Getting the right test, at the right time, to the right population is key to effective dengue control

When a parent presents their child at a clinic with a high fever, clinicians often find it hard to determine the cause based on the symptoms alone. After all, it could be malaria, dengue, Zika, chikungunya or one of a host of other possibilities.

“Whenever it’s rainy season and there’s a dengue outbreak, emergency rooms are full of anxious parents with children with a fever,” states Professor Rosanna Peeling, Professor and Chair of Diagnostics Research at the London School of Hygiene and Tropical Medicine (LSHTM) and Director of the International Diagnostics Centre (IDC). “For them, efficient and accurate dengue diagnostics are very important for early confirmation of dengue as it can quickly progress to severe dengue in children.”

More than that, diagnostics also have a vital role to play in identifying infectious diseases that have the potential to become an epidemic – including dengue. Diagnostics not only helps with quickly identifying the cause of the outbreak; it also allows the impact of any interventions to be assessed.

Getting it right

The dengue diagnostics available for detecting and confirming the disease are wide-ranging. At one end of the spectrum are reliable, but time-consuming, laboratory tests; at the other are rapid testing kits that can be used in the field but vary substantially in their accuracy.

In developing countries, clinicians seldom have access to laboratory tests. Instead, they rely on the rapid tests, which are often sold and used without evidence that they work.

“Dengue and malaria diagnostics are not regulated in most countries in terms of their quality and safety,” states Professor Peeling. “There is a real need for the global community to share information on the latest diagnostics, how well they work, and what they should be used for.”

But it’s not just the effectiveness of the tests that is a concern; it’s also how and when the tests are used since the presence of the dengue virus in the patient’s blood becomes harder to detect over time. From day six onwards, diagnostic tests should be used to look for antibodies rather than the virus in the patient’s blood.

“People shed the virus in the first five days from the onset of fever,” states Professor Peeling. “We have shown that no matter how good the test is for detecting the virus, they can only really be used in the very early phase of infection since sensitivity drops down to as low as 30 percent from day six onwards. We need the right test, at the right time, for the right population.”

Understanding dengue diagnostics

In its 2009 report, Dengue: Guidelines for diagnosis, treatment, prevention and control, the World Health Organization devotes a whole chapter to dengue diagnosis; it describes in some detail the timeline for the evolution of the virus, the body’s response from the onset of fever and the role of diagnostics as time progresses.

In their early stages, dengue infections can be diagnosed by identifying dengue antigens (foreign bodies that cause the immune system to react) in the patient’s blood: isolating the virus itself or by detecting its genes (DNA/RNA) or its proteins (NS1). In their later stages, when the virus has disappeared from the patient’s blood, dengue infections can be diagnosed by detecting dengue antibodies (IgM and IgG) in the patient’s blood. The patient’s immune system will have produced these in response to the virus.

Image via WHO http://www.who.int/tdr/publications/documents/dengue-diagnosis.pdf

The report also compares the various dengue diagnostic methods available back in 2009, along with their advantages and disadvantages. It also notes: “Unfortunately, an ideal diagnostic test that permits early and rapid diagnosis, is affordable for different health systems, is easy to perform, and has a robust performance, is not yet available.”

Where we are today

Traditionally, confirmation of an acute dengue infection has required detection of IgM antibodies or detection of a four-fold rise in the concentration of IgG antibodies in paired specimens of the patient’s blood – one collected during the acute disease and once the patient is recovering.

An article published in the Nature Research Journal last year discussed the viability of rapid test kits that can be used outside of the laboratory for detecting the virus’ NS1 protein. In many cases, it notes, “the infection status of patients limit the sensitivity and reliability of these tests and laboratory confirmation is often required.” And so in dengue endemic areas, a test that takes several hours and requires specialized personnel and laboratory facility remain the norm.

And so it seems clinicians caring for patients with high fevers continue to contend with delayed results that are of limited value.

We can, however, expect this to change soon. The urgent need for rapid, accurate and affordable diagnostics has accelerated with the WHO declaring the Zika outbreak a health emergency of international concern. With dengue, Zika and chikungunya all displaying similar symptoms, developing tests that can be used outside of a laboratory and are sufficiently sensitive to identify which of these three diseases is the cause of a patient’s fever is now a top priority.

New dengue diagnostics possibilities

New diagnostics are emerging, specifically, diagnostics that combine virus or antigen detection with detection of IgM antibodies. A recent publication by Hunsperger et al in the Journal of Infectious Diseases showed that if we combine the detection of dengue virus or NS1 proteins with a test for IgM antibodies using a single sample collected during the first 10 days of illness, we can accurately identify more that 90 percent of primary and secondary dengue infections.

Professor Peeling comments: “Recent advances in diagnostics will be incorporated in the new WHO guidelines for dengue, Zika, and chikungunya, which can cause outbreaks in the same population.”

The US Centers for Disease Control and Prevention (CDC) have already done quite a bit of work in this area, sharing their findings.

New diagnostics products

There are a number of companies working on products in this area. Towards the end of 2015, we published an article about an innovative rapid test from start-up BluSense Diagnostics.

Catching up with Dr. Marco Donolato, the company’s Chief Scientific Officer, he told us how the company is about to embark on testing of its prototype for detecting the NS1 and that it is also expanding the biomarkers its technology can detect. “We are now also working on detecting the antibodies IgG and IgM and will be testing that in the field during November,” states Dr. Donolato.

With such good progress, BluSense Diagnostics has been awarded a substantial grant by the US Agency for International Development (USAID) for developing its technology as a diagnostic for Zika. Dr. Donolato adds: “We have seen that we can detect Zika in NS1 and we hope to finalize our product for both dengue and Zika next year.”

To get there the company must ensure its technology meets the performance requirements set out by WHO and gain ISO certification as a manufacturer of medical devices, which it hopes to achieve by February.

Also in the pipeline is a new rapid test kit that’s being developed by GlowDX – Break Dengue will have a feature interview with the company next month.

Diagnostics is clearly taking some great steps forward in the helping clinicians treat dengue. More than that, it may well also have a critical role to play in dengue vaccination programs too. Look out for future discussions to learn why.

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