Published: October 4, 2018
https://doi.org/10.1371/journal.pntd.0006593
The Dengue Illness Index (DII) was recently developed to improve the assessment of vaccine and drug efficacy by including variables related to the subjective disease experience of an individual having contracted the dengue virus. What gaps in the understanding of the disease is this index trying to bridge and what applications could this have in improving disease management?
There have been several guidelines for the diagnosis and treatment of dengue - the World Health Organisation has been at the centre of these efforts but there have also been other groups. One of the main issues has been to improve the classification or characterisation of the severity of dengue cases, and to use that information to try to prognosticate patients early on in their illness course to understand who is at risk for developing severe dengue and its potential complications. This then helps to decide who can be managed as in- an out-patients. The index which we have just published in PLOS NTDs came out of a NIH-driven initiative to try and improve the description and characterisation of a wide spectrum of dengue cases, for the purposes of research rather than just for clinical use.
What does the index capture in terms of the large differences in types of dengue infection?
Severe dengue is really the tip of the iceberg when it comes to dengue cases; the largest part of dengue infections may go completely unnoticed as many people can be asymptomatic and don’t experience any clinical ailments. There is also a very large proportion of patients who will experience some illness, but this won’t be clinically relevant, and they can still function normally and engage with work and school for example; they will likely not even seek treatment. The next smaller category will be those with classic dengue fever symptoms such as fever, a rash, bone pain and feeling unwell. And finally, the tip of the iceberg, the severe dengue cases, will
represent 2-4% of all dengue infections and are usually those infected for a second time with a different strain of dengue. So the co-authors and I are trying to describe a spectrum of dengue illness to address the fact that a very large segment of dengue illness was largely remaining ignored.
However, this silent majority is just as concerning from a public health point of view than the smallest and most severe segment because most of the people with these milder dengue symptoms are being managed as outpatients in dengue-endemic regions, which are largely in the developing world. But being managed as an outpatient doesn’t mean that those patients aren’t placing a burden on the health system – they represent a significant burden in terms of disability adjusted life years or other metrics. For example, if a child is not admitted to hospital but stays home, this still means she is missing school and an adult must stay home and miss a day of earning; they might be bringing the child back and forth to healthcare providers etc.
So when you take the number of non-severe but clinically relevant dengue cases and start layering all those potential impacts, it really does add to a public health burden. If you don’t have a way to measure that, then it’s possible that the true potential public health benefits of vaccines, drugs and other counter measures aren’t being fully measured. So while lots of work was being done on severe dengue, Bob and I wanted to work on dengue infection signs in a much more meaningful way for less severe dengue and that was the motivation behind starting the work and publication that you saw.
Your index considers a much wider spectrum of dengue symptoms, including the milder cases where fever is detected, in areas where febrile illnesses are often misdiagnosed. How could the DII address the misdiagnosis of dengue as malaria or other febrile illnesses?
We are planning to link the Dengue Illness Index to a Dengue Illness Card that will be provided to patients to facilitate the record of their symptoms and experiences – although this will be used in a clinical setting, this isn’t aimed to be a clinical tool to help clinicians make decisions. Rather we are trying to capture the experience of those with dengue illness and capture subjective illness experiences to try and objectify what that experience is and what the implications are for the functional pyramid of dengue infection. For example, in context of a vaccine trial, half the group will get a vaccine and half gets a placebo – the patients are instructed to come in if they have a fever and fill in a card and if subsequently if turns out it’s not dengue then they are categorised as non-dengue febrile (for example influenza) – the Dengue Index Card and scores could help to inform of a diagnosis. This can also help to gather data for comparisons to help characterise what different illnesses look like from a patient perspective, but the card won’t be used in a clinical context to diagnose the patient to come up with an immediate treatment plan.
One other value of the card is that it will record an experience of the illness over time unlike clinicians who have to make a decision at a moment in time. Retrospectively, this can be a useful tool to determine what illnesses such as flu or dengue looked like from the patient perspective and this could refine the questioning of doctors.
Your concept of the Dengue Illness Card (DIC) revolves around significant patient involvement to build a quantifiable measure of dengue illness experience. Patient voices in many diseases can sometimes be neglected: what do you forsee will be the benefits and reactions (whether from patients, healthcare providers or even vaccine makers) of such patient involvement and ownership?
We are now looking to validating the DIC in a clinical situation, and getting the Card deployed into research situations in natural infection situations so we can get the type of patient feedback you mention. We have some studies coming up that we plan to include this card into. We also have a large pharmaceutical organisation that has a great interest in applying this card into its dengue therapeutic development program – they are interested in making a significant investment in the concept of this card and turning it into something that would generate very high-quality data that could be accepted by regulatory agencies. This to me is incredibly exciting and it really exceeded our expectations of what the deliverables of this exercise would be because what it means is that the FDA or EMA or other regulatory agencies would ultimately use the data package and make determinations about a counter measure for dengue based on the data collected through this card. I think this is great because the card is capturing the individual experience of illness which in my experience of making vaccines is not often a data that is presented to regulatory bodies – it is usually rigid data that is measurable and repeatable and very objective.
This could potentially impact other fields. For example, although influenza kills 80,000 people in the USA a year, it is still not looked at as being a severe disease. When the CDC states that influenza vaccines are 35% effective, that is using a very specific set of metrics to measure effectiveness. If you were able to develop a card like this and make it specific for influenza, it would be possible to show that the influenza vaccine is much more effective at protecting against influenza of a wide range of severity.
So indeed, the concept could be potentially applied to other diseases and other counter measures in development. In addition, the patient would have a voice in that which I think is so great – it’s like encouraging the consumer to participate in what products should look like.
In the case of many tropical diseases, the patient voice was inexistent for a long time - a lot of grassroots patients movements completely changed that. How could your patient-centred approach, which would quantify their views and experiences, accelerate this momentum? How will turning patient stories into robust data make the patient voice a very powerful policy making tool?
We are looking forward to the DIC strengthening the patient voice not just for dengue but as an important public health tool and approach. Just look at the case of Zika – how would you define efficacy of a zika vaccine? Let’s say there is another outbreak in future, and you have the opportunity to do a clinical end point study: what would be the measure of a vaccine effectiveness? Is it complete prevention of infection, or complete prevention of symptomatic disease, or even prevention of maternal infection which can be related to congenital zika syndrome? These are all reasonable things to measure but because the spectrum of congenital zika infection seems to be evolving and is so broad and diverse, a tool like this would be a really valuable insight into understanding how therapeutics or passive and active immunisation impacted the outcome. There would be a different impact on the families, public health system and financial system between a child with microcephaly and severe disability related and a child that had a physical and isolated learning disability. I think that those nuances of public health impact are important to measure and should be actively considered when evaluating the potential value of a vaccine or a drug or an immune therapeutic I think we are beyond the binary system where you prevent or not a disease – rather, we need to look at these diseases in a more nuanced way.
How will your index and card be used as an advocacy tool and how do you feel that a World Dengue Day can help to amplify the objectives that you are trying to achieve with your work?
I think that a World Dengue Day can be used as an excellent vehicle to educate and inform about the suffering which dengue imparts on individuals, their families, countries, regions. Dengue is endemic in 130 countries; every year, it’s infecting 400 million people and making 100 million people sick. Dengue is killing about 5-10,000 people a year, mostly children. We live in a time of shiny objects – at some point people will be looking at the next ‘shiny object’ and might move their interest away from dengue, not appreciating the persistence of the problem. So I think that one thing that the World Dengue Day will do is to give those people affected by dengue a voice, which is a goal we also want for the Dengue Illness Card, for example helping patients to share their story that for three months after dengue, patients still couldn’t work and provide for their families and had food insecurity as a result of dengue. Or echo the voices of the Ministers of Health who are charged with protecting or trying to bolster the health of their community and want to make a case to spend a sufficient part of their budgets on vector control, routine immunization or nutrition. A World Dengue Day could really deliver a greater understanding of dengue at many levels and will be very valuable in sharing the multiple facets of the disease.
